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Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs
Abstract
The effects of longstanding non-steroidal anti-inflammatory drug (NSAID) treatment on gastric mucosal synthesis of leukotriene B4 (LTB4), leukotriene C4 (LTC4), and prostaglandin E2 (PGE2) was studied. Gastric antral biopsies in 65 patients with arthritis taking NSAIDs and 23 control patients were taken and eicosanoid concentrations, stimulated by vortex mixing or calcium ionophore, were measured by radioimmunoassay. Median gastric mucosal synthesis of LTB4 was increased in patients taking NSAIDs compared with non-users: (0.9(0.2-2.5) pg/mg v 0 (0-0.6) pg/mg (p < 0.001)). These differences persisted when subgroups of patients were analysed according to Helicobacter pylori colonisation or degree of mucosal injury. Synthesis of LTB4 was strongly associated with the presence of type C (chemical) gastritis. Increased synthesis of LTC4 was associated with Helicobacter pylori colonisation but not NSAID use. Synthesis of PGE2 was decreased in patients taking NSAIDs compared with control patients (p < 0.001). Enhanced gastric mucosal synthesis of LTB4 in patients taking NSAIDs may represent a primary effect of these drugs and could be implicated in the pathogenesis of gastritis and ulceration associated with NSAIDs.
... In the early stages of osteoarthritis patients with mild to moderate disease typically rely on easily available, relatively inexpensive, over-the-counter NSAIDs for the alleviation of pain and stiffness [3]. Originally designed only to be taken for up to three months at a time, the blockade of cyclooxygenase enzymes that these pharmaceuticals produce reduces prostaglandin production and instead diverts phospholipid breakdown through the equally powerful lipoxygenase (LOX) pathway generating leukotrienes [108,130,131]. Osteoarthritis pathology is associated with leukotriene B4 (LTB4), which recruits inflammatory cells, increases sensitivity to pain and promotes bone loss [108]. ...
... Osteoarthritis pathology is associated with leukotriene B4 (LTB4), which recruits inflammatory cells, increases sensitivity to pain and promotes bone loss [108]. Taking NSAIDs for more than 3 months increases osteoarthritis degenerative changes and this is directly attributable to the cellular shift into leukotriene synthesis [131]. Increased LTB4 also contributes to the NSAID side effects of gastric ulcers and irritation that occur annually in up to 2% of people taking these medications [33,131]. ...
... Taking NSAIDs for more than 3 months increases osteoarthritis degenerative changes and this is directly attributable to the cellular shift into leukotriene synthesis [131]. Increased LTB4 also contributes to the NSAID side effects of gastric ulcers and irritation that occur annually in up to 2% of people taking these medications [33,131]. The second issue with NSAIDs is that they interfere with NF-Kβ activation by preventing the removal of the "blocking" protein inhibitory nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (Iκβ) and therefore hold cells in forced homeostasis [102]. ...
Osteoarthritis results from a chronic inflammation-mediated destruction of synovial joints particularly in the hand, hip, and knee. Intervention strategies primarily focus on reducing this inflammation and its associated pain and involve a hierarchy of pharmaceuticals designed to prolong activity and prevent early joint replacement. Unfortunately, side effects from these agents are significant and their efficacy, especially in the later stages of the condition, variable. For this reason, many patients are seeking out alternative interventions, including herbal medicines, which are natural and safe. This review will evaluate the current understanding of the pathophysiology and immunological changes that occur in osteoarthritis and identify areas where herbal medicines could improve treatment strategies.
... On the other hand, prolonged use of NSAIDs shifts AA for LTs synthesis over that of PGs by inhibiting COXs (Hudson et al. 1993;Marquette et al. 2022). NSAIDs enhance the synthesis of LTB4 in the gastric mucosa (Hudson et al. 1993). ...
... On the other hand, prolonged use of NSAIDs shifts AA for LTs synthesis over that of PGs by inhibiting COXs (Hudson et al. 1993;Marquette et al. 2022). NSAIDs enhance the synthesis of LTB4 in the gastric mucosa (Hudson et al. 1993). Likewise, a systematic review illustrated that NSAIDs promote urinary LTE4 in patients with exacerbation of respiratory disorders following the use of NSAIDs (Marquette et al. 2022). ...
Parkinson's disease (PD) is an advanced neurodegenerative disease (NDD) caused by the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). As PD is an age-related disorder, the majority of PD patients are associated with musculoskeletal disorders with prolonged use of analgesic and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, NSAIDs can affect PD neuropathology in different ways. Thus, the objective of the present narrative review was to clarify the potential role of NSAIDs in PD according to the assorted view of preponderance. Inhibition of neuroinflammation and modulation of immune response by NSAIDs could be an effective way in preventing the development of NDD. NSAIDs affect PD neuropathology in different manners could be beneficial or detrimental effects. Inhibition of cyclooxygenase 2 (COX2) by NSAIDs may prevent the development of PD. NSAIDs afforded a neuroprotec-tive role against the development and progression of PD neuropathology through the modulation of neuroinflammation. Though, NSAIDs may lead to neutral or harmful effects by inhibiting neuroprotective prostacyclin (PGI2) and accentuation of pro-inflammatory leukotrienes (LTs). In conclusion, there is still a potential conflict regarding the effect of NSAIDs on PD neuropathology.
... The inhibition of COX-1/ COX-2 result in an increased formation of leukotrienes (LTs) through the lipoxygenase (LOX) pathway 11 . Overproduction of LTs induces asthmatic problems, gastric damage, and ulceration [12][13][14][15][16][17] . Moreover, 5-LOX has been related to several undesirable physiological effects which are involved in the progression of inflammation, osteoarthritis, and asthma [18][19][20] . ...
... Pale pink crystals, yield 80%, m.p0.96-98 C. IR (KBr, v cm À1 ): 1749. 15 General procedure for synthesis of 5-(4-Substitutedphenyl)-1-(4substitutedphenyl)-1H-pyrazole-3-carbohydrazides (7a-i). ...
New thymol − 1,5-disubstitutedpyrazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 8b, 8g, 8c, and 4a displayed in vitro inhibitory activity against COX-2 (IC50 = 0.043, 0.045, 0.063, and 0.068 µM) nearly equal to celecoxib (IC50 = 0.045 µM) with high SI (316, 268, 204, and 151, respectively) comparable to celecoxib (327). All target compounds, 4a–c and 8a–i, showed in vitro 5-LOX inhibitory activity higher than reference quercetin. Besides, they possessed in vivo inhibition of formalin-induced paw oedema higher than celecoxib. In addition, compounds 4a, 4b, 8b, and 8g showed superior gastrointestinal safety profile (no ulceration) as celecoxib and diclofenac sodium in the population of fasted rats. In conclusion, compounds 4a, 8b, and 8g achieved the target goal. They elicited in vitro dual inhibition of COX-2/5-LOX higher than celecoxib and quercetin, in vivo potent anti-inflammatory activity higher than celecoxib and in vivo superior gastrointestinal safety profile (no ulceration) as celecoxib.
... Prostaglandins exhibit gastric cytoprotection by enhancing blood flow through the gastric mucosa, stabilising lysosomal membrane, stimulating surface epithelial regeneration and bicarbonate release as well as increasing mucous production. Additionally, increased mucosal synthesis of leukotrienes (mainly leukotriene B4 in the perivascular environment, which may affect leukocyte adherence to endothelium), reduced EGF secretion from the salivary glands, increased histamine synthesis and direct vascular damage in the mucosa occur (31) . NSAIDs reduce mucosal blood flow via formation of 'white thrombi' in the mucosal microcirculation, which leads to cellular ischaemia. ...
... Safety and efficacy of topical NSAIDs in acute pain were also assessed in clinical trials. A meta-analysis of 26 studies in 2853 patients błony śluzowej (31) . NLPZ powodują zmniejszenie przepływu śluzówkowego przez powstawanie tzw. ...
Non-steroidal anti-inflammatory drugs are drugs of choice for chronic pain, which is most common in chronic conditions,
rheumatism in particular. According to current recommendations, these medications should be used continuously
or intermittently, and their choice should be tailored to each patient. Unfortunately, non-steroidal anti-inflammatory drugs have
multiple adverse effects ranging from the most insignificant dyspepsia to severe upper gastrointestinal bleeding. Therefore,
gastroscopy and, in the case of confirmed Helicobacter pylori infection, eradication is advisable for planned long-term treatment
with these agents. Long-term use of proton pump inhibitors is recommended in rheumatic patients chronically receiving
non-selective non-steroidal anti-inflammatory drugs, while celecoxib (a selective COX-2 inhibitor) combined with proton pump inhibitor should be administered in patients at high risk of gastrointestinal complications. In rheumatic patients, the type
of non-steroidal anti-inflammatory drug and the route of its administration should be tailored to each patient in terms of strength and duration of drug action, the type of disease and comorbidities as well as contraindications. Adverse gastrointestinal effects are due to the mechanism of action of non-steroidal anti-inflammatory drugs, and therefore independent of the route of administration. The use of proton pump inhibitors with cardioprotective doses of aspirin should be limited to patients with risk factors for gastrointestinal complications. High non-steroidal anti-inflammatory drug doses are limited to gout attack, acute pain and axial spondyloarthropathy showing high clinical activity. In other cases, the lowest effective non-steroidal anti-inflammatory drug dose is recommended. Advancing age is characterised by impairment in the function of all organs, therefore elderly patients should receive lower non-steroidal anti-inflammatory drug doses. Concomitant use of two or more non-steroidal anti-inflammatory drugs in rheumatic diseases is not recommended. According to the latest recommendations, non-steroidal anti-inflammatory drugs can be combined with paracetamol and medicinal products with different mechanisms of action.
... Besides, COX-2 is constitutive in some tissues, like the brain and kidneys while it is inducible in inflammatory processes 4-9 . On the other hand, LTs play a major role in inflammatory processes like allergic rhinitis, asthma, osteoarthritis, atopic dermatitis, gastric damage, ulceration ischaemia, atherosclerosis, septic shock, and tumorigenesis [10][11][12][13][14][15][16][17][18][19][20][21][22][23] . In addition, LTC4 and LTD4 are potent contractors of blood vessels and bronchi smooth muscles and inducers of mucus secretion. ...
New thymol–3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC50= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC50= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a–l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a–f, 6i–l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h–l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.
... Moreover, the catalysis products of 5-LOX were reported as a risk factor for several inflammatory diseases such as asthma, ulcerative colitis, rhinitis, and even cancer development (Zhao et al. 2012). In the case of COX inhibition by NSAIDs, the 5-LOX pathway is upregulated, thus increasing the possibility for all these adverse effects (Rainsford 1987(Rainsford , 1993Hudson et al. 1993). Therefore, dual inhibition of COXs and 5-LOX may present a better alternative approach to provide relatively safe NSAIDs. ...
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently prescribed drug classes with wide therapeutic applications over the centuries. Starting from the use of salicylate-containing willow leaves to the recent rise and fall of highly selective cyclooxygenase-2 (COX-2) inhibitors and the latest dual-acting anti-inflammatory molecules, they have displayed a rapid and ongoing evolution. Despite the enormous advances in the last twenty years, investigators are still in search of the design and development of more potent and safer therapy against inflammatory conditions. This challenge has been increasingly attractive as the emergence of inflammation as a common seed and unifying mechanism for most chronic diseases. Indeed, this fact put the NSAIDs in the spotlight for repurposing against inflammation-related disorders. This review attempts to present a historical perspective on the evolution of NSAIDs, regarding their COX-dependent/independent mode of actions, structural and mechanism-based classifications, and adverse effects. Additionally, a systematic review of previous studies was carried out to show the current situation in drug repurposing, particularly in cancers associated with the GI tract such as gastric and colorectal carcinoma. In the case of non-GI-related cancers, preclinical studies elucidating the effects and modes of action were collected and summarized.
... Подавление активности ЦОГ на фоне применения НПВП приводит к изменению метаболизма арахидоновой кислоты, переключая его с простагландинового на липооксигеназный путь, сопровождаю щийся выработкой лейкотриенов (в частности лейкотриена В4) [28,29]. Лейкотриены вызывают воспаление и ишемию тканей, что ведет к дополнительному повреждению слизистой [30,31]. ...
Peptic ulcer disease (PUD) is a chronic polyetiological recurrent disease of gastroduodenal region. In most cases, the pathogenesis of PU is caused by imbalance between the aggressive factors and protective factors of the gastric or duodenal mucosa. Helicobacter pylori (H. pylori ) infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the major causative factors leading to PUD development. 65% of gastric ulcers and 80% of duodenal ulcers were found to be associated with H. pylori infection. In turn, NSAIDs account for 30% of gastric ulcers and 15% of duodenal ulcers. About 0.1–1% of all PUs are caused by Zollinger-Ellison syndrome. Abdominal pain is the leading symptom in the clinical findings of patients with exacerbation of PUD. Dyspeptic syndrome (vomiting, nausea, belching, abnormal bowel pattern) is much less common in patients with PUD. Endoscopic examination of the upper gastrointestinal tract is currently the gold standard test used in the diagnosis of PUD and is recommended for all patients suspected of having this disease (unless contraindicated). Antisecretory therapy including proton pump inhibitors is the main approach to the treatment of PUD, as well as the prevention of its complications. Integral to the treatment of patients with H. pylori -associated PU is the eradication therapy of the infection. It is reasonable to use a cytoprotector rebamipide, which accelerates ulcer healing and improves the resulting scar quality, as part of the pharmacotherapy of PUD. In addition, the use of rebamipide in H. pylori eradication therapy regimens contributes to increased efficiency of elimination of the microorganisms.
... Further, it is postulated that the inhibition of COX pathways by NSAIDs may shift the direction of AA metabolism towards the 5-LOX pathway which means the over-production of pro-inflammatory leukotrienes ( Figure 3). It could also be considered the other way around; the inhibition of 5-LOX may change the direction of metabolism towards the COX pathway (Hudson, Balsitis, Everitt, & Hawkey, 1993;K. Rainsford, 1987K. ...
The inflammation indicates the innate immune response of organisms against detrimental stimuli including a variety of pathogens, damaged cells, or even worse living conditions. Prolonged-inflammation is associated with the occurrence of diseases such as arthritis, diabetes, asthma. Thus, inhibition of chronic inflammation could be an alternative therapeutic and preventive strategy for several diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most prescribed drug class in the pharmaceutical industry for their strong analgesic and anti-inflammatory effects. Their action mechanism is based on the inhibition of cyclooxygenase enzymes (COXs)-mediated prostaglandin production. Prolonged use of NSAIDs may promote the risk of cardiovascular, urinary, and gastrointestinal problems. The underlying reason for these adverse effects is the undesirable COX-1 enzyme inhibition. Further studies demonstrated that preferential COX inhibitors, which inhibit the COX-2 enzyme eloquently and COX-1 with at a limited rate, might be safe therapeutics as compared to the non-selective classical NSAIDs. The second reason is the deterioration of homeostasis in arachidonic acid metabolism towards lipoxygenases (LOX) pathways. 5-LOX is another enzyme playing a role in the inflammatory response. Over-activation of 5-LOX leads to an excess amount of gastro-damaging leukotrienes.
Nimesulide is one of the proven preferential COX-2 inhibitors which have anti-inflammatory analgesic and antipyretic effects. The therapeutic action of nimesulide is based on the inhibition of pro-inflammatory prostaglandin and cytokine productions. Apart from these pharmacological effects, nimesulide reduces the level of reactive oxygen species (ROS), nitric oxide (NO), and leukotriene B4 (LTB4). Besides, nimesulide inhibits cancer cell proliferation, cerebral ischemia, and NSAIDs-induced ulcer. In this study, the anti-inflammatory and anticancer effects of seventeen novel amide/sulfonamide containing nimesulide derivatives were aimed to be elucidated.
With this aim, each compound was tested for its selective COX-2/COX-1 enzyme inhibitory properties. Accordingly the compounds N8 and N10 showed better selectivity on the COX-2 enzyme as compared to the reference drug nimesulide. Moreover, both N8 and N10 selectively reduced the LPS-stimulated COX-2 mRNA expression while the level of COX-1 remained stable in macrophages. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed in the N8 and N10 treatment group. Furthermore, these two compounds reduced the mRNA level of IL-1β and TNF-α statistically significant. Screening efforts to identify anticancer properties of derivatives resulted in compound N17 with considerable cytotoxicity in the colon (IC50: 9.24 μM) and breast (IC50:11.35 μM) cancer cell lines. To sum up, these findings suggest that N8 and N10 could be promising agents with anti-inflammatory properties while cytotoxic N17 might be studied as a lead for subsequent potential anticancer drug development.
... This leads to an increase in the levels of TXA 2 (Thromboxane A2), which is prothrombotic and in the absence of prostacyclin PGI 2 (Prostaglandin I2, a product of COX-2), causes a loss of haemostatic balance leading to cardiovascular complications. Additionally, the prolonged usage of COXIBS, as well as NSAIDs causes shunting of AA through the leukotriene pathway, leading to an increase in the leukotrienes (LTB 4 ) (Hudson et al., 1993). The increased levels of LTB 4 led to increased activation and adherence of macrophages, resulting in further deterioration of the GI (gastrointestinal) mucosa and progression of the inflammation in the GI tract (Wallace, 2019;Wallace & Keenan, 1990). ...
Eicosanoid pathways play a crucial role in the progression and resolution of inflammation. NSAIDs act as anti-inflammatory agents by inhibiting both the isoforms of cyclooxygenases (COXs) whereas, COXIBs act as specific COX-2 inhibitors. Excessive usage of the same is linked with gastrointestinal bleeding and increased cardiovascular risk, respectively. The current in-silico study was aimed at evaluating the potential of major alkaloids of A. vasica (vasicine (VAS), vasicinone (VAE), and Deoxyvasicine (DOV)) as inhibitors of COXs. The results of the computed binding energy (ΔG) indicate that Celecoxib (CEL), DOV, and VAS have a higher affinity to COX-2, while VAE has a higher affinity to COX-1, and Mefenamic acid (MEF) was not selective. Among the alkaloids, VAE exhibited the best ΔG (of −8.2 kcal/mol) with COX-1, while VAS exhibited the best ΔG (of −8.2 kcal/mol) with COX-2. This was comparable to the ΔG exhibited by Mefenamic acid (-8.7 kcal/mol with both the COXs). With their potential to remain gastroprotective while having the ability to inhibit enzymes of both the prostaglandin and leukotriene pathways, the alkaloids of A. vasica could be promising leads for the design of Eicosanoid pathway modulators/inhibitors.
Communicated by Ramaswamy H. Sarma
... [34] Elevated concentrations of LTB 4 can lead to gastrointestinal toxicity. [35] Only a few studies reported leukotrienes in marine algae. The two red macroalgae G. vermiculophylla and Murrayella periclados form LTB 4 and derivatives with unknown biological function for the producers. ...
Oxylipins constitute a family of oxidized fatty acids, that are well known as tissue hormones in mammals. They contribute to inflammation and its resolution. The major classes of these lipid mediators are inflammatory prostaglandins (PGs) and leukotrienes (LTs) as well as pro‐resolving resolvins (Rvs). Understanding their biosynthetic pathways and modes of action is important for anti‐inflammatory interventions. Besides mammals, marine algae also biosynthesize mammalian‐like oxylipins and thus offer new opportunities for oxylipin research. They provide prolific sources for these compounds and offer unique opportunities to study alternative biosynthetic pathways to the well‐known lipid mediators. Herein, we discuss recent findings on the biosynthesis of oxylipins in mammals and algae including an alternative pathway to prostaglandin E2, a novel pathway to a precursor of leukotriene B4, and the production of resolvins in algae. We evaluate the pharmacological potential of the algal metabolites with implications in health and disease.
... [35] Regarding ingestion of raw alga, increased levels of leukotriene B 4 and 1 are toxic for the gastrointestinal tract. [36,37] Both lipid mediators may be formed from labile precursors such as thermally unstable 3 or acid-labile 5R,8R-dihydroxy-eicosatetraenoic acid. [17] In conclusion, we reveal here an alternative biosynthetic pathway to PGE 2 (1)i na lgae and in mammals.U pon cell activation, 1 is formed either by the canonical AA-PGG 2 -PGH 2 -1 route catalyzed by COX, COXp eroxidase,a nd PGES or by the newly identified AA-PGG 2 -3-1 pathway mediated by COX, PGES,and hydroperoxide reduction. ...
Arachidonic‐acid‐derived prostaglandins (PGs), specifically PGE2, play a central role in inflammation and numerous immunological reactions. The enzymes of PGE2 biosynthesis are important pharmacological targets for anti‐inflammatory drugs. Besides mammals, certain edible marine algae possess a comprehensive repertoire of bioactive arachidonic‐acid‐derived oxylipins including PGs that may account for food poisoning. Described here is the analysis of PGE2 biosynthesis in the red macroalga Gracilaria vermiculophylla that led to the identification of 15‐hydroperoxy‐PGE2, a novel precursor of PGE2 and 15‐keto‐PGE2. Interestingly, this novel precursor is also produced in human macrophages where it represents a key metabolite in an alternative biosynthetic PGE2 pathway in addition to the well‐established arachidonic acid‐PGG2‐PGH2‐PGE2 route. This alternative pathway of mammalian PGE2 biosynthesis may open novel opportunities to intervene with inflammation‐related diseases.
... [35] Regarding ingestion of raw alga, increased levels of leukotriene B 4 and 1 are toxic for the gastrointestinal tract. [36,37] Both lipid mediators may be formed from labile precursors such as thermally unstable 3 or acid-labile 5R,8R-dihydroxy-eicosatetraenoic acid. [17] In conclusion, we reveal here an alternative biosynthetic pathway to PGE 2 (1)i na lgae and in mammals.U pon cell activation, 1 is formed either by the canonical AA-PGG 2 -PGH 2 -1 route catalyzed by COX, COXp eroxidase,a nd PGES or by the newly identified AA-PGG 2 -3-1 pathway mediated by COX, PGES,and hydroperoxide reduction. ...
Ein neuer Biosyntheseweg für einen lange bekannten Lipidmediator, PGE2, wurde in der Rotalge Gracilaria vermiculophylla entdeckt (siehe Bild oben). Durch eine neuerliche Studie der Biosynthese des entzündungsvermittelnden Hormons in Makrophagen wurde dieser alternative Weg über intermediäres 15‐Hydroperoxy‐PGE2 auch in Säugern etabliert.
Abstract
Arachidonic‐acid‐derived prostaglandins (PGs), specifically PGE2, play a central role in inflammation and numerous immunological reactions. The enzymes of PGE2 biosynthesis are important pharmacological targets for anti‐inflammatory drugs. Besides mammals, certain edible marine algae possess a comprehensive repertoire of bioactive arachidonic‐acid‐derived oxylipins including PGs that may account for food poisoning. Described here is the analysis of PGE2 biosynthesis in the red macroalga Gracilaria vermiculophylla that led to the identification of 15‐hydroperoxy‐PGE2, a novel precursor of PGE2 and 15‐keto‐PGE2. Interestingly, this novel precursor is also produced in human macrophages where it represents a key metabolite in an alternative biosynthetic PGE2 pathway in addition to the well‐established arachidonic acid‐PGG2‐PGH2‐PGE2 route. This alternative pathway of mammalian PGE2 biosynthesis may open novel opportunities to intervene with inflammation‐related diseases.
... Leukotrienes themselves are implicated in the development of gastrointestinal ulcers, asthmas, and different inflammatory processes [18,19]. It is noteworthy that COX isozymes and LOX share the same substrate arachidonic acid; therefore, inhibition of prostaglandins production by cyclooxygenase pathway can lead to increased substrate availability and increased production of leukotrienes by lipoxygenase pathway [20][21][22]. Although, R. Mashima and T. Okuyama reported that 15-LOX performs multiple functions and that down regulation or general inhibition of 15-LOX delays the resolving of inflammation [23]. It is now clear that PGs and LTs have complementary effects regarding development and persistent inflammatory processes [24]. ...
A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates with aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC50 range of 6.4 – 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC50 = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC50 range of 1.77- 4.91 nM comparing to meclofenamate sodium (IC50 = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.
... Using selective or non-selective COX-2 inhibitors apparently cause an imbalance that shift the pathways to 5-LOX, consequently diverting arachdonic acid to overproduction of the noxious and chemo attractant leukotrienes. 6,[8][9][10] These events may justify the reason why a 5-LOX inhibitor like licofelone is much better tolerated than selective and nonselective COX-2 inhibitors. ...
Despite the extensive application of nonsteroidal anti-inflammatory drugs (NSAIDs), the use of these drugs is limited due to their adverse effects especially on gastric mucosa. Dual inhibitors that inhibit both cyclooxygenase (COX) and lipoxygenase (LOX) metabolites are considered to have less gastric toxicity in comparison to non-selective and COX-2 selective inhibitors. In this study, fifteen mixed breed dogs were randomly divided into three groups: group 1 (n=5) received placebo, group 2 (n=5) licofelone, an inhibitor of COX- 1, COX-2, and 5-LOX (2.5 mg/kg; twice daily) and group 3 (n=5) celecoxib, a COX-2 selective inhibitor (3 mg/kg; twice daily) per os for 14 days. All dogs underwent blinded gastroscopies on days 0, 7, 14 and one week after cessation of treatment and gastric lesions were scored. Examinations to detect fecal occult blood were performed daily. Results showed that licofelone is significantly better tolerated than celecoxib in terms of gastric side effects (P=0.008). Therefore, it seems that licofelone can be an appropriate alternative in dogs when NSAID therapy is necessary. Occult blood was not detected in any dog during the study.
... These mediators cause vasoconstriction and release oxygen free radicals, which add to damage caused by the impairment of mucosal defense. 80 Enhanced gastric mucosal leukotriene B 4 (LTB 4 ) synthesis is seen in patients taking NSAIDs, 83 corroborating the animal data. A summary of the mechanisms involved in NSAID-associated upper GI mucosal damage is presented in Fig. 4. ...
Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or COX1) and PTGS1 (COX2), other factors are involved. We review mechanisms of gastrointestinal damage induction by NSAIDs, via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID's inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.
... In fact, inhibition of LTB 4 production has been shown to be neuroprotective in cases of brain injury [35]. Finally, elevated LTB 4 levels have been found in a disparate array of tissues including corneal and conjunctival tissues of the eye [36], loose connective tissues such as adipocytes [37], endocrinal glands such as thyroid [38] and by mucosal epithelial cells in pathological conditions such as during ulcerative colitis [39] and type C gastritis [40]. ...
Directed leukocyte migration is a hallmark of inflammatory immune responses. Leukotrienes are derived from arachidonic acid and represent a class of potent lipid mediators of leukocyte migration. In this review, we summarize the essential steps leading to the production of LTB4 in leukocytes. We discuss the recent findings on the exosomal packaging and transport of LTB4 in the context of chemotactic gradients formation and regulation of leukocyte recruitment. We also discuss the dynamic roles of the LTB4 receptors, BLT1 and BLT2, in mediating chemotactic signaling in leukocytes and contrast them to other structurally related leukotrienes that bind to distinct GPCRs. Finally, we highlight the specific roles of the LTB4-BLT1 axis in mediating signal-relay between chemotaxing neutrophils and its potential contribution to a wide variety of inflammatory conditions including tumor progression and metastasis, where LTB4 is emerging as a key signaling component.
... [3][4][5][6] En particular, la gastrotoxicidad inducida por los AINEs no solo se debe a la inhibición de la síntesis de PG gastroprotectoras, sino al aumento de LT gastrotóxicos que refuerzan el daño generado por el déficit de PG, detectándose altas concentraciones de LTB 4 en las paredes de las úlceras gástricas inducidas por AINEs, agente que atrae leucocitos a la mucosa y contribuye a aumentar la ulceración. 7 El D-002, mezcla de seis alcoholes alifáticos primarios (C 26 , C 26 , C 28 , C 30 , C 32 , C 34 ) purificada de la cera de abejas (Apis mellifera, L), muestra efectos antiinflamatorios demostrados en modelos de inflamación aguda y crónica. [8][9][10] Sin embargo, y a diferencia de los AINEs, el D-002 no produce efectos gastrotóxicos, sino que por el contrario, reduce el daño ulcerogénico inducido por diferentes agentes, incluyendo los propios AINEs, mediante un mecanismo que implica un aumento de la secreción del mucus gástrico y la reducción de los procesos de peroxidación lipídica en la mucosa gástrica. ...
Introduction: D-002, a mixture of six high molecular weight primary aliphatic alcohols purified from beeswax, has been shown to produce anti-inflammatory effects with no secondary gastrotoxicity in experimental models. Oral treatment with D-002 was effective for lowering the concentrations of B4 leukotriene (LTB4) in pleural exudates of rats with carragenin-induced pleurisy, suggesting that it could inhibit 5-lipooxigenase (5-LOX) enzyme activity. The mechanisms of the anti-inflammatory action of D-002, however, had not been explored yet. Objective: to evaluate the effects of D-002 on 5-LOX enzyme activity in vitro by using the cytosolic preparations from rat liver homogenates. Methods: testing conditions were as follows: cytosolic fraction (50 µg of protein) dissolved in 0.2 mol/L borate buffer solution (pH 9) and linoleic acid (7.8-250 mmol/L) as substrate. Parallel samples were incubated with Tween-20/H2O (2 %) only (vehicle, control samples), D-002 (0.9-1 000 µg/mL) or Lyprinol (500 µg/mL) (reference substance). The enzyme activity, evaluated through the formation of conjugated dienes, was assessed by the absorbance changes at 234 nm (5-lox) measured in a UV-visible spectrophotometer. Results: the in vitro addition of D-002 produced a significant, dose-dependent (r=0.980; p
... NSAID-induced gastrointestinal injury is mediated by increased LTB 4 synthesis, too. LTB 4 level is elevated in arthritis treated with NSAIDs [75] (Figures 3(a) and 3(b)). Indomethacin may cause acute gastropathy, and the induced overproduction of tumor necrosis factor (TNF ) has also been implicated in the pathogenesis of disease state [76]. ...
Clinical Relevance
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including aspirin are of intensive use nowadays. These drugs exert their activity via the metabolism of arachidonic acid (AA) by cyclooxygenase inhibition. Though beneficial for health in some instances, both unspecific and specific cyclooxygenase inhibitor activity interfere with AA metabolism producing also proinflammatory lipids that may promote cancer.
Materials and Methods
This review is based on available literature on clinical uses, biochemical investigations, molecular medicine, pharmacology, toxicity, and epidemiology-clinical studies on NSAIDs and other drugs that may be used accordingly, which was collected from electronic (SciFinder, Medline, Science Direct, and ACS among others) and library searches of books and journals.
Results
Relevant literature supports the notion that NDSAID use may also promote proinflammatory biochemical events that are also related to precancerous predisposition. Several agents are proposed that may be employed in immediate future to supplement and optimize treatment with NSAIDs. In this way serious side effects arising from promotion of inflammation and cancer, especially in chronic NSAID users and high risk groups of patients, could be avoided.
... LOX activity is associated to many chronic diseases like asthma, allergic disorders, liver fibrosis, atherosclerosis, among others (Dwyer et al., 2004). Since COX and LOX share the same substrate (AA), inhibiting COX pathway leads to a shift towards the production of leukotriene (pro-inflammatory mediator) by 5-LOX, due to increased substrate availability (Hudson et al., 1993). As a result, it is necessary to search for dual inhibitors to treat chronic inflammation effectively. ...
Ethnopharmacological relevance:
Human groups in the Argentinean Andes highlands (Puna) selected native plants as anti-inflammatory agents. The indications of use are mainly to relieve pain, as infusions, ethanolic extracts or plasters.
Aim of the study:
The objective of the study was to assess the effect of hydroalcoholic extracts from native highland plants as anti-inflammatory agents according to the traditional indications of use. The chemical profile of the three most active species was analyzed by HPLC-ESI-MS to get an insight into the constituents and the effects observed according to the ethnopharmacological information.
Materials and methods:
Hydroalcoholic extracts from 13 Argentinean Puna plants used as anti-inflammatory were evaluated as inhibitors of the pro-inflammatory enzymes phospholipase A2(sPLA2), lipoxygenase (LOX), hyaluronidase, and for their capacity to stabilize red blood cells membrane. In addition, the extracts were evaluated to determine their reducing power, iron chelating capacity and ABTS•+radical scavenging effect. The chemical profiles of the most active species were analyzed by HPLC-ESI-MS.
Results:
Among the species investigated, Ephedra multiflora was the most active as LOX inhibitor (IC50:132µg/mL), by reducing the non-heme iron group and by scavenging radicals. The IC50values of the reference compounds caffeic acid and naproxen were 57.0 and 14.0µg/mL, respectively. Parastrephia lucida showed the highest sPLA2inhibitory effect (63% of inhibition at 200µg/mL). Under the same experimental conditions, the IC50of the reference compound acetylsalicylic acid was 65±1µg/mL. Tessaria absinthioides exhibited the best inhibition towards hyaluronidase with an IC50of 93.2±4.3µg/mL. Under the same experimental conditions, the reference compounds quercetin and indomethacin presented IC50values of 340.0±17.0 and 502.0±10.0µg/mL, respectively. Among the most active species, 13 compounds were tentatively identified by HPLC-ESI-MS in E. multiflora and P. lucida, and 12 compounds in T. absinthioides. The constituents included caffeoyl- and feruloylquinic acid derivatives, flavonoids, simple phenolics and sesquiterpene glycosides.
Conclusions:
Six out of the 13 species investigated showed a moderate to strong effect towards the enzyme sPLA2(>40% inhibition at 200µg/mL) while three species presented a strong activity against LOX with IC50<250µg/mL and three were very active against hyaluronidase. Most of the crude drug extracts were able to stabilize the red blood cells membrane, preventing their lysis. The compounds identified in the extracts explain, at least in part, the activity found in the samples. The effect observed for the most active species supports their traditional use as anti-inflammatory agents. However, more studies should be undertaken to disclose the potential of the Puna plants as anti-inflammatory crude drugs.
... It has now been suggested that the therapeutic effects of agents inhibiting only COX-1 and COX-2 may be limited by preferential conversion of arachidonic acid to leukotrienes through the LOX pathway since leukotriene B 4 (LTB 4 ) is the main leukotriene that plays a major role in the inflammatory response (Hudson et al., 1993). Therefore, medications that inhibit both COX-1/2 and 5-LOX pathways are believed to be superior to conventional NSAIDs since they could produce a synergistic effect and achieve optimal anti-inflammatory activity by blocking the production of both leukotrienes and prostaglandins (Celotti & Laufer, 2001;Martel-Pelletier et al., 2003). ...
Introduction: Lipoxygenase (LOX) is an important enzyme as the biological target in developing anti-inflammatory drugs. The products of LOX pathway, hydroperoxides are associated with numerous inflammatory diseases such as atherosclerosis, asthma and inflammatory bowel disease. The ferrous oxidation-xylenol orange (FOX) assay is a rapid and robust assay suitable for measuring the hydroperoxides activity in LOX. In a previous study, Chisocheton polyandrus Merr., a local Malaysian plant was reported to exhibit anti-inflammatory properties. In this study, FOX assay was optimised and applied in the bioassay-guided fractionation of the plant to isolate and identify the active anti-inflammatory compounds. Methods: FOX assay was carried out in a 96-well microplate by incubating 50 µl of LOX with 20 µl of plant extract of various concentrations for 5 minutes. The reaction was started by addition of 50 µl of linoleic acid and kept for 15 minutes. The assay was terminated by addition of 100 µl of FOX reagent. The absorbance readings were measured at 560 nm using microplate reader and were used to calculate the percentage inhibition of LOX. Results: The dichloromethane and methanol crude extract of the leaves showed LOX inhibitory activities with IC50 value of 8.16 ± 1.81 µg/ml and 10.19 ± 1.78 µg/ml respectively. The crude extract of the leaves was further fractionated by using silica gel column chromatography (solvent hexane: acetone) to afford 15 fractions. Preliminary results of 15 fractions screening showed 5 fractions that exhibit LOX inhibitory activities with percentage inhibition > 50% at concentration of 10 µg/ml. Compound 1 was isolated from one of the 5 fractions and identified to be a dammarane triterpenoid which gives percentage inhibition > 90% at concentration of 10 µg/ml. Conclusion: The dichloromethane crude extract showed a higher LOX inhibitory activity and used for further fractionation. Bioassay-guided fractionation using optimised FOX assay has identified one active compound at the moment.
... NSAIDs block the formation not only of proinflammatory cytokines but also of gastroprotective prostaglandins those maintain gastric mucosal blood flow and bicarbonate production [24]. The enhanced synthesis of leukotrienes may occur by shunting the arachidonic acid metabolism towards the 5-lipoxygenase pathway [25][26][27]. COX inhibition, enhanced synthesis of leukotrienes, contributing to gastric mucosal injury by promoting tissue ischemia and inflammation [28][29][30][31]. ...
... 8-10 LTC4 may promote gastric mucosal damage through a reduction of tissue perfusion resulting from the promotion of vascular stasis. 8,11,12 Symptoms help differentiate ulcer type The classic symptom is burning epigastric pain after meals. Pain that occurs immediately after meals is a classic symptom of gastric ulcer. ...
... COX inhibitors curtail prostaglandins formation, which turn the AA metabolism towards the LOX pathway, increasing the production of LT and enhancing the toxicity due to the prostaglandins deficit, as demonstrated the high concentrations of LTB4 seen in gastric ulcers induced by COX inhibitors, which attract leukocytes to the stomach and contributes to produce the ulceration. 17,18 Nevertheless, this study was conducted in vitro, so that we cannot exclude that policosanol may inhibit 5-LOX in vivo. In such regard, we should remember that policosanol and octacosanol administered orally, 19,20 but not added in vitro, 21 exhibits antioxidant effects. ...
Introduction: policosanol, a mixture of high molecular weight aliphatic alcohols purified from sugarcane with octacosanol as the main component, shows cholesterol-lowering and antiplatelet effects in addition to an inhibitory effect on type I cicloxygenase. Objective: to determine whether policosanol may inhibit 5-LOX enzyme activity in vitro. Methods: effects on 5-LOX enzyme activities were assessed in rat blood polymorphonuclear leukocytes. Vehicle or Policosanol suspensions (0.6 to 6 000 µg/mL) were added to tubes containing the reaction mix and then absorbance changes at 234 nm were measured. Results: added Policosanol inhibited in vitro 5-LOX activity by 30 %, which was not a significant figure but depended on the concentration(r= 0.992; p< 0.05); it was 1 250 µg/mL. Conclusions: policosanol did not significantly inhibit 5-LOX enzyme activity in rat PMNL preparations, so that it does not seem to be a dual inhibitor of COX and-LOX enzymes. This result differs from that found for beeswax alcohols and underlines the different effects of the mixtures of long-chain fatty alcohols purified from the sugarcane and the beeswax.
... Lipoxygenase (LOX) pathway plays an important role in the inflammatory response in the human body (13). The main enzyme involved in the LOX pathway is 5-LOX. ...
Abstract: Limnocharis flava is an edible wetland plant, whose phenolic acid and flavonoid compositions as well as bioactivities were underexplored. This study analyzed the profiles of selected hydroxybenzoic acids, hydroxycinnamic acids and flavonoids in the aqueous extracts of L. flava leaf, rhizome and root by high performance liquid chromatography (HPLC). Anti-lipoxygenase and antioxidant (iron chelating, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, and nitric oxide (NO) scavenging) activities of the extracts were also evaluated. Leaf extract had the highest phenolic contents, being most abundant in p-hydroxybenzoic acid (3861.2 nmol/g dry matter), ferulic acid (648.8 nmol/g dry matter), and rutin (4110.7 nmol/g dry matter). Leaf extract exhibited the strongest anti-lipoxygenase (EC50 6.47 mg/mL), iron chelating (EC50 6.65 mg/mL), DPPH scavenging (EC50 15.82 mg/mL) and NO scavenging (EC50 3.80 mg/mL) activities. Leaf extract also had the highest ferric reducing ability. This is the most extensive HPLC profiling of phenolic acids and flavonoids in L. flava to date. In conclusion, L. flava leaf is a source of health-promoting phenolics, anti-lipoxygenase agents and antioxidants.
... COX-2 selective inhibition has been believed to be advantageous over inhibition of COX-1 but several studies proved the role of COX-1 in carcinogenesis [3]. However, recent studies demonstrated that COX inhibition caused over production of leukotrienes from AA through the LOX pathway as a result of diversion of the pathway456789. In the same way, LOX inhibition caused pathway diversion that resulted generation of PGs by the COX pathway. ...
Phospholipase A 2 s (PLA 2 s) are group of enzymes, which cleave phospholipids specifically at sn-2 position to liberate free fatty acid, mostly arachidonic acid (AA) and lysophospholipids (LPLs). Inhibition of PLA 2 prevents the liberation of AA and LPLs. Hence, researchers have been considering PLA 2 s could be a better therapeutic target than the downstream enzymes cyclooxygense and lipoxygenase. Several isoforms of PLA 2 s exist; they are mainly divided into secretory PLA 2 s (sPLA 2), cytosolic PLA 2 s (cPLA 2), and calcium independent PLA 2 s (iPLA 2), platelet activating factor-acyl hydrolase (PAF-AH), lysosomal PLA 2 (LPLA 2), adipose-specific PLA 2 (AdPLA). Each isoform of PLA 2 s is different in its chemical structure and physiological functions. sPLA 2 s (Groups IIA, V and X) are well characterized as proinflammatory mediating enzymes but their role in cancer is controversial. Groups IVA, IVB and IVC cPLA 2 s are present in humans but only Group IVA cPLA 2 plays key role in pathophysiology of various cancers and inflammation. The role of iPLA 2 in inflammation and cancer is limited. Lipoprotein associated PLA 2 (Group VIIA PLA 2), a PAF-AH isoform, has key role in atherosclerosis. Several isoform specific PLA 2 inhibitors have been developed and some of the PLA 2 s inhibitors are currently under clinical trials for various inflammatory and oncologic diseases. This review focuses on the recent experimental evidences to support the notion that PLA 2 s are causally implicated in the pathobiology of cancer and inflammatory related disorders and discuss the potential utility of isoform specific PLA 2 inhibitors as preventive and/or therapeutic agents.
... However, recent reports demonstrated that both COX-1 and COX-2 enzymes play vital roles in carcinogenesis. Recent studies demonstrated that COX inhibition caused increase in leukotrines production from arachidonic acid through the 5-LOX pathway as a result of metabolic pathway diversion [11][12][13][14][15][16]. In the same way, 5-LOX inhibitor zileuton, increases the availability of arachidonic acid to cyclooxygenase enzyme that leads to increase the production of PGs. ...
Dammarane triterpenoid 1, a cyclooxygenase and
5-lipoxygenase dual inhibitor from Borassus flabellifer
seed coat, showed substantial antiproliferative effect
against various human cancer cells including prostate
cancer cells. However, the possible mechanism of dammarane
triterpenoid 1 on prostate cancer remains to be
determined. Hence, in vitro pro-apoptotic studies were
carried out using DU145 human prostate cancer cell line
to demonstrate apoptosis-inducing potential of dammarane
triterpenoid 1.
Human prostate carcinoma DU145 cells (1x106
/ml) were
treated with dammarane triterpenoid 1 (5 and 10 μM) for
24 h. Flow cytometric cell cycle analysis and mitochondrial
membrane potential assay, ELISA based quantification
of cytosolic cytochrome c, Bax and Bcl-2 levels and
colorimetric assays of caspases-3 and -9 were performed
using DU145 prostate cancer cells to demonstrate the
pro-apoptotic activity of dammarane triterpenoid 1.
In pro-apoptotic studies, sub-G0 cell phase population
elevation, cell cycle arrest at G0/G1 phase, mitochondrian
membrane potential loss, increase of cytosolic cytochrome
c and Bax levels, decrease of Bcl-2 levels and
enhanced caspases-3 and -9 activities were observed
in dammarane triterpenoid 1-treated DU145 prostate
cancer cells.
The results confirmed that the apoptosis-inducing
potential of dammarane triterpenoid 1 in DU145 prostate
cancer cells via intrinsic pathway. The study also
demonstrated that dammarane triterpenoid 1 exerted
anticancer activity through induction of apoptosis and
cell cycle arrest in DU145 prostate cancer cells. These
findings suggest a need for in vivo studies with dammarane
triterpenoid 1 in preclinical prostate cancer
models. Our preliminary but encouraging results may
facilitate the development of dammarane triterpenoid 1as
an effective drug for patients with prostate cancer.
Duodenal and gastric ulcers were twice as common among males than females, and duodenal ulcers were more common than gastric ulcers. However, the incidence of gastric ulcers has recently increased among females, resulting in gastric ulcers becoming relatively more prevalent and attenuating sex/gender differences. Important causes of peptic ulcers are Helicobacter pylori (H. pylori) infection and nonsteroidal anti-inflammatory drug (NSAID) use. As the prevalence of H. pylori rapidly decreased in recent years, it was expected that peptic ulcers would become less common. Indeed, the prevalence of gastric and duodenal ulcers did decrease in 2011 and 2016–2018 health check-up center studies. However, in a multicenter, tertiary hospital study, the prevalence of duodenal ulcers decreased slightly, while the prevalence of gastric ulcers increased. This result is interpreted as a consequence of the increased use of aspirin or other NSAIDs among the aging population. NSAID use, including aspirin, impacts the incidence of gastric ulcers more than it does the incidence of duodenal ulcers. In contrast, duodenal ulcers are more influenced by H. pylori infection than gastric ulcers. As complications of peptic ulcers, bleeding and perforation are more common in males than in females mainly because the female sex hormone estrogen increases the expression of tight junction proteins that seal the gap between cells, reduce mucosal permeability, and stimulate the excretion of bicarbonate ion in the duodenal mucosa.KeywordsPeptic ulcerSexGenderGastric ulcerDuodenal ulcer
Helicobacter pylori
NSAID
Clostridioides difficile is one of the leading causes of nosocomial infections worldwide. Increases in incidence, severity, and healthcare cost associated with C. difficile infection (CDI) have made this pathogen an urgent public health threat worldwide. The factors shaping the evolving epidemiology of CDI and impacting clinical outcomes of infection are not well understood, but involve tripartite interactions between the host, microbiota, and C. difficile. In addition to this, emerging data suggests an underappreciated role for environmental factors, such as diet and pharmaceutical drugs, in CDI. In this review, we discuss the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and eicosanoids in CDI.
Purpose
Osteoarthritis (OA) is a chronic and degenerative disorder associated with joint pain and loss of joint function. It is reported that polyphenols could yield articular benefits in patients with OA through the inhabitation of key inflammatory pathways. This meta-analysis was conducted to assess the efficacy and safety of polyphenol products for OA treatment.
Methods
This study included searches of PubMed, EMBASE, and the Cochrane Library databases from inception to November 6, 2019. Randomized controlled trials (RCTs) comparing polyphenols versus NSAIDs or placebo for human OA were included. Standardized mean differences (SMD) or risk ratios (RRs) were calculated for all relevant outcomes. Meta-analyses were conducted by using random effect models, and heterogeneity was assessed by using the I² statistic.
Findings
A total of 18 RCTs (N = 1724) were eligible for analysis. Polyphenol products showed a significant advantage over placebo on pain relief (SMD, –1.11; 95% CI, –1.35 to –0.87) and functional improvement (SMD, –1.14; 95% CI, –1.38 to –0.90). No differences in safety outcomes were detected between polyphenols and placebo. There were no differences in efficacy outcomes between polyphenols and NSAIDs, although patients receiving polyphenols had a lower but nonsignificant risk of experiencing gastrointestinal dysfunction compared with those treated with NSAIDs. Polyphenols and NSAIDs in combination yielded more significant benefits in efficacy than NSAIDs alone.
Implications
The results of our study suggest that polyphenols may be a promising alternative for OA by relieving symptoms while reducing safety risks. However, the generalizability of our results may be limited by the quality and sample size of the available research, as well as the heterogeneity between RCTs. High-quality clinical trials are needed to make meaningful clinical practice recommendations.
Oxidized lipids function as tissue hormones in mammals. An important class of these oxylipins are the immunomodulatory leukotrienes (LTs). Besides mammals, marine algae produce bioactive oxylipins, including LTs. The novel acid-labile oxylipin, (5 R,8 S)-dihydroxy eicosatetraenoic acid, from the edible alga Gracilaria vermiculophylla rearranges via a 1,8-diol-forming mechanism to inflammatory LTB4 enantiomers that exhibit an enantio-specific potency toward LTB4 receptor 1. This alternative pathway to a well-known leukotriene may explain food poisoning after Gracilaria consumption.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (LDA) are the main causes of peptic ulcer (PU), and cause major complication such as bleeding and perforation. The interaction of Helicobacter pylori infection with NSAIDs or LDA is complex and remains unclear. However, H. pylori infection may play additive, synergistic, or antagonistic roles in the development of drug-induced PU. H. pylori infection and NSAID use are independent risk factors for the development of PU, which is thought to be a synergistic effect. Eradication of H. pylori significantly reduces the incidence of PU in NSAID-naïve patients. However, the effect of secondary prevention is controversial, especially in chronic NSAID users. The use of a gastroprotective agent such as a proton pump inhibitor (PPI) is mandatory to prevent the recurrence of PU in patients with a previous history, especially in chronic NSAID users. H. pylori infection may also increase the risk of LDA-associated complicated and uncomplicated PU, including the risk of upper gastrointestinal bleeding. In patients taking LDA, H. pylori eradication alone may prevent the recurrence of PU bleeding. However, PPI maintenance is necessary with concomitant use of an NSAID, steroid, anticoagulant, or other antiplatelet agents.
Eicosanoids play important roles in modulating inflammation throughout the body. The gastrointestinal (GI) tract, in part because of its intimate relationship with the gut microbiota, is in a constant state of low‐grade inflammation. Eicosanoids like PGs, lipoxins and leukotrienes play essential roles in maintenance of mucosal integrity. On the other hand, in some circumstances, these mediators can become major drivers of inflammatory processes when the lining of the GI tract is breached. Drugs such as nonsteroidal anti‐inflammatories, by altering the production of various eicosanoids, can dramatically impact the ability of the GI tract to respond appropriately to injury. Disorders such as inflammatory bowel disease appear to be driven in part by altered production of eicosanoids. Several classes of drugs have been developed that target eicosanoids.
Linked Articles
This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc
Introduction: D-003, a mix of higher primary aliphatic acids purified from sugarcane, inhibits cholesterol synthesis. Recent studies have demonstrated that D-003 is effective in experimental models of osteoarthritis and inhibits the enzymatic activities of COX1 and COX2, mainly that of COX1, without causing gastrotoxicity. It has been mentioned that the dual inhibitors of COX and 5-LOX enzymes present with anti-inflammatory effects and no gastrotoxicity or even they can have gastroprotective actions. According to this background, D-003 could be a dual inhibitor of COX and 5-LOX enzymes. Objective: to study the effects of D-003 on the enzymatic activity of 5-LOX in vitro, by using the cytosolic fraction of polymorphonuclear leukocytes of rats. Methods: the following testing conditions were used: cytosolic fraction (50 µg of protein) dissolved into 0,2 mol/L borate buffer solution (pH 9) and linoleic acid (7,8-250 mmol/L) as substrate. Parallel samples were incubated with Tween-20/H2O (2 %) only (vehicle), D-003 (0,6-6 000 µg/mL) or green-lipped mussel (Perna canaliculus) extract (50 µg/mL) (reference substance). The enzymatic activity, evaluated by the conjugated diene formation, was assessed by the absorbance changes at 234 nm (5-LOX) measured in a UV-visible spectrophotometer. Results: by adding D-003, produced a dose dependent (r= 0,975; p
Introduction: policosanol, a mixture of high molecular weight aliphatic alcohols purified from sugarcane with octacosanol as the main component, shows cholesterol-lowering and antiplatelet effects in addition to an inhibitory effect on type I cicloxygenase. Objective: to determine whether policosanol may inhibit 5-LOX enzyme activity in vitro. Methods: effects on 5-LOX enzyme activities were assessed in rat blood polymorphonuclear leukocytes. Vehicle or Policosanol suspensions (0.6 to 6 000 µg/mL) were added to tubes containing the reaction mix and then absorbance changes at 234 nm were measured. Results: added Policosanol inhibited in vitro 5-LOX activity by 30 %, which was not a significant figure but depended on the concentration(r= 0.992; p
Objective:
The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used.
Methods:
Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.
Results:
Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group.
Conclusion:
5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors.
Despite decreasing Helicobacter pylori prevalence, the prevalence of peptic ulcer disease is increasing in the aged population, mainly due to increasing use of NSAIDs to manage pain and inflammation. In addition, low dose aspirin is employed as an anti-coagulant for those who have suffered or are at high risk of ischemic stroke and cardiovascular disease. However, NSAIDs and aspirin are injurious to mucosa of stomach and duodenum. NSAID-induced inhibition of mucosal prostaglandin synthesis is thought to be a major mechanism of gastrointestinal mucosal injury. The proportion of elderly has increased rapidly in Korea, with the proportion over 65 years old expected to be 24.3% in 2030. In this higher-risk population, the strategy to reduce the incidence of NSAID-related peptic ulcers and complications such as bleeding, obstruction and perforation is very important. Proton pump inhibitors (PPIs) with cyclooxygenase-2 inhibitor can be used for reducing the risk of NSAID-related ulcers and upper gastrointestinal (GI) complications. However, continuous use of PPI has several problems. In addition, NSAID-related problems in the lower GI tract have increased, in contrast to the decrease of NSAID-related upper GI disease. The aim of this review is to provide an evidence-based knowledge regarding the mechanism, complications of treatment, and prevention strategies for NSAID- or aspirin-related peptic ulcer disease in Korea.
It is now one hundred years since Felix Hoffman first synthesized aspirin by acetylating salicylic acid1. This manoeuvre resulted in a molecule that caused less dyspepsia than the parent compound2. Aspirin proved highly effective as an analgesic and as an anti-inflammatory agent and has become the world’s most successful drug. Because aspirin was given to patients with rheumatic fever, it was initially feared that it might be cardiotoxic1, but this has turned out to be spurious guilt by association. However, sporadic observations that aspirin was gastrotoxic were formally confirmed in 1937 when endoscopic studies clearly showed it caused haemorrhages, erosions and ulcers in the gastric mucosa3.
Arachidonic acid can be liberated from membrane phospholipids via the action of phospholipase A2 or phospholipase C. The liberated arachidonic acid can then be metabolized via several enzymes to yield a vast array of vasoactive and immunomodulatory substances, termed “eicosanoids” (Fig. 1). Included in this group are the prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs). In general, eicosanoids have a short half-life (seconds to minutes), and act in a paracrine or autocrine manner. The enzymes that catalyze the formation of eicosanoids have been well characterized, and several new drugs have been developed that inhibit their activity. In addition, the receptors for the eicosanoids have been identified and specific antagonists have been developed as potential therapies for a number of inflammatory conditions. This subject has been reviewed in detail by Halushka et al. (1989). In this chapter, the biological actions of the eicosanoids are reviewed, as are the enzymes through which they are formed, and the receptors through which they act. The potential of drugs that block the activity of these enzymes or the eicosanoid receptors is reviewed, particularly with respect to their potential utility in the treatment of inflammatory diseases of the gastrointestinal (GI) tract.
Effect of nonsteroidal antiinfammatory drugs on lipoxygenase and cyclooxygenase activities on human colon segments from patients with neoplasia. Lysine clonixinate (LC) is a nonsteroidal anti-inflammatory drug (NSAID) with good gastrointestinal tolerance. Treatment with LC at levels equivalent to those found in plasma following therapeutic doses resulted in significant inhibition of both cyclooxygenase 2 (COX-2) and production of 5 hydroxy-eicosatetraeonic acid (5-HETE) and slightly affected levels of cyclooxygenase 1 (COX-1) in in vitro studies carried out on human tissues. This study deals with the in vivo effect of the drug on human colon segments. Experiment 1: Five patients about to undergo hemicholechtomy due to colon neoplasia were treated preoperatively with a continuous infusion of LC, to achieve a steady-state concentration between 4 and 6 mg/ml. Human colon segments from the five patients and from another five control patients receiving no treatment with [C-14]-arachidonic acid were incubated. Human colon segments treated with LC showed significant inhibition of PGE(2), the only prostaglandin (PG) synthesised by the tissue, as well as of 5-HETE. Experiment 2: Fifteen patients received an i.v. bolus of LC 100 mg (n1=5); LC 200mg (n2=5) or indomethacin (INDO) 50 mg (n3=5). Both doses of LC showed greater inhibition of PGE 2 synthesis than the INDO bolus. Both NSAIDs studied proved to have different effects on the production of 5-HETE; while treatment with LC elicited significant Inhibition, levels with INDO remained unchanged. Western blotting analysis showed expression of both COX isoforms in colon segments, COX-2 levels being 20% higher. Both types of in vivo studies conducted continuous infusion and i.v, bolus, revealed that LC exerted significant inhibition of basal synthesis of PGE2 and 5-HETE.
Osteoarthritis (OA) is a multi-factorial disease with a large metabolic component involving the accumulation of arachidonic acid (AA) metabolites that contribute to joint deterioration. Laboratory Studies have shown that specific flavonoid Mixtures, composed of baicalin and catechin, act to inhibit cyclooxgenase-1 (COX-1) and COX-2 in a balanced manner with additional 5-lipoxygenase (5-LOX) inhibitory activity. The safety and efficacy of the flavonoid formulation, FlexileRx (TM), however, is not known in dogs. Enzyme inhibition results for COX-1, COX-2, and 5-LOX demonstrate that, compared to celecoxib, meloxicam, naproxen, ibuprofen, carprofen, and aspirin, only FlexileRx has balanced COX and additional 5-LOX enzyme inhibition activity. In a multi-site, double-blind, randomized, direct-comparator trial in dogs weighing at least 15 lbs, FlexileRx (n=33) showed statistically significant improvement in pain scores over the combination formulation of chondroitin sulfate, glucosamine hydrochloride, and manganese ascorbate (n=36) (Cosequin (R) DS) using veterinarian and owner Visual analog scale (VAS) assessments. At both the interim (28 days) and final analysis (56 days), FlexileRx was more than twice as effective as CosequinDS at relieving pain. Adverse events were generally mild in both groups. This study demonstrates that FlexileRx is a relatively fast-acting therapy for reduction of pain scores in dogs with OA.
Introduction: D-002, a mixture of six high molecular weight primary aliphatic alcohols purified from beeswax, has been shown to produce anti-inflammatory effects with no secondary gastrotoxicity in experimental models. Oral treatment with D-002 was effective for lowering the concentrations of B4 leukotriene (LTB4) in pleural exudates of rats with carragenin-induced pleurisy, suggesting that it could inhibit 5-lipooxigenase (5-LOX) enzyme activity. The mechanisms of the anti-inflammatory action of D-002, however, had not been explored yet. Objective: to evaluate the effects of D-002 on 5-LOX enzyme activity in vitro by using the cytosolic preparations from rat liver homogenates. Methods: testing conditions were as follows: cytosolic fraction (50 μg of protein) dissolved in 0.2 mol/L borate buffer solution (pH 9) and linoleic acid (7.8-250 mmol/L) as substrate. Parallel samples were incubated with Tween-20/H2O (2 %) only (vehicle, control samples), D-002 (0.9-1 000 μg/mL) or Lyprinol (500 μg/mL) (reference substance). The enzyme activity, evaluated through the formation of conjugated dienes, was assessed by the absorbance changes at 234 nm (5-lox) measured in a UV-visible spectrophotometer. Results: the in vitro addition of D-002 produced a significant, dose-dependent (r=0.980; p< 0.001) (IC 50= 95.34 μg/mL) and uncompetitive inhibition of 5-LOX activity, whose maximal inhibition (70 %) was achieved with 500 μg/mL). Conclusions: this study demonstrates that D-002 effectively inhibits 5-LOX enzymatic activity, an effect that may partially explain the anti-inflammatory effects of D-002 in experimental models in vivo.
Introduction Targets of the Eicosanoid Pathway Rationale for Development of Dual Inhibitors of the Cyclooxygenase–5-Lipoxygenase Pathway Dual Inhibitors of the Cyclooxygenase–5-Lipoxygenase Pathway Development of Licofelone Conclusions References
Introduction: policosanol, a mixture of higher aliphatic alcohols purified from sugar cane wax, is used to treat hypercholesterolemia. D-002 (Abexol), a mixture of higher aliphatic alcohols from beeswax, is an antioxidant supplement with gastroprotective effects. Then, concomitant intake of D-002 and policosanol may occur in routine practice, so potential pharmacological interactions between them should be researched on. Objective: to find out the influence of policosanol on the gastroprotective effect of D-002 on the ethanol-induced gastric ulcer model. Methods: rats were randomized into eight groups: one treated with the vehicle (control), two with D-002 (25 and 200 mg/kg), two with policosanol (25 and 200 mg/kg), two with the same doses of D-002 + policosanol and other with sucralfate (100 mg/kg). Treatments were given as single oral doses. One hour after treatment, rats received 60% ethanol orally and one hour later they were killed and their stomachs exposed. Effects on ulcer indexes (UI) were assessed. Results: acute oral administration of D-002 (25 and 200 mg/kg) significantly reduced the ulcer indexes by 40% and 68%, respectively, as compared to the control group, and policosanol by 26% and 47%, respectively. The concomitant administration of the same doses of D-002 and policosanol significantly decreased ulcer indexes by 64% (both given at 25 mg/kg) and by 92% (both given at 200 mg/kg) as compared to the respective monotherapies. Sucralfate (100 mg/kg) significantly reduced ( 99%) ulcer indexes compared to the control group. Conclusions: the concomitant oral administration of policosanol with D-00 2 gives greater gastroprotection than D-002 monotherapy, so both products can be taken together.
The gastric mucosa barrier is a complex of interacting physical and chemical defense mechanisms that protect the gastric mucosa from erosions and ulcers. Several conditions can. disrupt the gastric mucosal barrier leading to gastric mucosa damage (e.g., gastritis, gastric erosions, ulcers). Causative factors include the use of NSAIDs or glucocorticoids, hepatic or renal disease, hypoadrenocorticism, shock, spinal cord disease, primary gastrointestinal disease, and neoplasia.This article reviews the normal physiology of the gastric mucosal barrier and the pathophysiologic factors that disrupt it.
Introduction Pharmacokinetics Pharmacodynamics Inhalant Anesthetics Injectable Anesthetics Opioids Non-Steroidal Antiinflammatories Neuroleptics References
The in vitro synthesis of leukotriene B4 (LTB4) was evaluated in colorectal biopsy specimens and resection tissue from patients with inflammatory bowel disease. The in vitro formation of LTB4 from biopsy tissues stimulated with calcium ionophore A23187 correlated with the degree of mucosal inflammation assessed at sigmoidoscopy, and with neutrophil infiltration measured as myeloperoxidase activity. Biopsy specimens from patients taking prednisolone formed less LTB4 than those from patients not on prednisolone, with comparable levels of inflammation seen at sigmoidoscopy. The formation of LTB4 was reduced dose-dependently by the acetohydroxamic acid 5-lipoxygenase inhibitor BWA4C, with no significant inhibition of prostaglandin E2 or thromboxane B2 synthesis. In inflamed colonic resection tissue from colitic patients, the IC50 for inhibition of LTB4 formation by BWA4C was 0.03 mumol/l, compared with an IC50 of 0.8 mumol/l for NDGA. Thus, BWA4C is a potent and selective inhibitor of LTB4 synthesis in colonic tissue from patients with ulcerative colitis. Acetohydroxamic acid 5-lipoxygenase inhibitors, exemplified by BWA4C, may be useful to evaluate the clinical importance of LTB4 in ulcerative colitis, and offer a novel therapy for the disease.
Although the pathogenetic mechanisms underlying indomethacin-induced mucosal injury remain undefined, the results from recent studies suggest that leukocyte adherence in gastric microvessels may be an important component of this injury process. The objective of this study was to determine whether clinically relevant plasma concentrations of indomethacin promote leukocyte-endothelial cell adhesive interactions in postcapillary venules. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 s) and emigrated leukocytes were measured in rat mesenteric venules. Repeat measurements of all parameters were obtained within 20 min after addition of either 2.5 or 25 micrograms/ml indomethacin to the mesenteric superfusate. In some experiments, rats were pretreated with either a leukotriene (LT) synthesis inhibitor (L 663,536), an LTD4 (MK-571) or LTB4 (SC 41930) receptor antagonist, misoprostol, or prostacyclin (PGI2). Indomethacin alone increased the number of adherent leukocytes, reduced both leukocyte rolling velocity and venular shear rate, but did not promote leukocyte emigration. L 663,536 and SC 41930 prevented all of the adhesive and hemodynamic alterations induced by indomethacin; misoprostol and PGI2, but not MK-571, exerted similar beneficial effects. These results indicate that indomethacin promotes leukocyte adherence in postcapillary venules through an LTB4-dependent mechanism.
To evaluate the prevalence and significance of chemical gastritis, in comparison with gastritis related to Helicobacter pylori in patients receiving non-steroidal anti inflammatory drugs (NSAIDs).
Two hundred and eighteen patients were studied, 174 of whom were taking NSAIDs. Chemical gastritis was defined as the presence of foveolar hyperplasia, muscle fibres in the lamina propria, oedema and vasodilation, in the absence of a chronic inflammatory cell infiltrate.
Chemical gastritis was found in 46 (26%) patients taking NSAIDs, and three (7%) in subjects not taking these drugs (p less than 0.01). H pylori was detected in 56 (32%) subjects taking NSAIDs compared with 22 (50%) not taking these agents (p less than 0.02). Ulcers were found in 16 out of 72 patients (22%) taking NSAIDs and without H pylori infection or chemical gastritis compared with 27 out of 56 (48%) with H pylori related gastritis (p less than 0.01), and 25 out of 46 (54%) with chemical gastritis (p less than 0.01).
Peptic ulcers associated with the use of NSAIDs seem to occur more commonly in patients with chemical gastritis or H pylori infection. Patients taking NSAIDs also seem to have a greater prevalence of chemical gastritis but a lower prevalence of H pylori than those not taking these drugs.
The hypothesis that neutrophils play an important role in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in rats. Rats made neutropenic by prior treatment with an antibody to rat neutrophils raised in goat were found to be significantly more resistant to the gastric-damaging actions of indomethacin or naproxen than were control rats or rats pretreated with normal goat serum. The reduction of damage in neutropenic rats was not due to effects of the antineutrophil serum on either gastric acid secretion or the ability of indomethacin or naproxen to inhibit prostaglandin synthesis. Gastric cyclooxygenase activity was inhibited by greater than 95% in both normal and neutropenic rats that received indomethacin or naproxen. Reduction of circulating neutrophil numbers by treating rats with methotrexate also resulted in a significant reduction in the susceptibility to gastric damage induced by indomethacin. Since activation of circulating neutrophils appeared to be important in the development of gastric erosions after administration of indomethacin, and in the significant changes in vascular endothelial integrity (Monastral Blue staining) observed within 15 min of indomethacin administration, we investigated the possibility that leukotrienes (LTs) and platelet-activating factor (PAF) might be involved in the pathogenesis of indomethacin-induced ulceration. Changes in gastric LTB4 synthesis were not observed after indomethacin administration. Pretreatment with either an LTD4 antagonist or a PAF antagonist was without significant effect on the extent of gastric damage induced by indomethacin. These results suggest an important role for neutrophils in the pathogenesis of NSAID-induced gastric ulceration. Neutrophils may be important in the vascular injury that occurs early after administration of these compounds.
Gastric biopsy specimens from patients who have undergone gastric surgery frequently exhibit foveolar hyperplasia, oedema, vasodilatation and congestion, and a paucity of inflammatory cells as consequences of entero-gastric reflux. Similar, albeit generally milder, changes were found in 47 of 316 (15%) non-surgical patients undergoing endoscopy for dyspeptic symptoms. To relate these changes to bile reflux or other potential gastric irritants the total bile acid concentration was measured in samples of fasting gastric juice, and the use of a symptom questionnaire ascertained the patients' cigarette consumption, use of non-steroidal anti-inflammatory drugs (NSAIDs), and alcohol intake. When patients with reflux gastritis were compared with normal controls (n = 91), significant increases in associated peptic ulceration and NSAID use were found in the group with reflux, but no increases in bile acid concentrations. Indeed, only one patient had evidence of duodenogastric reflux. It is concluded that most cases of "reflux gastritis" in the intact stomach are not due to reflux of bile. Our findings indicate an important pathogenic role for long term NSAID use, in what might be usefully termed type C or "chemical" gastritis.
The role of leukotriene (LT) C4 as a mediator of ethanol-induced gastric mucosal damage was investigated. Rats were pretreated with a number of compounds, including inhibitors of leukotriene biosynthesis [4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one (L651,392), 3-amino-[m-(trifluoromethyl)-phenyl]-2-pyrazoline hydrochloride (BW755c), and dexamethasone] and agents that have previously been shown to reduce ethanol-induced damage [prostaglandin E2, 2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16- methyl prostaglandin E1 (Rioprostil), FPL52694] prior to oral administration of absolute ethanol. Ethanol administration resulted in a fourfold increase in LTC4 synthesis. LTC4 synthesis could be reduced significantly by pretreatment with L651,392 or dexamethasone without altering the susceptibility of the gastric mucosa to ethanol-induced damage. LTC4 release from hemorrhagic tissue was not significantly increased above that from samples of nonhemorrhagic tissue from the same stomachs. Furthermore, changes in LTB4 synthesis paralleled the changes in LTC4 synthesis observed after ethanol administration. The effects of ethanol on gastric eicosanoid synthesis were further examined using an ex vivo gastric chamber preparation that allowed for application of ethanol to only one side of the stomach. Such treatment resulted in significant increases in LTC4 synthesis on both sides of the stomach (compared with controls), although the increase on the challenged side was significantly greater than that on the nonchallenged side. These studies, thus, confirm that ethanol can stimulate gastric leukotriene synthesis independent of the production of hemorrhagic damage. Inhibition of LTC4 synthesis does not confer protection to the mucosa, suggesting that LTC4 does not play an important role in the etiology of ethanol-induced gastric damage.
Lipoxygenase metabolites of guinea pig peritoneal polymorphonuclear leukocytes stimulated with 10 microM A23187 plus arachidonic acid were isolated and identified. These metabolites were compared with each other and to chemically synthesized arachidonate metabolites for their ability to stimulate leukocyte degranulation. 5(S),12(R)-Dihydroxy-6,8,10-(cis/trans/trans)14-cis-eicosatetraenoic acid (leukotriene B4) produced a significant release of lysozyme, but not beta-glucuronidase or beta-N-acetylglucosaminidase at low concentrations (EC50 = 6.5 x 10(-9) M), while the leukocyte nonenzymatically generated 5,12-or 5,6-dihydroxyeicosatetraenoic acids had no effect at these concentrations. Higher concentrations (1--10 microM) of all the dihydroxyeicosatetraenoic acids, 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and its hydroperoxy precursor stimulated significant lysozyme release which was greater than that produced by 15-hydroxy-5,8,11-13-eicosatetraenoic acid, arachidonic acid, or its acetylene analogue, 5,8,11,14-eicosatetraynoic acid. Micromolar concentrations of leukotriene B4 and 5-HETE also stimulated significant release of beta-N-acetylglucosaminidase above controls, but not beta-glucuronidase. These results suggest that leukotriene B4 may play a role in regulating the release of certain granule-bound enzymes from polymorphonuclear leukocytes.
Arachidonic acid is metabolized via two pathways in leukocytes: cyclo-oxygenase, leading to the stable prostaglandins, and lipoxygenase, leading to hydroxyacids. Indomethacin inhibits the cyclo-oxygenase selectively, whereas compound BW755C (3-amino-1-(m-(trifluoromethyl)phenyl)-2-pyrazoline) inhibits both pathways equally. This offers a possible explanation for the differing activities of these two compounds in inflammatory models in vivo. The patterns of product inhibition by the two compounds support the suggestion that 11-HETE (hydroxy-eicosatetraenoic acid) and 15-HETE can arise by incomplete operation of the cyclo-oxygenase pathway.
The ability of BW755C to reduce ethanol- or indomethacin-induced gastric damage and the role of prostanoids in the mechanism of this action were examined in the rat. BW755C (1–100 mg/kg) caused a dose-related reduction in the amount of damage produced by oral administration of 40% ethanol in 100 mM HCl. At the doses tested, BW755C had no significant effect on mucosal 6-keto-prostaglandin F1α synthesis, but did cause a dose-dependent reduction in thromboxane B2 synthesis. The effect on thromboxane synthesis may be due to a selective inhibition of platelet cyclo-oxygenase by BW755C. The higher doses of BW755C (50 and 100 mg/kg) caused a significant increase in the volume of fluid present in the gastric lumen, which may contribute to the protective action of the drug against ethanol-induced damage. Oral administration of BW755C (50 mg/kg) significantly reduced the extent of gastric damage caused by subcutaneous injection of indomethacin (20 mg/kg) indicating that it is unlikely that the protective action of BW755C is mediated by endogenous prostanoids. The mechanism of the protective actions of BW755C may be related to its reported ability to inhibit lipoxygenase or to its actions as a free-radical scavenger.
To evaluate behavioral, demographic, clinical, and histologic variables that independently influence gastroduodenal mucosal prostaglandin concentrations.
Prospective study.
A clinical research laboratory located in a Department of Veterans Affairs hospital.
Fifty-two healthy adults who had no history of peptic ulcer disease and who were not receiving nonsteroidal anti-inflammatory drugs.
Mucosal biopsy specimens were obtained endoscopically from the stomach (body and antrum) and the duodenum (bulb and postbulbar area). Mucosal extracts from each of these four regions were assessed by radioimmunoassay to determine prostaglandin E2 and prostaglandin F2 alpha concentrations. Specimens were also examined histologically for inflammation and the presence of Helicobacter pylori. A multivariate linear regression model was used to determine which behavioral, demographic, and histologic variables significantly and independently influenced gastroduodenal mucosal prostaglandin concentrations.
Smoking and older age were independently associated with lower prostaglandin concentrations in all four mucosal regions (P = 0.0001 to P = 0.05). Compared with results in young nonsmokers, mucosal prostaglandin concentrations were reduced by 70% to 80% in older smokers. Gender, alcohol use, endoscopic appearance, dyspeptic symptoms, mucosal inflammation, and the presence of H. pylori had no consistent effect on prostaglandin content.
Smoking and older age are associated with significantly reduced gastric and duodenal prostaglandin concentrations. These observations may help explain the predisposition to ulcer disease in smokers and older persons.
Intragastric ethanol stimulates mucosal formation of leukotriene C4 in the rat stomach. The present study demonstrates that the increase in leukotriene C4 formation begins within 30 seconds and is maximal within 5 minutes, closely paralleled by the appearance of hemorrhagic lesions. Leukotriene C4 formation returns to prechallenge levels within 3 hours, although erosions still persist. Intragastric 0.2N NaOH, acidified 100 mmol/L taurocholate, 25% NaCl, or 0.6N HCl did not consistently increase leukotriene C4 formation despite severe mucosal injury. A number of sulfhydryl-containing or sulfhydryl-blocking agents as well as metals protected against mucosal damage and simultaneously prevented the stimulation of leukotriene C4 formation induced by ethanol. None of the agents increased and some virtually abolished mucosal formation of prostaglandin E2, indicating that gastroprotection can occur completely independently of the endogenous prostaglandin system. The leukotriene biosynthesis inhibitor MK-886 markedly suppressed gastric leukotriene C4 formation but did not protect against damage caused by ethanol, NaOH, NaCl, or acidified taurocholate. Oral indomethacin reduced the ex vivo formation of both prostaglandin E2 and, to a lesser extent, leukotriene C4 in the gastric mucosa, inducing a shift in the balance from protective prostaglandins to proulcerogenic leukotriene C4. Pretreatment with MK-886, however, did not significantly diminish indomethacin-induced lesions. These data suggest that leukotriene C4 is not the exclusive mediator of gastric injury caused by necrotizing agents or indomethacin. On the other hand, certain protective compounds exhibit a striking parallelism between protection and inhibition of ethanol-induced leukotriene C4 formation, suggesting that they may affect a target crucial for both mucosal injury and stimulation of 5-lipoxygenase.
The synthesis of gastric and duodenal mucosal prostaglandin E2, prostaglandin I2, and thromboxane B2 during a 60 minute incubation of biopsy specimens, the degree of endoscopic and histological damage, and the anti-inflammatory response were all studied after a four week, double blind study of therapeutic doses of two non-steroidal anti-inflammatory drugs, naproxen and etodolac, received by 27 patients with active rheumatoid arthritis (13 receiving naproxen, 14 etodolac). Prostaglandin values after treatment did not differ from the baseline levels when all the patients were analysed as one group. Subgroup analysis showed that naproxen suppressed gastric prostaglandin E2 from a median of 29 to 9 ng/mg protein, duodenal prostaglandin E2 from 34 to 11 ng/mg, and duodenal prostaglandin I2 from 62 to 15 ng/mg protein. No overall suppression occurred with etodolac. Also, on the second assessment patients receiving naproxen had lower gastric and duodenal prostaglandin E2 and prostaglandin I2, but higher values of duodenal thromboxane B2, than patients receiving etodolac. Both drugs had comparable anti-arthritic activity and caused microscopic gastritis in similar proportions of patients. No correlation was detected between prostaglandin values and the mucosal damage which developed in seven patients receiving naproxen (54%) and three receiving etodolac (21%). These findings indicate that, unlike naproxen, etodolac does not seem to affect gastric or duodenal prostaglandin synthesis; other mechanisms of injury need to be considered.
The ability of various leukotrienes to alter the susceptibility of the rat gastric mucosa to injury by 20% ethanol and the possible mechanism of action were examined using an ex vivo gastric chamber preparation. Intraarterial infusions of leukotriene B4 or N-acetyl leukotriene E4 (0.01-1.0 microgram/kg per min for 10 min) had no significant effect on the extent of damage induced by topically applied 20% ethanol. However, infusion of leukotriene C4, D4, or E4 (1.0 micrograms/kg per min) significantly increased ethanol-induced damage, as measured macroscopically, histologically, and functionally. Lower doses of leukotriene C4, D4, or E4 were without significant effect in this model. The increase in damage induced by these three leukotrienes could be blocked by pretreatment with either of two structurally unrelated leukotriene D4 antagonists (L-649,923 or L-660,711). The augmentation of damage by leukotriene C4 was not affected by pretreatment with indomethacin or with a specific thromboxane A2-receptor antagonist (L-670,596). At the dose that increased ethanol-induced damage, none of the leukotrienes tested significantly altered gastric vascular permeability, as measured by Evan's blue leakage. However, using laser-Doppler flowmetry, leukotrienes C4 and D4 were found, when administered intraarterially at doses in the 0.05-1.0 micrograms/kg per min range, to produce dose-dependent reductions of gastric blood flow while N-acetyl leukotriene E4 was without effect and leukotriene B4 induced slight increases. The effects of leukotrienes C4 and D4 on gastric blood flow could be inhibited by the two leukotriene D4 antagonists but not by the thromboxane antagonist. These results demonstrate that although they do not produce damage by themselves, leukotrienes C4, D4, and E4 are capable of augmenting ethanol-induced injury to the gastric mucosa. Changes in vascular permeability do not appear to play a role in the mechanism of action of the leukotrienes, while their effects on gastric blood flow are likely to be important. Under certain condition it is therefore possible that local release of leukotrienes could, at least in part through reducing vascular perfusion, predispose the surrounding tissue necrosis.
Platelet-activating factor (PAF), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) generation by gastroduodenal mucosa was assessed in duodenal ulcer patients and in normal subjects, to elucidate their possible role in the pathogenesis of peptic ulcer disease. Endoscopic fundic, antral, and duodenal biopsy specimens were obtained from 35 duodenal ulcer patients on the day the diagnosis was established and from 42 normal controls. In duodenal ulcer patients PAF generation, determined by platelet aggregation, was two- to three-fold higher than its respective generation by normal subjects. LTB4 and LTC4 synthesis by cultured antral and duodenal mucosa obtained from duodenal ulcer patients was twofold higher than their synthesis by normal subjects. Fundic LTB4 and LTC4 generation was similar in ulcer patients and controls. In 11 patients PAF, LTB4, and LTC4 generation was also assessed after 4 weeks of treatment resulting in ulcer healing and found to be significantly reduced when compared with their synthesis when the ulcer was active. These results thus suggest that PAF, LTB4, and LTC4 may have a role in the pathogenesis of duodenal ulcer, and therefore their modulation may have therapeutic benefits.
This study was done to evaluate the role of leukotrienes (LTs) in gastritis associated with Campylobacter pylori. Biopsy specimens of gastric mucosa were obtained endoscopically from 18 patients with nonulcer dyspepsia for bacteriological and histological examination and extraction of LTs. There was correlation between the LTB4 level in the mucosa and the degree of gastritis evaluated histologically. The level was higher when infiltration of neutrophils in the gastric mucosa was more extensive. The LTB4 level in mucosa infected with C. pylori was higher than that in noninfected mucosa. These findings suggest that endogenous LTs may be related to the pathogenesis of gastritis associated with C. pylori.
The role of lipoxygenase metabolites in ethanol-induced gastric mucosal injury and submucosal microvascular change in the rat was studied by in vivo microscopy. Intragastric ethanol-instillation caused marked submucosal venular constriction, dilatation of small arterioles, and corpus mucosal gross lesion formation. The venoconstriction was greater in the lesion than in the nonlesion area. Intragastric pretreatment with either BW755C, a lipoxygenase inhibitor, or Rioprostil, a synthetic prostaglandin E1 analogue, significantly inhibited both the ethanol-induced venoconstriction and the gross lesion formation. In contrast, pretreatment by the submucosal application of either BW755C (50 micrograms/ml) or Rioprostil (50-500 ng/ml) had no effect on either the submucosal venoconstriction or the mucosal lesion formation. In conclusion, leukotrienes released from the gastric mucosa appear to be involved in the ethanol-induced submucosal venoconstriction associated with gastric mucosal injury. Prostaglandin pretreatment protects against this venoconstriction and gross lesion by a mucosal effect but not by a direct effect on submucosal venules.
The role of leukotriene synthesis in the gastrointestinal damage induced by platelet-activating factor (PAF) was examined in the rat. The effects of a 20-min infusion of PAF (100 ng/kg per min) on leukotriene B4 (LTB4) and leukotriene C4 (LTC4) synthesis were examined in samples of the stomach, duodenum, jejunum, ileum and colon. Administration of PAF resulted in marked hemoconcentration and extensive hemorrhagic damage which was only observed in the corpus region of the stomach and in the small intestine. However, LTB4 synthesis was increased significantly in all regions studied, while LTC4 synthesis was increased significantly only in the duodenum. Pretreatment of the rats with dexamethasone significantly reduced the PAF-induced increase in LTB4 synthesis in all tissues studied. However, a reduction of PAF-induced damage following dexamethasone treatment was observed in the small intestine, but not the stomach. To further investigate the role of leukotrienes as mediators of PAF-induced gastrointestinal damage, the effects of a 10-min infusion of PAF (100 ng/kg per min i.v.) were compared to those of similar infusions of LTB4, LTC4 or leukotriene D4 (LTD4) (0.3-3 micrograms/kg per min). None of the doses of leukotrienes tested produced hemoconcentration or gastrointestinal damage comparable to that observed with the much lower dose of PAF, with the single exception of significant hemoconcentration observed with the highest dose of LTC4. The results of this study therefore suggest that leukotrienes are unlikely to play a major role as mediators of PAF-induced gastrointestinal damage in the rat.
Release of sulfidopeptide (SP)-leukotrienes (LT) in vitro from normal human colonic mucosa and from mucosal tissue obtained from patients with Crohn's disease (CD) and ulcerative colitis (UC) was investigated. It was found that inflamed mucosal tissue released significantly more SP-LT than normal colonic mucosa both under control conditions and after addition of calcium ionophore A23187. These results indicate the presence of endogenous stimuli as well as an increased responsiveness to an exogenous stimulus of LT formation in the inflamed mucosa. Sulfasalazine (SASP), a drug used in inflammatory bowel diseases, and its active metabolite 5-aminosalicylic acid (5-ASA) were found to inhibit colonic mucosal SP-LT formation, while only 5-ASA inhibited simultaneously synthesis of another arachidonic acid-derived inflammatory mediator, prostaglandin (PG) E2. The results suggest that SP-LT might be important mediators of inflammation in CD and UC.
The gastric vasoconstrictor actions of the arachidonate lipoxygenase products leukotrienes B4, C4, and D4 and the prostanoids prostaglandin F2 alpha (PGF2 alpha) and the endoperoxide analogue U-46619 have been investigated in vivo in the submucosal microcirculation of the anesthetized rat using direct microscopy. Topical application of PGF2 alpha (1-100 microM) to the exposed submucosa reduced vessel diameter of the venules, with peak vasoconstriction occurring within 1 min and remaining during the 3-min period of administration. Constriction of the arterioles by PGF2 alpha was less pronounced. U-46619 (1-1,000 nM), a thromboxane mimetic, induced vasoconstriction in both arterioles and venules, reaching plateau responses within 1.5-2.0 min of application. Leukotriene C4 (25-400 nM) induced vasoconstriction in the venules, which was more pronounced than in the arterioles, reaching peak responses within 1-1.5 min, which were unaffected by indomethacin administration. No significant vasoactive action with leukotrienes B4 or D4 in the submucosal microcirculation could be detected. With both leukotriene C4 and U-46619 intense focal vasoconstriction in the venules was observed, leading to sluggish blood flow or stasis within the vessel. In contrast, norepinephrine had no significant action on submucosal venules at concentrations that substantially reduced arteriolar vessel diameter. Such potent vasoconstrictor actions of leukotriene C4 and U-46619 in the gastric submucosa identify this leukotriene and thromboxane A2 as potential endogenous proulcerogenic agents and suggest that these arachidonate products could play a role in microcirculatory events accompanying gastric damage.
The role of leukotriene B 4 (LTB 4 ) and LTC 4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5‐lipoxygenase inhibitors, BW A4C and BW A137C.
Oral administration of ethanol to rats in vivo , induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5‐lipoxygenase products, LTB 4 and LTC 4 , from the mucosa ex vivo .
Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5–50 mg kg ⁻¹ p.o.) dose‐dependently reduced ethanol‐stimulated LTB 4 and LTC 4 formation by the gastric mucosa, with an ID 50 of approximately 5 mg kg ⁻¹ p.o.
A single oral dose of BW A4C (20 mg kg ⁻¹ ) induced near‐maximal inhibition of mucosal LTB 4 formation within 30 min, which was well maintained for 5h, whereas BW A137C (20 mg kg ⁻¹ p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h.
The mucosal formation of the cyclo‐oxygenase product, 6‐keto‐prostaglandin F 1α , which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B 2 formation following challenge was not inhibited by BW A4C.
Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB 4 or LTC 4 , reduced the macroscopic gastric mucosal damage induced by ethanol.
Pretreatment with the lipoxygenase inhibitor BW 755C (5–50 mg kg ⁻¹ p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis.
Oral administration of high doses of either BW A4C or BW A137C (300 mg kg ⁻¹ ) did not induce macroscopic gastric damage over a 3 h period.
These findings suggest that the leukotrienes, LTB 4 and LTC 4 are not the primary mediators of ethanol‐induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation.
This study was designed to determine the role of leukotriene C4 (LTC4) in the formation of acute gastric lesions induced by 100% ethanol, acidified taurocholate (TC), acidified aspirin (ASA), platelet-activating factor (PAF), and water-immersion and restraint stress. Exogenous LTC4 alone administered in gradually increasing doses (5-20 micrograms/kg/hr) caused only mild hemorrhagic lesions in the gastric mucosa but when combined with 100% ethanol, acidified TC, acidified ASA, or stress, it increased significantly the mean lesion area and lesion number as compared to those produced by these ulcerogens alone. FPL 55712, a LTC4 antagonist, given orally (2.5-10 mg/kg) reduced dose-dependently the extent of gastric lesions in all experimental models used and completely prevented the deleterious effects of exogenous LTC4 on gastric mucosa. PAF augmented the mucosal lesions induced by 100% ethanol, and this was also reduced by the pretreatment with FPL 55712. FPL 55712-induced gastroprotection against various ulcerogens was reversed, in part, by indomethacin, indicating that it could be attributed not only to the LTC4 antagonism but also to increased biosynthesis of PGs. This study provides evidence that LTC4 is involved in the formation of acute gastric damage and the antagonism of LTC4 may protect the mucosa against various ulcerogens.
Recent investigations indicate that microvascular injury, leading to increased vascular permeability and capillary stasis, precede the development of chemically induced hemorrhagic mucosal lesions in the stomach. The vascular damage is more amenable to protection by prostaglandins and sulfhydryls than the diffuse surface mucosal cell injury. The vascular and mucosal lesions may be the result of direct toxicity of damaging agents (eg, ethanol, HCl, NaOH) and the release of vasoactive amines and leukotrienes. We review here our recent studies performed in rats indicating that intraarterial infusion of LTC4 or LTD4 in the stomach caused vascular injury as revealed by monastral blue. Infusion of leukotrienes alone caused no hemorrhagic mucosal lesions but aggravated the damage caused by 25, 50, or 100% ethanol and 0.2 N HCl given intragastrically. The ethanol-induced mucosal lesions were slightly diminished by the lipoxygenase inhibitor L-651,392 and markedly decreased by eicosapentaenoic acid, which competes with arachiconic acid as a substrate for 5-lipoxygenase. These results are discussed and correlated with biochemical results from other laboratories demonstrating increased levels of leukotrienes in the gastric mucosa after administration of ethanol and decreased release following pretreatment with prostaglandins or sulfhydryl-related agents. New data thus support a mediatory role for leukotrienes in the pathogenesis of vascular injury and mucosal lesions in the stomach.
1. The effects of oral and subcutaneous administration of the non-steroidal anti-inflammatory drugs sodium salicylate, aspirin and indomethacin on ex vivo gastric mucosal release of leukotriene C4 (LTC4) prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) were investigated in rats under basal conditions as well as after challenge with ethanol. 2. Basal release of PGE2, 6-oxo-PGF1 alpha and TXB2 was inhibited by oral administration of aspirin (0.6-400 mgkg-1) and indomethacin (4 or 20 mgkg-1), but not by sodium salicylate (up to 400 mgkg-1), in a dose-dependent manner. Oral administration of aspirin in the dose range 3.2-400 mgkg-1 and of indomethacin (20 mgkg-1) additionally inhibited release of LTC4, while sodium salicylate (up to 400 mgkg-1) had no effect. Indomethacin (20 mgkg-1) and aspirin (400 mgkg-1) administered subcutaneously inhibited generation of cyclo-oxygenase products of arachidonate metabolism, but did not significantly affect LTC4 synthesis. 3. Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC4 from rat gastric mucosa, while release of cyclo-oxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanol-stimulated gastric mucosal LTC4 release in a dose-dependent manner. Sodium salicylate had no effects on the release of PGE2 and TXB2, while that of 6-oxo-PGF1 alpha was slightly increased. 4. Pretreatment with indomethacin (4 or 20mg kg- p.o.) or aspirin in doses up to 25mg kg-1 p.o. prior to oral instillation of ethanol did not inhibit gastric mucosal damage and had no effect on the stimulatory action of ethanol on LTC4 release. Higher doses of aspirin (100mgkg-1 or 400mgkg-1 p.o.) reduced the mucosal damaging effect of ethanol and simultaneously inhibited LTC4 release. 5. The results suggest that aspirin and indomethacin in concentrations higher than those necessary to inhibit the cyclo-oxygenase pathway of arachidonate metabolism additionally inhibit gastric mucosal LTC4 synthesis under basal conditions, while sodium salicylate has no such effect. On the other hand, sodium salicylate, but not indomethacin or low doses of aspirin (up to 25mg kg 1), by an unknown mechanism inhibits stimulation of LTC4 biosynthesis by ethanol and simultaneously protects the gastric mucosa against ethanol-induced damage. Similar effects of high oral doses (> 100mgkg- 1) of aspirin might be due to significant formation of salicylate. These results suggest that there is a causal relationship between enhanced LTC4 biosynthesis and the development of ethanol-induced gastric injury.
To determine the effect of smoking on gastroduodenal mucosal prostaglandin synthesis, endoscopies were done after an overnight fast on 10 nonsmokers, 12 active smokers who smoked four cigarettes in the hour before endoscopy, and then 11 of the smokers who refrained from smoking for 12 hours. Biopsy samples of fundic, antral, and duodenal mucosae were incubated, and the accumulation of prostaglandin E2 and 6-keto-prostaglandin F1 alpha in the incubation medium was measured by radioimmunoassay. We assumed that accumulation of prostaglandins in the medium reflected mucosal synthesis. Comparison of active and inactive smoking showed that active smoking significantly depressed 6-keto-prostaglandin F1 alpha synthesis in antral and fundic mucosa and prostaglandin E2 synthesis in antral mucosa. Comparison of nonsmokers and inactive smokers showed no difference in prostaglandin synthesis. Active smoking causes a transient decrease in prostaglandin synthesis in fundic and antral mucosae. This depression of prostaglandin synthesis may help explain slower ulcer healing and predisposition to ulcer recurrence in smokers.
Because endogenous prostaglandins may protect the gastric mucosa a study was conducted to determine factors influencing the synthesis of immunoreactive prostaglandin (iPG) E2 and thromboxane (iTx) B2 as measured by radioimmunoassay and prostaglandin catabolism measured radiometrically, in human gastric mucosa. Gastric mucosa was obtained at endoscopy. Synthesis of iPE2 and iTxB2 was inhibited in vitro by indomethacin; iTxB2 synthesis was also selectively inhibited by the thromboxane synthesis inhibitor dazmegrel. Prostaglandin catabolism was inhibited by carbenoxolone. Multivariate analysis showed that synthesis of iPGE2 from endogenous precursor during homogenisation was decreased in patients on non-steroidal anti-inflammatory drugs. Mucosal inflammation was associated with significantly increased synthesis of iPGE2 and decreased prostaglandin catabolism. There were no differences between the mucosa of patients with or without gastric ulcers, nor between the ulcer rim and mucosa 5 cm away. Age, sex, smoking history and ingestion of antisecretory drugs appeared to exert no influence. In this study gastritis was the major influence on prostaglandin synthesis. It seems unlikely that prostaglandin deficiency is a strong predisposing factor for gastric ulceration.
Campylobacter pyloridis colonization of the stomach may be an etiological factor in gastritis and peptic ulceration. Campylobacter pyloridis produces large amounts of urease, and the presence of this enzyme in gastric mucosa usually indicates infection with the organism. In this paper we describe the use of a rapid urease test (CLOtest) to detect C. pyloridis infection in gastric mucosal biopsies. In 141 consecutive endoscopy cases, antral biopsies were taken for culture and histology, and an extra biopsy was inserted into the CLOtest gel. There were 79 patients infected with C. pyloridis, 78 of whom were detected by CLOtest: 75% were positive at 20 min, 92% at 3 h, and 98% at 24 h. There were no false positive results. Eighteen infected patients were rebiopsied after a course of amoxycillin and bismuth subcitrate. Active chronic gastritis resolved in eight of nine who were cleared of the organism, but histological gastritis was unchanged in nine patients who were still infected. CLOtest is a simple, sensitive, and highly specific test that enables the endoscopist to diagnose C. pyloridis infection in the endoscopy room. A negative test after antibiotic therapy correlates with clearance of the bacteria and healing of active gastritis.
The frequency of gastritis in relation to its various predisposing conditions is unclear, as is the respective distribution of damage caused by its predisposing conditions. We studied 100 patients with the endoscopic diagnosis of gastritis. The incidence of gastritis in our university gastroenterology endoscopy service was 23%. A history of aspirin (ASA) or nonsteroidal anti-inflammatory drug (NSAID) use was present in 42%. No predisposing factors were found in 28% of cases. Stress gastritis was present in 10% of patients, all of whom were in the intensive care unit. Alcoholism, gastric resection, and portal hypertension were considered causative in 19%. Multiple predisposing factors were uncommon (3%). Coincident duodenal ulcer(s) and erosive duodenitis were common and were more frequent in the patients having idiopathic gastritis (46%) than in those who used ASA or NSAIDs (29%). The antrum was the portion of the stomach most frequently involved. This antral distribution of damage was predominant in both the ASA/NSAID-associated cases and in the idiopathic group. In contrast, patients with stress gastritis were more likely to have involvement of the gastric fundus and body.
In 1971 interest in the role of prostaglandins in the gastrointestinal tract was stimulated by the publication of two hypotheses--that aspirin damaged the gastric mucosa by inhibiting prostaglandin synthesis (1) and that cholera toxin caused diarrhea by stimulating it (2). Subsequent research into the gastrointestinal actions of prostaglandins has been considerable and now impinges on clinical practice. This paper reviews the involvement of prostaglandins and related compounds in mucosal protection, in ulcer healing, in diarrhea, and in gastrointestinal inflammation, with particular reference to the growing body of human data.
Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
Arachidonic acid is metabolised either by cyclooxygenases to produce prostaglandins and thromboxanes or by lipoxygenases to produce mono-, di- and trihydroxyeicosatetraenoic acids (HETEs). Polymorphonuclear leukocytes (PMNs) release HETEs, including mono- and dihydroxy fatty acids, when exposed to stimuli such as the calcium ionophore A23187 (refs 1, 2). The mono-HETEs are assumed to be of particular importance with respect to effects on leukocyte function because they have been shown to possess both chemotactic and chemokinetic activities towards PMNs and eosinophils. However, we have now shown that the chemokinetic and aggregating activities released from rat and human PMNs exposed to ionophore A23187 (ref. 5) are not due to the release of mono-HETEs but to that of 5, 12-di-HETE (leukotriene B). This compound is active over the concentration range 10 pg ml-1 to 5 ng ml-1.
The predominant lipoxygenase products of arachidonic acid were extracted and purified from synovial fluid and sonicates of synovial tissue of patients with rheumatoid arthritis (RA), spondyloarthritis (SA), or a noninflammatory arthropathy (NIA). The concentration of 5(S),12(R)-dihydroxy-6,8,10-(trans/trans/cis)-14-cis-eicosatetraenoic acid (leukotriene B4) in synovial fluid was elevated significantly in patients with RA and a positive latex test for rheumatoid factor (P < 0.05, n = 14) and in patients with SA (P < 0.05, n = 10), compared with that of subjects with NIA (n = 9). The content of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), but not of leukotriene B4, was elevated significantly in synovial tissue of seven patients with RA in comparison with that of four subjects with NIA (P < 0.05). A single intra-articular injection of corticosteroid significantly lowered the synovial fluid level of leukotriene B4 in six patients with RA. These data suggest an involvement of the potent chemotactic factors 5-HETE and leukotriene B4 in human inflammatory disease.
Dose-response relationships between aspirin-induced cyclo-oxygenase inhibition and gastric mucosal injury were studied in rats. Oral or parenteral aspirin, 25 mg/kg, inhibited prostaglandin generation by 87%-95% at 1, 3, and 6 h with no lesion formation. Aspirin, 100 mg/kg, inhibited prostaglandin generation by 95%-98% at 1, 3, and 6 h, but lesions were observed only when aspirin was given orally. Three-hour pretreatment with intraperitoneal aspirin, 12.5 mg/kg, did not enhance the mucosal injury caused by 10 mM acidified taurocholate, although prostaglandin generation was inhibited by 80%. Pretreatment with 25 mg/kg aspirin inhibited prostaglandin generation by 89% and was associated with significant mucosal injury by acidified taurocholate. We conclude that aspirin-induced 95% inhibition of gastric mucosal cyclo-oxygenase is not, by itself, sufficient to produce lesions and inhibition by greater than 80% is required to predispose the gastric mucosa to injury by otherwise mild irritants.
Inhibition of cyclooxygenase in the rat small intestine and gastric mucosa after subcutaneous administration of indomethacin has been investigated using prostacyclin (PGI2) production ex vivo as an index of prostaglandin biosynthesis. This has been compared with the formation of intestinal lesions and gastric erosions. Indomethacin caused marked inhibition of prostacyclin formation in the gastric mucosa, and this was accompanied by the development of gastric erosions, although after 48 h both inhibition of cyclooxygenase and gastric erosions were no longer apparent. There was no such temporal relationship between prostaglandin inhibition and the formation of lesions in the small intestine since the lesions became macroscopically apparent and developed at a time when cyclooxygenase inhibition was already declining. Aspirin caused a prolonged inhibition of small-intestinal cyclooxygenase activity, yet failed to cause intestinal damage. Thus, inhibition of prostaglandin synthesis alone may not be sufficient to initiate the processes which ultimately result in intestinal lesions. The prostaglandin-independent processes affected by indomethacin which lead to intestinal damage are as yet unknown.
Arachidonic acid is metabolized via two pathways in leukocytes: cyclo-oxygenase, leading to the stable prostaglandins, and lipoxygenase, leading to hydroxyacids. Indomethacin inhibits the cyclo-oxygenase selectively, whereas compound BW755C (3-amino-1-(m-(trifluoromethyl)phenyl)-2-pyrazoline) inhibits both pathways equally. This offers a possible explanation for the differing activities of these two compounds in inflammatory models in vivo. The patterns of product inhibition by the two compounds support the suggestion that 11-HETE (hydroxy-eicosate-traenoic acid) and 15-HETE can arise by incomplete operation of the cyclo-oxygenase pathway.
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