[Show abstract][Hide abstract] ABSTRACT: Allopurinol is a xanthine oxidase inhibitor and antioxidant free radical scavenger which facilitates the protection of ischemic organs in part via this mechanism of action. The accumulation of free radicals during ischemia and reperfusion is in great manner overcome by inhibitors of xanthine oxidase and by the development of endogenous antioxidants. The ischemic lesion generates a well-established inflammatory response with the subsequent production of inflammatory molecules characteristically present at the first stages of the injury. Inflammatory cytokines, chemokines, adhesion molecules, and other cellular and molecular compounds are consequently produced as the lesion sets in. Under these conditions, allopurinol diminishes the effect of inflammatory mediators during the ischemic inflammatory response. This study reviews the literature associated with allopurinol and renal ischemia making special emphasis on the best dose and time of administration of allopurinol regarding its protective effect. It also defines the most accepted mechanism of protection on ischemichally damaged kidneys.
Full-text · Article · Jun 2014 · Journal of Investigative Surgery
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Pentoxifylline is a methylxanthine compound which was first filed in 1973 and registered in 1974 in the United States by Sanofi-Aventis Deustchland Gmbh for the treatment of intermittent claudication for chronic occlusive arterial disease. This methylxanthine was later discovered to be a phosphodiesterase inhibitor. Furthermore, its hemorheological properties and its function as an inhibitor of inflammatory cytokines, like TNF-α, allowed researchers to study its effects in organ ischemia and reperfusion and transplantation. Although this drug has demonstrated beneficial effects, the mechanisms by which Pentoxifylline exerts a protective effect are not fully understood. This paper focuses on reviewing the literature to define the effect of Pentoxifylline when used in liver ischemia and reperfusion injury. Our research shows different animal models in which Pentoxifylline has been used as well as different doses and time of administration, as the ideal dose and timing have not yet been ascertained in liver ischemia and reperfusion. In conclusion, Pentoxifylline has shown positive effects in liver ischemia and reperfusion injury, and the main mechanism seems to be associated with the inhibition of TNF-α.
Full-text · Article · Oct 2013 · Journal of Investigative Surgery
[Show abstract][Hide abstract] ABSTRACT: Pentoxifylline, a methylxanthine derivative with significant hemorheologic properties, is used for claudication in patients with peripheral vascular disease, and experimentally for ischemic injury to organs because of its antioxidant and antiinflammatory effects. We used a rat model of severe small intestinal ischemia and reperfusion to determine the ability of pentoxifylline in improving survival, molecular response, and pathological protection.
We used 6 groups of male Wistar rats (n=25 each). The superior mesenteric artery was occluded for 120 minutes. Laboratory and tissue studies were done on 5 animals, 1 hour after reperfusion, and animal survival was assessed at 7 days. There were 2 control groups that received normal saline, either before ischemia or during reperfusion. The 4 treated groups received pentoxifylline 1 or 10 mg/kg at the same times mentioned above. Laboratory studies included measuring serum lactic acid dehydrogenase, tumor necrosis factor-α, interleukin-1β, and interleukin-6.Intestinal tissue malondialdehyde and myeloperoxidase in small intestine tissue also were measured. Histology and laser vascular blood flow at baseline and reperfusion were obtained, and survival was determined 7 days after ischemia.
A significant survival benefit in the animals treated with 10 mg/kg of pentoxifylline at reperfusion was noted. This coincided with a reduction in biochemical markers of cell damage - specifically, serum lactic acid dehydrogenase, and tissue malondialdehyde, ischemia, and reperfusion. Additionally, we saw decreased levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6. Improved postreperfusion blood flow shown by laser Doppler technology also was seen in the treated groups. Histologically, we observed less neutrophil infiltration in the intestine of ischemic-treated rats. Also seen in the control animals were increased necrotic lesions in the microvilli with a higher presence of lysozyme in the Paneth cells. Survival was significantly better at 7 days (70% vs 40%) when we compared the pentoxifylline group treated at reperfusion (10 mg/kg) to the ischemic controls.
Pentoxifylline had a significant protective effect on severely ischemic bowel when administered during reperfusion at a dosage of 10 mg/kg. Better survival, improved histology, and molecular response should urge consideration of the consideration of applying these findings in some general surgery and transplant conditions.
[Show abstract][Hide abstract] ABSTRACT: Of all milestones and achievements in medicine, conquering pain must be one of the very few that has potentially affected every human being in the world. It was in 1846 that one of mankind's greatest fears, the pain of surgery, was eliminated. This historical review article describes how the various elements of anesthesiology (gasses, laryngoscopes, endotracheal tubes, intravenous medications, masks, and delivery systems) were discovered and how some brilliant entrepreneurs and physicians of the past two centuries have delivered them to humanity. One name stands out amongst all others when the founder of modern anesthesia is discussed, William T.G. Morton (1819-1868). A young Boston Dentist, Dr. Morton had been in the search for a better agent than what had been used by many dentists: nitrous oxide. With Dr. Morton's tenacity driven by enthusiasm and discovery, he and renowned surgeon at Massachusetts General Hospital, John Collins Warren (1778-1856) made history on October 16, 1846 with the first successful surgical procedure performed with anesthesia. Dr. Morton had single-handedly proven to the world that ether is a gas that when inhaled in the proper dose, provided safe and effective anesthesia. One of the first accounts of an endotracheal tube being used for an airway comes from the pediatrician Joseph O'Dwyer (1841-1898). He used the metal "O'dwyer" tubes in diphtheria cases and passed them into the trachea blindly. Adding a cuff to the tube is credited to Arthur Guedel (1883-1956) and Ralph M. Waters (1883-1979) in 1932. This addition suddenly gave the practitioner the ability to provide positive pressure ventilation. The anesthesiologist Chevalier Jackson (1865-1958) promoted his handheld laryngoscope for the insertion of endotracheal tubes and its popularity quickly caught hold. Sir Robert Reynolds Macintosh's (1897-1989) breakthrough technique of direct laryngoscopy came after being appointed Nuffield professor of anesthetics at the University of Oxford in 1937. He was the first to describe the routinely placing of the tip of his newly re-designed laryngoscope in the epiglottic vallecula which is attached to the base of the tongue, thus when lifted exposed the entire larynx. Macintosh was genuinely astonished at what a great view he could achieve with his new blade and technique. The use of barbiturates as an intravenous anesthetic began in 1932. Sodium thiopental gained popularity after its use was described in detail by a Dr. John Lundy (1894-1973) of the Mayo Clinic. Other I.V. medications were tried over the past seventy years, but the newest induction drug which provided for a substantially shorter recovery period and seemed to actually suppress laryngeal reflexes has brought with it many benefits. Propofol, introduced clinically in 1977, demonstrated many positive effects even as an anti-emetic compound. Before October of 1846, surgery and pain were synonymous but not thereafter. As we entered the information age where the infrastructure of evidence based medicine and newer fields of genetics, transplantation, imaging radiology and even stem cells became quickly integrated into mainstream medicine, we can predict an excellent future on the progress to be made in anesthesia.
No preview · Article · Jun 2012 · Journal of Investigative Surgery
[Show abstract][Hide abstract] ABSTRACT: Allopurinol as an effective inhibitor of the enzyme xanthine oxidase (XO) has been used for several decades for the treatment of patients with gout and hyperuricemia. Because the inhibition of XO limits the formation of radical oxygen species as well as uric acid (UA) production, allopurinol has been used experimentally for the treatment of conditions associated with ischemia and reperfusion (I/R) injury.Although there have been many ischemic organs treated in the laboratory with allopurinol, the heart has been of particular interest. Therefore, we emphasize our attention to the administration of XO inhibitors such as allopurinol on cardiac I/R as well as cardiac failure. Experimental data also support allopurinol as a possible consideration for biochemical support after acute myocardial infarction. Anker and associates (Circulation. 2003;107:1991-1997) have observed a direct correlation between uric acid levels and mortality in treated heart failure patients. Anker and associates showed a 100% mortality rate in patients with UA levels 800 micromol/L or less over a period of 3 years. Comparing this to a 27% mortality rate in patients with UA levels 400 micromol/L or less over a period of 10 years, it seems that the suppression of XO activity ameliorates myocardial inefficiency, and poor vascular flow may present innovative contributions to the future treatment of I/R heart failure patients. Our review focuses on the role of allopurinol on ischemic hearts as well as those with added chronic heart failure.
No preview · Article · Sep 2009 · Journal of Investigative Medicine
[Show abstract][Hide abstract] ABSTRACT: The signal transduction of mitogen-activated protein kinases (MAPKs) has appeared to be an important mediator of ischemic-related events. Because of this, we analyzed the participation of p38 and JNK in liver ischemia and reperfusion, as two individual members of the MAPK family of proteins.
All papers referred to in PubMed for the past 15 years were analyzed to determine how and when these MAPKs were considered to be an intricate part of the ischemic event. References were cross-studied to ascertain whether other papers could be found in the literature.
The role of p38 and JNK in liver ischemia was confirmed in the literature. The activation of these mediators was associated with the induction of apoptosis and necrosis. Inhibitors of p38 and JNK reduced the liver ischemia and reperfusion damage, probably through the mechanisms mentioned before.
The development of effective inhibitors of p38 and JNK protein mediators is important for minimizing the harmful effects associated with liver ischemia and reperfusion.
No preview · Article · Sep 2009 · Journal of Hepato-Biliary-Pancreatic Surgery
[Show abstract][Hide abstract] ABSTRACT: John Collins Warren (1778-1856) represented the apex of surgery and medicine of the first half of nineteenth century Boston. Educated at Harvard College where he obtained a Bachelor of Arts in 1797, he contemplated the idea of a business career prior to setting sail for a traditional medical education at Europe's finest universities. From 1799 to 1802, he attended prestigious medical and surgical lectures in London, Edinburgh, and Paris. Warren received an honorary MD from Scotland's St. Andrews University in 1802. He then returned to Boston and joined his father's practice. In 1815, he followed his accomplished father as the Hersey Professor of Anatomy and Surgery at Harvard Medical School. He held this position with great distinction until 1847 when he retired as professor emeritus. From 1816 to 1819 he served as Harvard Medical School dean and received an honorary medical degree at the end of his term.John Collins Warren had numerous surgical accomplishments during his illustrious career. Clinically, he was active and varied in his practice, operating on strangulated hernias, tumors, and cataracts, in addition to performing vascular surgery and amputations. He published many articles and books of widespread circulation. Professor Warren also performed the first reported case of ether anesthesia administered by William T. Morton on October 16, 1846. Outside the operating theatre, Doctor Warren and his colleagues were revered for founding the Massachusetts General Hospital in 1821, and years before, in 1812, Warren and his associates established the New England Journal of Medicine and Surgery. In light of his varied contributions, John Collins Warren is remembered as a dedicated and innovative surgeon, as well as a committed medical educator, able administrator and effective leader.
No preview · Article · Nov 2006 · Journal of Investigative Surgery
[Show abstract][Hide abstract] ABSTRACT: Liver ischemia and reperfusion injury is associated with activation of multiple inflammatory pathways, including free radicals, cytokines, and neutrophil-mediated tissue damage among others. Tacrolimus (FK506) has shown important regulatory effects on some inflammatory pathways, such as cytokines, neutrophils, and adhesion molecules. In this study, we explored a new potential protective mechanism for tacrolimus in the liver inflammatory response after ischemia and reperfusion, specifically its effect on liver tissue free radicals.
Total hepatic ischemia was produced in the rat for 90 min with an extracorporeal portosystemic shunt. Animals (n=96) were divided into four groups: group 1 comprised normal rats for reference values; group 2 comprised sham operated rats; in group 3, ischemic control rats received only the vehicle; and the experimental treatment group, group 4, received tacrolimus at a dose of 0.3 mg/kg, 4 hr before ischemia. Animal survival was followed up to 7 days. Liver function tests were performed and liver tissue free radicals and myeloperoxidase, serum cytokines (interleukin 1, tumor necrosis factor-alpha), and liver histology were measured 4 hr after reperfusion.
Seven-day survival was significantly improved from only 20% in the control group to 55% in the tacrolimus group (P<0.01). Liver function tests, histology, and myeloperoxidase tissue values were significantly improved (P<0.05) with tacrolimus pretreatment. Furthermore, a significant (P<0.05) down-regulation of serum cytokines and liver tissue free radicals was observed.
These data indicate a new and different protective mechanism for FK506 in regard to its ability to down-regulate free radical levels in livers subjected to severe ischemia and reperfusion. Tacrolimus, also confirmed to be a potent suppressor of the cytokine response, specifically interleukin 1 and tumor necrosis, decreased neutrophil tissue migration as well.
[Show abstract][Hide abstract] ABSTRACT: Background. Successful blockade of p-selectin has been demonstrated to protect organs from the neutrophil-dependent injury seen in ischemia/reperfusion. However, its possible role in the regulation of other inflammatory mediators has not been thoroughly studied. Thus, the purpose of this study was to determine the effect of P-selectin on the response of tissue free-radicals and serum cytokines after liver ischemia/reperfusion, in addition to its well known blockade of neutrophil migration. Material and methods. Total hepatic ischemia was produced in the rat for 90 minutes using an extracorporeal portosystemic shunt. The animals (n = 122) were divided into four groups including normal rats for reference values (group 1), sham-operated rats (group 2), ischemic control rats that received only the vehicle (group 3) and rats treated with PB1.3. a monoclonal antibody against P-selectin, at a dose of 1 mg/kg body wt i.v., 30 minutes before reperfusion (group 4). Animal survival was followed up to day 7 and liver function tests, determination of liver tissue free radicals and myeloperoxidase (MPO), assessment of serum cytokines (interleukin 1 and tumor necrosis factor) and liver histology were performed four hours after reperfusion. Results. Seven-day survival was significantly improved from only 20% in the control group to 65% in the PB1.3-treated group (p < 0.01). Liver function tests, histology and MPO tissue values were also significantly improved by treatment (p < 0.05). Furthermore, a significant downregulation of liver tissue free radicals was observed with the administration of PB1.3. Surprisingly, the anti-P-selectin monoclonal antibody did not significantly affect serum cytokine levels in comparison to controls. Conclusion. This data supports the existence of a protective mechanism for monoclonal antibody PB1.3 characterized by its ability to down regulate free radical levels in livers subjected to severe ischemia and reperfusion. As expected, the role of PB1.3 as a potent inhibitor of tissue neutrophil migration was confirmed, although the antibody did not affect the response of interleukin 1 or tumor necrosis factor to ischemia/reperfusion.
[Show abstract][Hide abstract] ABSTRACT: 21-Aminosteroids are antioxidant compounds that prevent iron-dependent lipid peroxidation and improve cell viability. In this work we attempt to define the role of 21-aminosteroids in liver ischemia and reperfusion and assess their possible mode of action, specifically their effect on neutrophil infiltration and nitrite/nitrate levels. Total liver ischemia for 90 min was produced in the rat with the use of a portosystemic shunt. Three groups of animals were studied. One group received the 21-aminosteroid U-74389G (10 mg/kg) divided into two equal doses 10 min prior to ischemia (7 mg/kg) and 10 min before reperfusion (3 mg/kg). The two other groups included the sham and the control animals. We studied survival at 7 days and serum liver enzymes, liver myeloperoxidase, plasma nitrites, nitrates, and liver histology at 6 hr postreperfusion. Animal survival improved from 13% in the ischemic control to 52% in the lazaroid treated group (P< 0.05). We observed significant improvements in liver function tests, liver myeloperoxidase levels, as well as in the liver histology (P< 0.05). We could not find statistical difference in plasma nitrite/nitrate (P> 0.1). The 21-aminosteroids significantly improved animal survival after total liver ischemia, through a mechanism that includes blocking neutrophil infiltration which is independent from nitrite/nitrate levels.
No preview · Article · Dec 1996 · Journal of Surgical Research
[Show abstract][Hide abstract] ABSTRACT: 21-Aminosteroids are antioxidant compounds that prevent iron-dependent lipid peroxidation and improve cell viability. In this work we attempt to define the role of 21-aminosteroids in liver ischemia and reperfusion and assess their possible mode of action, specifically their effect on neutrophil infiltration and nitrite/nitrate levels. Total liver ischemia for 90 min was produced in the rat with the use of a portosystemic shunt. Three groups of animals were studied. One group received the 21-aminosteroid U-74389G (10 mg/ kg) divided into two equal doses 10 min prior to ischemia (7 mg/kg) and 10 min before reperfusion (3 mg/ kg). The two other groups included the sham and the control animals. We studied survival at 7 days and serum liver enzymes, liver myeloperoxidase, plasma nitrites, nitrates, and liver histology at 6 hr postreperfusion. Animal survival improved from 13% in the ischemic control to 52% in the lazaroid treated group (P < 0.05). We observed significant improvements in liver function tests, liver myeloperoxidase levels, as well as in the liver histology (P < 0.05). We could not find statistical difference in plasma nitrite/nitrate (P > 0.1). The 21-aminosteroids significantly improved animal survival after total liver ischemia, through a mechanism that includes blocking neutrophil infiltration which is independent from nitrite/nitrate levels.
No preview · Article · Dec 1996 · Journal of Surgical Research
[Show abstract][Hide abstract] ABSTRACT: This work studies the role that nitric oxide (NO) plays in ischemia/reperfusion (I/R) of the rat kidney. Sprague-Dawley rats, weighing 250-300 g, were subjected to 75 min of warm ischemia and contralateral nephrectomy. The animals were divided into six groups (n = 12 per group): ischemic control (IC) with normal saline, L-NG-mono-methyl-arginine (L-NMMA) 50 mg/kg, L-arginine (L-Arg) 300 mg/kg, Na-nitroprusside (Na-NP) 2.5 mg/kg, the combination of L-NMMA+Na-NP at the doses used before, and the sham group. All animals received the drug intravenously 60 min prior to ischemia. Survival was evaluated at seven days. Renal damage was assessed by kidney function tests (serum creatinine and blood urea nitrogen) and light histology. Lipid peroxidation was measured in renal tissue using the thiobarbituric acid assay. Significantly better survival was seen in the Na-NP group, as compared to the rest of the study. Serum creatinine at 24 and 48 hr showed a significant difference between the Na-NP group and the other groups. Histological damage was minimal in the Na-NP group. Clearly, the Na-NP had the most beneficial effect in survival and histological structure. Lipid peroxidation was significantly different, with the lower levels seen in the L-NMMA group and the higher levels in the Na-NP group. In base to these results, we conclude that exogenous NO has a beneficial and protective effect of the ischemically damaged rat kidney. This protection is independent of lipid peroxidation. Endogenous NO production does not play a role in I/R injury in our model.
No preview · Article · Nov 1994 · Circulatory shock
[Show abstract][Hide abstract] ABSTRACT: 1954 marked the most important year for modern transplantation. It represented the date in which the first successful live kidney transplant was performed by the devoted group of Joseph Murray, Hartwell Harrison, and their Peter Bent Brigham associates in Boston. Intense preparation and careful analysis was required for a long time to arrive at the resounding success manifested in the case of the Herrick twin brothers. Years later, only the discovery of chemical immunosuppression such as azathioprine and the use of radiation therapy permitted occasional good results in kidney transplantation. Great contributors of this period included Elion and Hitchings, Calne and Zukowski, Woodruff, Goodwin, and many others. In a few more years, the use of steroids and an antilymphocyte preparation by the committed team of Tom Starzl from Colorado improved the opportunities for patient outcome. The latter part of the 1960s witnessed the maturation of the Minnesota program with the arrival of John Najarian from California. The 1970s introduced different morbidity and mortality associated with immunosuppressive treatment, and required adjustments in patient management were necessary. New advances were to come in years ahead.
No preview · Article · · Journal of Investigative Surgery