[Show abstract][Hide abstract] ABSTRACT: Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery.
Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network.
Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress.
These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function.
[Show abstract][Hide abstract] ABSTRACT: Immune cell infiltration in (white) adipose tissue (AT) during obesity is associated with the development of insulin resistance. In AT, the main population of leukocytes are macrophages. Macrophages can be classified into two major populations: M1, classically activated macrophages, and M2, alternatively activated macrophages, although recent studies have identified a broad range of macrophage subsets. During obesity, AT M1 macrophage numbers increase and correlate with AT inflammation and insulin resistance. Upon activation, pro-inflammatory M1 macrophages induce aerobic glycolysis. By contrast, in lean humans and mice, the number of M2 macrophages predominates. M2 macrophages secrete anti-inflammatory cytokines and utilize oxidative metabolism to maintain AT homeostasis. Here, we review the immunologic and metabolic functions of AT macrophages and their different facets in obesity and the metabolic syndrome.
Full-text · Article · Jan 2016 · Frontiers in Immunology
[Show abstract][Hide abstract] ABSTRACT: Cachexia affects about 80% of gastrointestinal cancer patients. This multifactorial syndrome resulting in involuntary and continuous weight loss is accompanied by systemic inflammation and immune cell infiltration in various tissues. Understanding the interactions among tumor, immune cells, and peripheral tissues could help attenuating systemic inflammation. Therefore, we investigated inflammation in the subcutaneous adipose tissue and in the tumor, in weight stable and cachectic cancer patients with same diagnosis, in order to establish correlations between tumor microenvironment and secretory pattern with adipose tissue and systemic inflammation. Infiltrating monocyte phenotypes of subcutaneous and tumor vascular-stromal fraction were identified by flow cytometry. Gene and protein expression of inflammatory and chemotactic factors was measured with qRT-PCR and Multiplex Magpix® system, respectively. Subcutaneous vascular-stromal fraction exhibited no differences in regard to macrophage subtypes, while in the tumor, the percentage of M2 macrophages was decreased in the cachectic patients, in comparison to weight-stable counterparts. CCL3, CCL4, and IL-1β expression was higher in the adipose tissue and tumor tissue in the cachectic group. In both tissues, chemotactic factors were positively correlated with IL-1β. Furthermore, positive correlations were found for the content of chemoattractants and cytokines in the tumor and adipose tissue. The results strongly suggest that the crosstalk between the tumor and peripheral tissues is more pronounced in cachectic patients, compared to weight-stable patients with the same tumor diagnosis.
Full-text · Article · Dec 2015 · Frontiers in Immunology
[Show abstract][Hide abstract] ABSTRACT: Background:
Physical exercise induces positive alterations in gene expression involved in the metabolism of obesity. Maternal exercise provokes adaptations soon after birth in the offspring. Here, we investigated whether adult mouse offspring of swim-trained mothers is protected against the development of the deleterious effects of high fat diet (HFD).
Our study comprises two parts. First, female C57BL/6 mice were divided into one sedentary and one swim-trained group (before and during pregnancy, n = 18). In the second part, adult offspring (n = 12) of trained and sedentary mothers was challenged to HFD for 16 weeks. Notably, most of the analysis was done in male offspring.
Our results demonstrate that maternal exercise has several beneficial effects on the mouse offspring and protects them from the deleterious effects of HFD in the adult. Specifically, swimming during pregnancy leads to lower birth weight in offspring through 2 months of age. When subjected to HFD for 4 month in the adulthood, our study presents novel data on the male offspring's metabolism of trained mothers. The offspring gained less weight, which was accompanied by less body fat, and they used more calories during daytime compared with offspring of sedentary mothers. Furthermore, we observed increased adiponectin expression in skeletal muscle, which was accompanied by decreased leptin levels and increased insulin sensitivity. Decreased interleukin-6 expression and increased peptide PYY levels were observed in sera of adult offspring of mothers that swam during pregnancy.
Our results point to the conclusion that maternal exercise is beneficial to protect the offspring from developing obesity, which could be important for succeeding generations as well.
Full-text · Article · Dec 2015 · Nutrition & Metabolism
[Show abstract][Hide abstract] ABSTRACT: Material and methods:
We analyzed data from 136 post-reperfusion biopsies performed in deceased donor renal transplanted patients from November 2008 to May 2012. We analyzed presence of acute tubular necrosis (ATN), arteriolar hyalinosis (AH), intimal thickness (IT), interstitial fibrosis (IF) and glomerulosclerosis (GS). We also analyzed the impact of donor features on the following outcomes: delayed graft function (DGF) and chronic allograft dysfunction defined as eGFR < 60 ml/min at 1 year.
The mean donors age was 41 years, 26% of them were extended criteria donors (ECD), 33% had hypertension and 50% had cerebral vascular accident (CVA) as the cause of death. ATN was present in 87% of these biopsies, AH in 31%, IF in 21%, IT in 27% and GS in 32%. DGF occurred in 80% and chronic allograft dysfunction was presented in 53%. AH was the only histological finding associated with DGF and chronic allograft dysfunction at 1 year. Patients with AH had a lower eGFR at 1 year than patients without it (49.8 ml/min x 64.5 ml/min, p = 0.02). In the multivariate analysis, risk variables for development of chronic graft dysfunction were male sex (odds ratio [OR] = 3.159 [CI: 1.22-8.16]; p = 0.018), acute rejection (OR = 8.91 [CI: 2.21-35.92]; p = 0.002), donor hypertension (OR = 2.94 [CI: 1.10-7.84]; p = 0.031), AH (OR = 3.96 [CI: 1.46-10.70]; p = 0.007) and eGFR at discharge (OR = 0.96 [CI: 0.93-0.98]; p = 0.005). In multivariate analysis, risk factors for AH were donor age > 50 years (OR = 2.46 [CI: 1.10-5.44]; p = 0.027) and CVA as the cause of donor death (OR = 2.33 [CI:1.05-5.15]; p = 0.007).
Presence of AH in post-reperfusion biopsies is a marker of ageing and vascular disease and was associated with DGF and a one year poorer renal function. AH in donor biopsies superimposed to long ischemic time is a predictor of renal function. The management of immunosuppression based on presence of AH in post-reperfusion biopsy could be useful to improve long term graft function. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Macrophages play essential activities in homeostasis maintenance during different organism’s conditions. They may be polarized according to various stimuli, which subsequently subdivide them into distinct populations. Macrophages with inflammatory activity function mainly during pathological context, while those with regulatory activity control inflammation and also remodel the repairing process. Here, we propose to review and to present a concise discuss on the role of different components during tissue repair, including those related to innate immune receptors and metabolic modifications. The scar formation is directly related to the degree of inflammation, but also with the appearance of M2 macrophages. In spite of greater numbers of macrophages in the fibrotic phase, regulatory macrophages present some characteristics related to promotion of fibrosis but also with the control of scar formation. These regulatory macrophages present an oxidative metabolism, and differ from the initial inflammatory macrophages, which in turn, present a glycolytic characteristic, which allow regulatory ones to optimize the oxygen consumption and minimizing their ROS production. We will emphasize the difference in macrophage subpopulations and the origin and plasticity of these cells during fibrotic processes.
Preview · Article · Nov 2015 · Frontiers in Immunology
[Show abstract][Hide abstract] ABSTRACT: Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT) has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA), an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1%) or vehicle (distillated water) during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure). Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.
[Show abstract][Hide abstract] ABSTRACT: Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.
[Show abstract][Hide abstract] ABSTRACT: Aim:
Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis.
Mice were immunized with MOG35-55 and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry.
Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-β mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1β secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells.
Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.
Full-text · Article · Nov 2015 · Inflammopharmacology
[Show abstract][Hide abstract] ABSTRACT: Natural killer (NK) cells have been implicated in graft dysfunction. Here, we formulated hypothesis that distinct patterns of expression NK cells markers correlated with acute rejection in kidney transplantation. Therefore, we studied the pattern of NK cell markers CD56, CD57 and CD16 in different compartments of biopsies obtained from recipients diagnosed with acute graft rejection, with or without donor-specific antibodies (DSA). DSA-negative biopsies-from patients with acute T-cell mediated rejection (aTCMR) had an increased expression of CD56+ and CD57+ cells (P = 0.004 and P < 0.001) in the interstitial compartment in comparison with DSA-positive biopsies from patients acute antibody-mediated rejection (aABMR) with (aABMR C4d+) and without C4d deposition (aABMR C4d-). CD16+ cells was increased (P = 0.03) in the glomerular compartment in DSA-positive biopsies. We assume that CD16+ expression and antibody-dependent cellular cytotoxicity (ADCC) in microvascular injury can be associated with aABMR. IFN-γ release from cytoplasmic granules of NK cell could be associated with aTCMR. Our findings suggest that NK cells need to be carefully evaluated because variations in NK cell marker expression might imply the involvement of different immune system pathways in graft rejection. This article is protected by copyright. All rights reserved.
No preview · Article · Nov 2015 · Transplant International
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoke-induced chronic obstructive pulmonary disease is a very debilitating disease, with a very high prevalence worldwide, which results in a expressive economic and social burden. Therefore, new therapeutic approaches to treat these patients are of unquestionable relevance. The use of mesenchymal stromal cells (MSCs) is an innovative and yet accessible approach for pulmonary acute and chronic diseases, mainly due to its important immunoregulatory, anti-fibrogenic, anti-apoptotic and pro-angiogenic. Besides, the use of adjuvant therapies, whose aim is to boost or synergize with their function should be tested. Low level laser (LLL) therapy is a relatively new and promising approach, with very low cost, no invasiveness and no side effects. Here, we aimed to study the effectiveness of human tube derived MSCs (htMSCs) cell therapy associated with a 30mW/3J-660 nm LLL irradiation in experimental cigarette smoke-induced chronic obstructive pulmonary disease. Thus, C57BL/6 mice were exposed to cigarette smoke for 75 days (twice a day) and all experiments were performed on day 76. Experimental groups receive htMSCS either intraperitoneally or intranasally and/or LLL irradiation either alone or in association. We show that cotherapy greatly reduces lung inflammation, lowering the cellular infiltrate and pro-inflammatory cytokine secretion (IL-1β, IL-6, TNF-α and KC), which were followed by decreased mucus production, collagen accumulation and tissue damage. These findings seemed to be secondary to the reduction of both NF-κB and NF-AT activation in lung tissues with a concomitant increase in IL-10. In summary, our data suggests that the concomitant use of MSCs + LLLT may be a promising therapeutic approach for lung inflammatory diseases as COPD.
[Show abstract][Hide abstract] ABSTRACT: Background:
Severe scorpion envenomation can evolve to lung injury and, in some cases, death. The lung injury could be attributed to acute left ventricular failure and increased pulmonary vascular permeability secondary to the release of inflammatory mediators. In clinical practice, corticosteroids have been administered to reduce the early side effects of the anti-venom. We propose to study the effects of Tityus serrulatus venom and dexamethasone on pulmonary expression of sodium and water transporters, as well as on the inflammatory response.
Wistar rats were injected intraperitoneally with saline (control group), dexamethasone, and saline (2.0 mg/kg body weight-60 min before saline injection; dexamethasone + saline group), venom (T. serrulatus venom-3.8 mg/kg body weight), or dexamethasone and venom (2.0 mg/kg body weight-60 min before venom injection; dexamethasone + venom group). At 60 min after venom/saline injection, experiments were performed in ventilated and non-ventilated animals. We analyzed sodium transporters, water transporters, and Toll-like receptor 4 (TLR4) by Western blotting, macrophage infiltration by immunohistochemistry, and serum interleukin (IL) by cytokine assay.
In the lung tissue of non-ventilated envenomed animals, protein expression of the epithelial sodium channel alpha subunit (α-ENaC) and aquaporin 5 (AQP5) were markedly downregulated whereas that of the Na-K-2Cl cotransporter (NKCC1) and TLR4 was elevated although expression of the Na,K-ATPase alpha 1 subunit was unaffected. Dexamethasone protected protein expression of α-ENaC, NKCC1, and TLR4 but not that of AQP5. We found that IL-6, IL-10, and tumor necrosis factor alpha were elevated in the venom and dexamethasone + venom groups although CD68 expression in lung tissue was elevated only in the venom group. Among the ventilated animals, both envenomed groups presented hypotension at 50 min after injection, and the arterial oxygen tension/fraction of inspired oxygen ratio was lower at 60 min than at baseline.
Our results suggest that T. serrulatus venom and dexamethasone both regulate sodium transport in the lung and that T serrulatus venom regulates sodium transport via the TLR4 pathway.
[Show abstract][Hide abstract] ABSTRACT: Quantitative alterations in mast cell numbers in pancreatic lymph nodes (PLNs) have been reported to be associated with type 1 diabetes (T1D) progression, but theirpotential role during T1D remains unclear. In this study, we evaluated the role of mast cells in T1D induced by multiple low-dose streptozotocin (MLD-STZ) treatments, using two strains of mast cell-deficient mice (W/W(v) or Wsh/Wsh) and the adoptive transfer of mast cells. Mast cell-deficient mice developed severe insulitis and accelerated hyperglycemia, with 100% of mice becoming diabetic compared to their littermates. In parallel, these diabetic mice had decreased numbers of T regulatory (Treg) cells in the PLNs. Additionally, mast cell deficiency caused a significant reduction in IL-10, TGF-β and IL-6 expression in the pancreatic tissue. Interestingly, IL-6-deficient mice are more susceptible to T1D associated with reduced Treg-cell numbers in the PLNs, but mast cell transfer from wild-type mice induced protection to T1D in these mice. Finally, mast cell adoptive transfer prior to MLD-STZ administration conferred resistance to T1D, promoted increased Treg cells and decreased IL-17-producing T cells in the PLNs. Taken together, our results indicate that mast cells are implicated in resistance to STZ-induced T1D via an immunological tolerance mechanism mediated by Treg cells. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Jul 2015 · European Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: Homeostasis of the immune system depends on several factors. The gastrointestinal tract plays an important role in maintaining our immune system. With this aim, the intestinal immune system interacts with epithelial barrier molecules, especially tight junction proteins, that are key molecules involved in controlling paracellular permeability to increase the protection barrier against external antigens or possibly to respond to commensal microorganisms. During intestinal inflammatory diseases, the expression of innate immune receptors in intestinal epithelial cells and infiltration of immune cells are related, but it is still unclear how the immune system induces modulation of paracellular permeability. In this review, we provide an overview of the understanding of how the immune system modulates the expression of tight junctions to maintain the mucosal immune system.
No preview · Article · Jun 2015 · Current Protein and Peptide Science
[Show abstract][Hide abstract] ABSTRACT: Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema.
Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2α and p65-NF-κB in the fixed tissues as well as to evaluate cytokine levels and p65-NF-κB protein expression.
In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-α, IL-1β and M-CSF in the BALF as well as the levels of NF-κB and 8-iso-PGF-2α in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function.
These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema.
Full-text · Article · Jun 2015 · Respiratory research
[Show abstract][Hide abstract] ABSTRACT: NKT cells are a subset of lymphocytes that reacts to glycolipids presented by CD1d. Invariant NKT cells (iNKT) correspond to more than 90% of the total population of NKTs and reacts to α-Galactosylceramide (αGalCer). αGalCer promotes a complex mixture of Th1 and Th2 cytokines, as IFN-γ and IL-4. NKT cells and IFN-γ are known to participate in some models of renal diseases, but further studies are still necessary to elucidate their mechanisms. The aim of our study was to analyze the participation of iNKT cells in an experimental model of tubule-interstitial nephritis. We used 8-week-old C57BL/6j, Jα18KO and IFN-γKO mice. They were fed a 0.25% adenine diet for 10 days. Both adenine-fed WT and Jα18KO mice exhibited renal dysfunction, but adenine-fed Jα18 KO mice presented higher expression of KIM-1, TNF-α and type I collagen. To analyze the role of activated iNKT cells in our model, we administered αGalCer in WT mice during adenine ingestion. After αGalCer injection we observed a significantly reduction in serum creatinine, pro-inflammatory cytokines and renal fibrosis. However, this improvement in renal function was not observed in IFN-γKO mice after αGalCer treatment and adenine feeding, illustrating that this cytokine plays a role in our model. Our findings may suggest that IFN-γ production is one of the factors contributing to improved renal function after αGalCer administration.
Full-text · Article · Jun 2015 · Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The glomerular filtration rate (GFR) is considered an especially important tool for the measurement of renal function. Inulin clearance (InCl) is the classic reference method for this purpose, although it is associated with a number of disadvantages; thus, other markers have been proposed, including iohexol. Determination of iohexol clearance (IoCl) has been established for clinical use; however, its application as a GFR marker in experimental rat models has not been reported.
This study aims to standardize a methodology for the measurement of iohexol clearance and to evaluate its applicability as a marker of GFR in rats with induced toxic acute renal failure (ARF), using InCl as the gold standard.
Materials and methods:
Twenty-six Wistar male rats (200-300 g) were divided into the following two groups: a control group (n=7) and an ARF group (n=19). ARF was induced by the subcutaneous administration of cisplatin (5 mg/kg); IoCl and InCl were determined simultaneously, and plasma creatinine (pCreat) dosage was measured colorimetrically.
The pCreat, InCl and IoCl levels were consistent with the expected values for the renal function ranges of the evaluated animals, and the IoCl and InCl levels were significantly correlated (r=0.792). An inverse moderate linear correlation between the IoCl and pCreat measurements (r=-0.587) and between the InCl and pCreat measurements (r=-0.722) were observed.
These results confirm a correlation between IoCl and the gold standard of GFR, InCl measurement. IoCl offers a relevant advantage over InCl because determination of the former allows the animal to live after the procedure.
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel diseases (IBD) is the result of dysregulation of mucosal innate and adaptive immune responses. Factors such as genetic, microbial and environmental are involved in the development of these disorders. Accordingly, animal models that mimic human diseases are tools for the understanding the immunological processes of the IBD as well as to evaluate new therapeutic strategies. Crotoxin (CTX) is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. Thus, we aimed to evaluate the modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS). The CTX was administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI), macroscopic tissue damage, histopathological score and myeloperoxidase (MPO) activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3) and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the induction of a local anti-inflammatory profile in mice.
[Show abstract][Hide abstract] ABSTRACT: Diabetes and obesity are worldwide health problems. White fat dynamically participates in hormonal and inflammatory regulation. White adipose tissue is recognized as a multifactorial organ that secretes several adipose-derived factors that have been collectively termed " adipokines. " Adipokines are pleiotropic molecules that gather factors such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidin, RBP4, and inflammatory cytokines, including TNF and IL-1í µí»½, among others. Multiple roles in metabolic and inflammatory responses have been assigned to these molecules. Several adipokines contribute to the self-styled " low-grade inflammatory state " of obese and insulin-resistant subjects, inducing the accumulation of metabolic anomalies within these individuals, including autoimmune and inflammatory diseases. Thus, adipokines are an interesting drug target to treat autoimmune diseases, obesity, insulin resistance, and adipose tissue inflammation. The aim of this review is to present an overview of the roles of adipokines in different immune and nonimmune cells, which will contribute to diabetes as well as to adipose tissue inflammation and insulin resistance development. We describe how adipokines regulate inflammation in these diseases and their therapeutic implications. We also survey current attempts to exploit adipokines for clinical applications, which hold potential as novel approaches to drug development in several immune-mediated diseases.
Full-text · Article · Apr 2015 · Journal of Diabetes Research