Biomedical subjects

Thiruma V Arumugam

Publications and source records attributed to Thiruma V Arumugam.

18 recordsLinked to original sources

PubMed2006

Complement mediators in ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (I/R) injury occurs when a tissue is temporarily deprived of blood supply and the return of the blood supply triggers an intense inflammatory response. Pathologically, increased complement activity can cause substantial damage to blood vessels, tissues and also facilitate leukocyte activation and recruitment following I/R injury. Herein, previously published studies are reported and critically reviewed. METHODS: Medline and the World Wide Web were searched and the relevant literature was classified under the following categories: (1) Complement pathways; (2) The complement system and the inflammatory response; (3) Complement in ischemia-reperfusion injuries; and (4) Therapeutic approaches against complement in I/R injuries. RESULTS AND CONCLUSIONS: I/R injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient and is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. Complement activation leads to the release of biologically active potent inflammatory complement substances including the anaphylatoxins (C3a and C5a) and the cytolytic terminal membrane attack complement complex C5b-9 (MAC). The use of specific complement inhibitors to block complement activation at various levels of the cascade has been shown to prevent or reduce local tissue injury after I/R. Several agents that inhibit all or part of the complement system, such as soluble complement receptor type 1 (sCR1), C1 inhibitor (C1-INH), C5a monoclonal antibodies, a C5a receptor antagonist and soluble CD59 (sCD59) have been shown to reduce I/R injury of various organs. The novel inhibitors of complement products may eventually find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

Animals↗

PubMed2006

Hormesis/preconditioning mechanisms, the nervous system and aging.

Throughout life, organisms and their cells are subjected to various stressors which they must respond to adaptively in order to avoid disease and death. Accordingly, cells possess a variety of stress-responsive signaling pathways that are coupled to kinase cascades and transcription factors that induce the expression of genes that encode cytoprotective proteins such as protein chaperones (PC), growth factors and antioxidant enzymes. Emerging findings suggest that many of the environmental factors that improve health and so prolong lifespan (for example, dietary restriction, exercise and cognitive stimulation) exert their beneficial effects through a hormesis-like mechanism. Here we describe data supporting the hormesis hypothesis of disease resistance and longevity, with a focus on findings from studies of the nervous system in this laboratory.

Adaptation, Physiological↗

PubMed2006

Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke.

Mice transgenic for antisense Notch and normal mice treated with inhibitors of the Notch-activating enzyme gamma-secretase showed reduced damage to brain cells and improved functional outcome in a model of focal ischemic stroke. Notch endangers neurons by modulating pathways that increase their vulnerability to apoptosis, and by activating microglial cells and stimulating the infiltration of proinflammatory leukocytes. These findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.

Amyloid Precursor Protein Secretases↗

PubMed2006

Role of T lymphocytes and interferon-gamma in ischemic stroke.

BACKGROUND: Although lymphocyte recruitment and activation are associated with cerebral ischemia-reperfusion (I/R) injury, the contributions of specific lymphocyte subpopulations and lymphocyte-derived interferon-gamma (IFN-gamma) to stroke remain unknown. The objectives of this study were to define the contribution of specific populations of lymphocytes to the inflammatory and prothrombogenic responses elicited in the cerebral microvasculature by I/R and to investigate the role of T-cell-associated IFN-gamma in the pathogenesis of ischemic stroke. METHODS AND RESULTS: Middle cerebral artery occlusion was induced for 1 hour (followed by 4 or 24 hours of reperfusion) in wild-type mice and mice deficient in lymphocytes (Rag1(-/-)), CD4+ T cells, CD8+ T cells, B cells, or IFN-gamma. Platelet and leukocyte adhesion was assessed in cortical venules with intravital video microscopy. Neurological deficit and infarct volume were determined 24 hours after reperfusion. Rag1(-/-), CD4+ T-cell(-/-), CD8+ T-cell(-/-), and IFN-gamma(-/-) mice exhibited comparable significant reductions in I/R-induced leukocyte and platelet adhesion compared with wild-type mice exposed to I/R. Infarct volume was reduced and I/R-induced neurological deficit was improved in immunodeficient Rag1(-/-) mice. These protective responses were reversed in Rag1(-/-) mice reconstituted with either wild-type or, to a lesser extent, IFN-gamma(-/-) splenocytes. B-cell-deficient mice failed to show improvement against ischemic stroke injury. CONCLUSIONS: These findings indicate that CD4+ and CD8+ T lymphocytes, but not B lymphocytes, contribute to the inflammatory and thrombogenic responses, brain injury, and neurological deficit associated with experimental stroke. Although IFN-gamma plays a pivotal role in stroke-induced inflammatory responses, T lymphocytes appear to be a minor source of this cytokine.

Animals↗

PubMed2005

CD40/CD40 ligand signaling in mouse cerebral microvasculature after focal ischemia/reperfusion.

BACKGROUND: CD40/CD40 ligand (CD40L) signaling contributes to proinflammatory and prothrombogenic responses in the vasculature. CD40/CD40L expression is elevated in patients after a transient ischemic attack or stroke. The purpose of this study was to investigate the role of CD40/CD40L signaling in cerebral microvascular dysfunction and tissue injury response to middle cerebral artery occlusion (MCAO) and reperfusion. METHODS AND RESULTS: Intravital fluorescence microscopy was used to visualize the cerebral microcirculation of wild-type (WT), CD40-deficient, and CD40L-deficient mice subjected to 1-hour MCAO and 4-hour reperfusion. The adhesion of platelets and of leukocytes and vascular permeability were measured in postcapillary venules after 4-hour and 1-hour reperfusions, respectively. Cerebral infarct volume was analyzed 24 hours after reperfusion. Platelet and leukocyte adhesion was elevated and blood/brain barrier function was compromised by MCAO in WT mice. Blood cell recruitment and increased permeability were blunted in both CD40-deficient and CD40L-deficient mice. Infarct volume was also reduced in CD40- and CD40L-deficient mice compared with WT mice. CONCLUSIONS: Our findings indicate that CD40/CD40L signaling contributes to inflammatory and prothrombogenic responses and brain infarction induced by MCAO and reperfusion. The CD40/CD40L dyad may play a significant pathogenic role in the acute phase of ischemic stroke.

Animals↗

PubMed2005

A potent and selective inhibitor of group IIa secretory phospholipase A2 protects rats from TNBS-induced colitis.

Secretory phospholipase A(2) (sPLA(2)) enzymes have been implicated in the pathogenesis of human inflammatory bowel disease (IBD). In this study we compared the efficacy of a potent, new and highly selective inhibitor of group IIa human sPLA(2) enzyme (5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)-pentanoic acid; sPLA(2)I), with that of sulfasalazine, in a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Following a single oral dose of sPLA(2)I (5 mg/kg), pharmacoactive levels of drug were detected in the serum within 15 min and for up to 24 h by liquid chromatography mass spectrometry analysis. Rats treated with sPLA(2)I (5 mg/kg/day) prior to induction of colitis were significantly healthier than TNBS-alone rats, as shown by reduced mortality, improved food intake and increased body weight, and significantly reduced colon myeloperoxidase levels, edema, tumour necrosis factor-alpha levels, and colon macroscopic pathology scores after 8 days. Rats pretreated with sulfasalazine (100 mg/kg/day) also had reduced disease expression markers similar to the sPLA(2)I, but exhibited no improvement in colon edema. This study supports a role for the group IIa sPLA(2) enzyme in pathology associated with the TNBS rat model of IBD, and suggests a possible therapeutic application for selective inhibitors of group IIa sPLA(2) inhibitors in the treatment of IBD.

Animals↗

PubMed2005

Stroke and T-cells.

The microvasculature of the brain region affected by a stroke assumes an inflammatory phenotype that is characterized by endothelial cell activation and barrier dysfunction and the recruitment of adherent leukocytes. Although most attention has been devoted to the possible role of neutrophils in the tissue responses to ischemic stroke there is evidence that T-lymphocytes also accumulate in the postischemic brain. Although comparable detailed analyses of lymphocyte involvement in ischemic brain injury have not been performed, emerging findings suggest a role for T-cells in the pathogenesis of ischemic stroke. The recruitment of T-cells to the site of brain injury is critically dependent on the coordinated expression of adhesion molecules on the activated capillary endothelium. Whether the recruited lymphocytes are acting directly on brain tissue or indirectly through activation of other circulating blood cells and/or extravascular cells remain unclear. Cytotoxic CD8+ T-cells may induce brain injury through molecules released from their cytotoxic granules. CD4+ T-helper 1 (TH1) cells, which secrete proinflammatory cytokines, including interleukin-2 (IL-2), IL-12, interferon-gamma, and tumor necrosis factor-alpha, may play a key role in the pathogenesis of stroke, whereas CD4+TH2 cells may play a protective role through anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13. T-cells should be considered as therapeutic targets for ischemic stroke. However, because infection is a leading cause of mortality in the postacute phase of ischemic stroke, and considering anti-inflammatory role of CD4+TH2, treatment targeting T-cells should be carefully designed to reduce deleterious and enhance protective actions of T-cells.

Brain↗

PubMed2004

Contributions of LFA-1 and Mac-1 to brain injury and microvascular dysfunction induced by transient middle cerebral artery occlusion.

Although the beta2-integrins have been implicated in the pathogenesis of cerebral ischemia-reperfusion (I/R) injury, the relative contributions of the alpha-subunits to the pathogenesis of ischemic stroke remains unclear. The objective of this study was to determine whether and how genetic deficiency of either lymphocyte function-associated antigen-1 (LFA-1) or macrophage-1 (Mac-1) alters the blood cell-endothelial cell interactions, tissue injury, and organ dysfunction in the mouse brain exposed to focal I/R. Middle cerebral artery occlusion was induced for 1 h (followed by either 4 or 24 h of reperfusion) in wild-type mice and in mice with null mutations for either LFA-1 or Mac-1. Neurological deficit and infarct volume were monitored for 24 h after reperfusion. Platelet- and leukocyte-vessel wall adhesive interactions were monitored in cortical venules by intravital microscopy. Mice with null mutations for LFA-1 or Mac-1 exhibited significant reductions in infarct volume. This was associated with a significant improvement in the I/R-induced neurological deficit. Leukocyte adhesion in cerebral venules did not differ between wild-type and mutant mice at 4 h after reperfusion. However, after 24 h of reperfusion, leukocyte adhesion was reduced in both LFA-1- and Mac-1-deficient mice compared with their wild-type counterparts. Platelet adhesion was also reduced at both 4 and 24 h after reperfusion in the LFA-1- and Mac-1-deficient mice. These findings indicate that both alpha-subunits of the beta2-integrins contribute to the brain injury and blood cell-vessel wall interactions that are associated with transient focal cerebral ischemia.

Animals↗

PubMed2004

Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury.

1. Complement activation is implicated in the pathogenesis of intestinal ischaemia-reperfusion injury (I/R), although the relative importance of individual complement components is unclear. A C3a receptor antagonist N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine (C3aRA) has been compared with a C5a receptor antagonist (C5aRA), AcF-[OPdChaWR], in a rat model of intestinal I/R. 2. C3aRA (IC(50)=0.15 microm) and C5aRA (IC(50)=0.32 microm) bound selectively to human polymorphonuclear leukocyte (PMN) C3a and C5a receptors, respectively. Effects on circulating neutrophils and blood pressure in the rat were also assessed. 3. Anaesthetised rats, subjected to intestinal ischaemia (30 min) and reperfusion (120 min), were administered intravenously with either (A) the C3aRA (0.1-1.0 mg x kg(-1)); the C5aRA (1.0 mg x kg(-1)); the C3aRA+C5aRA (each 1.0 mg x kg(-1)); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg x kg(-1)) or vehicle, 120 min prior to reperfusion. 4. The C3aRA and C5aRA, administered 45 min prior to reperfusion, displayed similar efficacies at ameliorating several disease markers (increased oedema, elevated ALT levels and mucosal damage) of rat intestinal I/R. The combination drug treatment did not result in greater injury reduction than either antagonist alone. However, doses of the C3aRA (0.01-10 mg x kg(-1)) caused transient neutropaenia, and the highest dose (10 mg x kg(-1)) also caused a rapid and transient hypertension. 5. The C3aRA (1.0 mg x kg(-1)), delivered 120 min prior to reperfusion to remove the global effect of C3aRA-induced neutrophil sequestration, did not attenuate the markers of intestinal I/R, despite persistent C3aR antagonism at this time. 6. C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA in intestinal I/R in the rat. Instead, C3aRA-mediated global neutrophil tissue sequestration during ischaemia and early reperfusion may account for the protective effects observed.

Alanine Transaminase↗

PubMed2004

Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats.

BACKGROUND/AIMS: Complement activation is induced by ischaemia-reperfusion (I/R) and the complement factor C5a plays an important role in organ specific I/R injuries. This study investigated the efficacy of a small molecule C5a receptor (C5aR) antagonist against hepatic I/R injury. METHODS: Total hepatic ischaemia or partial hepatic ischaemia were induced in rats, followed by a period of reperfusion. The C5aR antagonist, AcF-[OPdChaWR], was administered at 1 mg/kg i.v. or 10 mg/kg p.o. or s.c. before induction of ischaemia. Total hepatic I/R-induced mortality was measured and partial hepatic ischaemia injury was assessed by measuring the serum levels of liver enzymes, tissue or serum TNFalpha, liver and lung myeloperoxidase activity, the number of infiltrating neutrophils, neutrophilia and liver histopathology. RESULTS: C5aR antagonist treatment reduced total hepatic I/R-induced mortality. In partial hepatic I/R rats, treatment with the C5aR antagonist significantly attenuated the increases in liver enzymes, serum and tissue TNFalpha, myeloperoxidase activity, infiltrating neutrophils, neutrophilia, and also reduced liver histopathology. CONCLUSIONS: This study shows that an orally active, small molecule C5aR antagonist is effective in reducing the markers of tissue damage caused by I/R in the rat, suggesting an important role for C5a in I/R injuries in the liver.

Alanine Transaminase↗

PubMed2004

Protective effects of a potent C5a receptor antagonist on experimental acute limb ischemia-reperfusion in rats.

OBJECTIVES: The capacity of a potent C5a receptor antagonist to inhibit various parameters of local and remote organ injury following lower limb ischemia-reperfusion (I/R) in rats was investigated. METHODS: Rats were subjected to 2 h bilateral hindlimb ischemia and 4 h reperfusion. Drug-treated rats received AcF-[OPdChaWR] (1 mg/kg) iv either 10 min before ischemia or 10 min prior to reperfusion, or orally (10 mg/kg) 30 min prior to ischemia. Levels of circulating creatine kinase (CK), lactate dehydrogenase (LDH), alanine and aspartate aminotransferase (ALT/AST), creatinine, blood urea nitrogen (BUN), polymorphonuclear leukocytes (PMNs), and calcium (Ca(++)) and potassium (K(+)) ions were determined. Other parameters measured included urinary protein levels, muscle edema, and myeloperoxidase (MPO) concentrations in the lung, liver, and muscle along with liver homogenate tumor necrosis factor-alpha (TNF-alpha) concentrations.L RESULTS: imb I/R injury was characterized by significant elevations of CK, LDH, ALT, AST, creatinine, BUN, proteinuria, PMNs, serum K(+), muscle edema, organ MPO, and liver homogenate TNF-alpha concentrations, but a significant reduction in serum Ca(2+) concentrations. When rats were treated with AcF-[OPdChaWR], there were significant improvements in all these parameters. CONCLUSIONS: These results indicate a pivotal role for C5a in inducing local and remote organ injury and suggest a possible new drug therapeutic category for preventing anticipated tissue injury associated with I/R.

Acute Disease↗

PubMed2004

The role of the complement system in ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient. Interruption of blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury. I/R is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. The use of specific inhibitors to block complement activation has been shown to prevent local tissue injury after I/R. Clinical and experimental studies in gut, kidney, limb, and liver have shown that I/R results in local activation of the complement system and leads to the production of the complement factors C3a, C5a, and the membrane attack complex. The novel inhibitors of complement products may find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

Animals↗

PubMed2004

Platelet-leukocyte-endothelial cell interactions after middle cerebral artery occlusion and reperfusion.

The adhesion of both leukocytes and platelets to microvascular endothelial cells has been implicated in the pathogenesis of ischemia/reperfusion (I/R) injury in several vascular beds. The objectives of this study were to (1) assess the platelet-leukocyte-endothelial cell interactions induced in the cerebral microvasculature by middle cerebral artery occlusion (MCAO)/reperfusion, and (2) define the molecular determinants of the prothrombogenic and inflammatory responses in this model of focal I/R. MCAO was induced for 1 hour in wild-type (WT) mice, WT mice treated with a monoclonal antibody (mAb) to either P-selectin or GPIIb/IIIa, and in P-selectin-/-(P-sel-/-) chimeras. Isolated platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) were administered intravenously and observed with intravital fluorescence microscopy. Leukocytes were observed after intravenous injection of rhodamine 6G. One hour of MCAO followed by 1 hour of reperfusion resulted in the rolling and adhesion of leukocytes in venules, and after 4 hours of reperfusion, the adhesion of both leukocytes and platelets was detected. Although both the P-selectin and GPIIb/IIIa mAbs significantly reduced the adhesion of leukocytes and platelets at 4 hours of reperfusion, the antiadhesive effects of the P-selectin mAb were much greater. The leukocyte and platelet adhesion responses were significantly attenuated in both P-sel-/- --> WT and WT --> P-sel-/- bone marrow chimeras, compared with WT --> WT chimeras. Neutropenia, induced by antineutrophil serum treatment, also reduced the recruitment of leukocytes and platelets after cerebral I/R. These findings implicate a major role for both platelet-associated and endothelial cell-associated P-selectin, as well as neutrophils in the inflammatory and prothrombogenic responses in the microcirculation after focal cerebral I/R.

Animals↗

PubMed2003

A potent human C5a receptor antagonist protects against disease pathology in a rat model of inflammatory bowel disease.

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

Animals↗

PubMed2003

Comparative protection against rat intestinal reperfusion injury by a new inhibitor of sPLA2, COX-1 and COX-2 selective inhibitors, and an LTC4 receptor antagonist.

(1) A new group IIa sPLA2 inhibitor was compared with selective inhibitors of COX-1, COX-2 and an LTC4 antagonist for effects on local and remote tissue injuries following ischaemia and reperfusion (I/R) of the small intestine in rats. (2) In an acute model of ischaemia (30 min) and reperfusion (150 min) injury in the absence of inhibitors, there was significant intestinal haemorrhage, oedema and mucosal damage, neutropenia, elevated serum levels of aspartate aminotransferase (AST) and hypotension. (3) Preischaemic treatment with the inhibitor of sPLA2 (Group IIa), at 5 mg kg-1 i.v. or 10 mg kg-1 p.o. significantly inhibited I/R-induced neutropenia, the elevation of serum levels of AST, intestinal oedema and hypotension. (4) Pretreatment with the COX-2 inhibitor celebrex (10 mg kg-1 i.v.) and the LTC4 antagonist zafirlukast (1 mg kg-1 i.v.) also showed marked improvement with I/R-induced AST, oedema and neutropenia. Hypotension was only reduced by the LTC4 antagonist. The COX-1 inhibitor flunixin (1 mg kg-1 i.v.) did not effect improvement in the markers of tissue injury. (5) Histological examination of rat I/R injury showed that all of the drugs offered some protection to the mucosal layer damage compared to no drug treatment. Given i.v., the sPLA2 inhibitor was more effective than either the COX-1 or COX-2 inhibitors in preventing rat I/R injury. (6) These results indicate that a potent new inhibitor of sPLA2 (group IIa) protects the rat small intestine from I/R injury after oral or intravenous administration. COX-2 and LTC4 inhibitors also showed some beneficial effects against intestinal I/R injury. Our study suggests that sPLA2 (Group IIa) may have a pathogenic role in intestinal I/R in rats.

Animals↗

PubMed2003

A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats.

BACKGROUND: C5a has been implicated in numerous pathophysiological conditions, including ischemia/reperfusion (I/R) injury of the kidney. We examined whether a novel and specific C5a receptor antagonist, the cyclic compound AcF-[OPdChaWR] could moderate I/R-induced renal injury in rats. METHODS: Female Wistar rats were subjected to renal ischemia (60 min) and reperfusion (5 h). Rats were treated with either 1 mg/kg IV in 5% ethanol/saline or 10 mg/kg PO in 25% ethanol/saline prior to ischemia. I/R injury was characterized by significant tissue hemorrhage with increased microvascular permeability, elevated renal tissue levels of tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO), increased serum levels of creatinine and aspartate aminotransferase (AST) and hematuria. RESULTS: Pre-ischemic treatment with the C5a receptor (C5aR) antagonist (1 mg/kg IV or 10 mg/kg PO) substantially inhibited or prevented I/R-induced hematuria, vascular leakage, tissue levels of TNF-alpha and MPO, and serum levels of AST and creatinine. Histological examination of kidneys from antagonist pretreated I/R animals showed a marked reduction in tissue damage compared to drug-free I/R rats. This antagonist, however, did not inhibit complement-mediated lysis of red blood cells, suggesting unimpaired formation of the membrane attack complex (MAC). CONCLUSIONS: The results demonstrate for the first time that a selective antagonist of both human and rat C5a receptors, given either intravenously or orally, significantly protects the kidney from I/R injury in the rat. We conclude that C5a is an important pathogenic agent in renal I/R injury, and that C5a receptor antagonists may be useful therapeutic agents for the pretreatment of anticipated renal reperfusion injury in humans.

Animals↗

PubMed2002

Protective effect of a new C5a receptor antagonist against ischemia-reperfusion injury in the rat small intestine.

BACKGROUND: The complement system is a major contributor to the pathogenesis of intestinal ischemia-reperfusion (I/R) injury. We have studied the action of an orally active complement factor 5a (C5a) receptor antagonist, the cyclic peptide AcF-(OPdChaWR) [Ac-Phe(Orn-Pro-d-cyclohexylalanine-Trp-Arg)] against local and remote intestinal I/R injuries in rats. MATERIALS AND METHODS: Anesthetized rats were administered with AcF-(OPdChaWR) at doses of 1 mg/kg intravenously or 0.3, 1, or 10 mg/kg orally with pyrogen-free saline for sham control animals. The superior mesenteric artery was occluded for 30 min and the intestine reperfused for 120 min. Changes associated with tissue injury were assessed by neutropenia, intestinal edema, serum tumor necrosis factor-alpha, serum haptoglobin, plasma aspartate aminotransferase, and histopathology. RESULTS: Pretreatment with either a single intravenous dose (1 mg/kg), or a single oral dose (10 mg/kg) of AcF-(OPdChaWR) significantly inhibited I/R induced neutropenia, the elevated serum levels of tumor necrosis factor-alpha, haptoglobin, and plasma aspartate aminotransferase, as well as intestinal edema. Histological analysis of AcF-(OPdChaWR)-treated I/R animals showed markedly reduced mucosal layer damage compared to that of untreated rats. CONCLUSIONS: These results indicate that a potent antagonist of C5a receptors on human cells protects the rat small intestine from I/R injury after oral or intravenous administration. Small molecule C5a antagonists may have some therapeutic utility in reperfusion injury.

Animals↗

PubMed2002

Pirfenidone attenuates ischaemia-reperfusion injury in the rat small intestine.

1. Pirfenidone, an antifibrotic compound with anti-inflammatory effects, has been investigated in a rat model of acute experimental ischaemia-reperfusion injury of the small intestine. 2. Occlusion of the superior mesenteric artery in young adult female rats for 30 min followed by reperfusion for 120 min induced significant local and systemic effects, including tissue haemorrhage with oedema, elevated serum concentrations of tumour necrosis factor (TNF)-alpha, neutropenia, hypotension and bradycardia. 3. Administration of pirfenidone (200 mg/kg, p.o., i.v. or i.p.) 30 min before occlusion completely inhibited the increase in serum TNF-alpha concentrations. Pirfenidone inhibited, but did not completely prevent, tissue damage in the small intestine, as well as hypotension and oedema, but neutropenia and bradycardia were not significantly changed by treatment. 4. Thus, pirfenidone effectively moderates both local and some systemic effects of ischaemia-reperfusion injury in the rat small intestine model.

Animals↗