Biomedical subjects

Ian A Shiels

Publications and source records attributed to Ian A Shiels.

15 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

Complement inhibitors selectively attenuate injury following administration of cobra venom factor to rats.

Systemic activation of complement is a pathophysiological response common to severe disturbances such as hemorrhagic shock, major burn injury and sepsis. Intravenous infusion of cobra venom factor (CVF) has been used as an animal model of acute respiratory distress syndrome (ARDS), and reliably and selectively induces rapid intravascular activation of the complement system, leading to acute organ damage. In the present study, we have used different complement inhibitors to investigate the roles of complement products in CVF-induced responses in the rat. Rats were treated with either a C5a receptor antagonist (C5aRA, AcF-[OP(d-Cha)WR], 1 mg/kg i.v. or 10 mg/kg p.o.), a C3a receptor antagonist (C3aRA, N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine, 0.1 mg/kg i.v.) or a convertase inhibitor, rosmarinic acid (RMA, 10 mg/kg i.v.), prior to CVF-induced complement challenge. Intravenous CVF resulted in hallmark events evident in the development of ARDS, including systemic neutropenia followed by neutrophil migration to the lung and bronchoalveolar vascular leakage, blood pressure alterations, and an increase in TNFalpha levels in both serum and bronchoalveolar lavage fluid. These hemodynamic changes were differentially inhibited by antagonism of C5a receptors, C3a receptors or by inhibition of the entire complement cascade using RMA. This evidence strongly implicates complement factors in the development of lung injury associated with systemic complement activation and identifies complement inhibition as a potential therapeutic target for acute syndromes such as ARDS and other severe systemic shock states mediated by activation of complement.

Administration, Oral↗

PubMed2006

Transdermal pharmacology of small molecule cyclic C5a antagonists.

Overproduction or underregulation of the proinflammatory complement component C5a has been implicated in numerous immune and inflammatory conditions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous animal models of inflammation following intravenous, subcutaneous, intraperitoneal, and oral administration. In the present study the transdermal pharmacology of PMX53 and three analogs designed with increased lipophilicity, hydrocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administration (10 mg/50 cm2 site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (1 mg/kg i.v.). Interestingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (<5 ng/ml) circulating levels following topical administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic effects. However, increasing lipophilicity in these compounds did not result in increased blood levels. Nonetheless, topical application of C5aR antagonists produced circulating levels of the drugs that antagonized the LPS-induced systemic responses of neutropenia and hypotension. This suggests that these small-molecule C5aR antagonists may be developed for topical administration for the treatment of local and systemic inflammatory conditions in the human and veterinary pharmaceutical markets.

Administration, Cutaneous↗

PubMed2006

Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration.

The complement system is thought to be involved in the pathogenesis of numerous neurological diseases, although its precise role remains controversial. In this study we used orally active C5a receptor antagonists (PMX53 and PMX205) developed in our laboratories in a rat model of 3-nitropropionic acid (3-NP) -induced Huntington's disease. Administration of the C5a antagonists (10 mg/kg/day, oral) either 48 h pre- or 48 h post-toxin significantly reduced body weight loss, anorexia, and behavioral and motor deficits associated with 3-NP intoxication. Striatal lesion size, apoptosis, neutrophil infiltration, and hemorrhage were also significantly reduced in C5a antagonist-treated rats. Immunohistochemical analysis demonstrated marked deposition of C3 and C9, and up-regulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF-alpha with ibuprofen or infliximab had no effect in this model. The C5a antagonists did not affect 3-NP-induced cell death when added directly to rat striatal neuronal cultures, indicating a secondary mechanism of action in vivo. Our findings demonstrate for the first time that complement activation in the brain, particularly C5a, is a key event in the pathogenesis of this disease model, and suggest a future role for inhibitors of C5a in the treatment of neurodegenerative diseases.

Animals↗

PubMed2005

Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease.

We have previously shown that complement factor 5a (C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(d-Cha)WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(d-Cha)WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(d-Cha)WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(d-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03-10 mg/kg/day p.o.) in the 8-day rat TNBS-colitis model, against the comparator drug AcF-[OP(d-Cha)WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(d-Cha)WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP(d-Cha)WR], equiactive in vitro to AcF-[OP(d-Cha)WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(d-Cha)WR]. However, in the rat TNBS-colitis model, HC-[OP(d-Cha)WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30-fold lower oral doses than AcF-[OP(d-Cha)WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(d-Cha)WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(d-Cha)WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

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↗

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↗

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

Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat.

OBJECTIVE: To determine if the new, orally active C5a receptor antagonist, the cyclic peptide AcF-[OPdChaWR], reduces the severity of pathology in a rat model of immune-mediated monarticular arthritis. METHODS: Arthritis was induced in the right knee of previously sensitized rats by the intraarticular injection of methylated bovine serum albumin. Rats were examined for either 14 days or 28 days, or for 49 days following a second antigen challenge at 28 days. The C5a antagonist (1 or 3 mg/kg/day) and/or ibuprofen (30 mg/kg/day) were administered orally on a daily basis either before or after arthritis induction. RESULTS: Rats receiving AcF-[OPdChaWR] had significant reductions in right knee swelling, gait disturbance, lavaged joint cell numbers, and right knee histopathology, as well as in serum levels of tumor necrosis factor alpha (TNFalpha) and intraarticular levels of interleukin-6 and TNFalpha on day 14. In the 14- and 28-day studies, ibuprofen resulted in a similar reduction in gait abnormalities and intraarticular inflammatory cells compared with the C5a antagonist, but was less effective in reducing knee swelling over the course of the study and had no effect on knee histopathology. Combination therapy with AcF-[OPdChaWR] and ibuprofen resulted in no greater efficacy than with the C5a antagonist alone. Rats injected twice with the antigen in the 49-day study displayed the most severe histopathology and this, as well as knee swelling and gait abnormalities, was significantly reduced by repeated treatment with the C5a antagonist. CONCLUSION: An agent that inhibits the action of C5a in this model significantly reduced joint pathology, while ibuprofen was not effective. C5a antagonists could therefore have broader therapeutic benefits than nonsteroidal antiinflammatory drugs as antiarthritic agents for rheumatoid arthritis.

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↗