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Here, we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal injury, dysfunction, and inflammation in interleukin (IL)-6 knockout (IL-6(-/-)) mice and mice administered a monoclonal antibody against IL-6. IL-6(-/-) mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (24 h). At the end of experiments, indicators and markers of renal dysfunction, injury, and inflammation were measured. Kidneys were used for histological evaluation of renal injury. Renal expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and P-selectin, as well as nitration of proteins in the kidney, were determined using immunohistochemistry. In addition, wild-type mice were pretreated (24 and 1 h before ischemia) with an IL-6 antibody to mimic the effects that would be seen in IL-6(-/-) mice. IL-6(-/-) mice and wild-type mice administered the IL-6 antibody demonstrated significantly reduced plasma urea and creatinine levels, indicating reduction of renal dysfunction caused by I/R. Neutrophil infiltration was also significantly reduced in IL-6(-/-) mice and wild-type mice administered the IL-6 antibody subjected to renal I/R. Proinflammatory cytokines (tumor necrosis factor-alpha and IL-1beta) in renal tissues were significantly attenuated in IL-6(-/-) mice to levels seen in wild-type mice. IL-6(-/-) mice demonstrated reduced histological evidence of tubular injury and markedly reduced immunohistochemical evidence of ICAM-1, P-selectin, and nitrotyrosine when subjected to renal I/R. We propose that endogenous IL-6 enhances the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules and subsequent oxidative and nitrosative stress.

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX(-/-)) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX(-/-) mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX(-/-) mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.

Objective Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. Rosiglitazone (Avandia) is a PPAR-gamma agonist (the most potent PPAR-gamma agonist of the thiazolidinedione antidiabetics). In the present study, we investigated the effects of rosiglitazone on the development of nonseptic shock caused by zymosan in mice. Design Experimental study. Setting University laboratory. Subjects Male CD mice. Interventions We investigated the effects of rosiglitazone (3 mg/kg) on the development of nonseptic shock caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in mice. Measurements and main results Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of zymosan and/or rosiglitazone and monitored for 12 days (for loss of body weight and mortality rate). Treatment of mice with rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, and poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, and poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from zymosan-treated mice that received rosiglitazone. To elucidate whether the protective effects of rosiglitazone are related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, GW 9662, on the protective effects of rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with rosiglitazone) significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the protective effect. Conclusions This study provides evidence, for the first time, that rosiglitazone attenuates the degree of zymosan-induced nonseptic shock in mice.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.

bstract OBJECTIVE: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. Rosiglitazone (Avandia) is a PPAR-gamma agonist (the most potent PPAR-gamma agonist of the thiazolidinedione antidiabetics). In the present study, we investigated the effects of rosiglitazone on the development of nonseptic shock caused by zymosan in mice. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: Male CD mice. INTERVENTIONS: We investigated the effects of rosiglitazone (3 mg/kg) on the development of nonseptic shock caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in mice. MEASUREMENTS AND MAIN RESULTS: Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of zymosan and/or rosiglitazone and monitored for 12 days (for loss of body weight and mortality rate). Treatment of mice with rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, and poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, and poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from zymosan-treated mice that received rosiglitazone. To elucidate whether the protective effects of rosiglitazone are related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, GW 9662, on the protective effects of rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with rosiglitazone) significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the protective effect. CONCLUSIONS: This study provides evidence, for the first time, that rosiglitazone attenuates the degree of zymosan-induced nonseptic shock in mice.

1. The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin (PG)D2 metabolite, 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2), are two PPAR-gamma ligands, which modulate the transcription of target genes. 2. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the tissue injury caused by ischaemia/reperfusion (I/R) of the gut. 3. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2 or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. 4. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10% of the animals survived for the entire 4 h reperfusion period. Surviving animals were killed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels and marked injury to the distal ileum. 5. Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody resulted in diffuse staining. 6. Administration at 30 min prior to the onset of gut ischaemia of the two PPAR-gamma agonists (rosiglitazone (0.3 mg kg-1 i.v.) and 15d-PGJ2 (0.3 mg kg-1 i.v.)) significantly reduced the (i) fall in mean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) production of proinflammatory cytokines (TNF-alpha and IL-1beta) and (vi) histological evidence of gut injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine formation and the upregulation of ICAM-1 during reperfusion. 7. In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2 are related to the activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d-PGJ2. BADGE (1 mg kg-1 administered i.v. 30 min prior to the treatment of rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists and thus abolished the protective effect against gut I/R. 8. These results demonstrate that the two PPAR-gamma agonists, rosiglitazone and 15d-PGJ2, significantly reduce I/R injury of the intestine.

1. Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy-delta(12,14)-PGJ(2) (15d- PGJ(2)) functions as an early anti-inflammatory signal. 2. The aim of the present paper is to investigate the effects of 15d-PGJ(2) in rats subjected to experimental colitis. 3. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d-PGJ(2) was administered daily as intraperitoneal injection (20 or 40 microg kg(-1)). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. 4. 15d-PGJ(2) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d-PGJ(2) also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 5. Furthermore, 15d-PGJ(2) reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP-ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM-1 caused by DNBS in the colon. 6. Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d- PGJ(2) also caused a substantial reduction of the activation of nuclear factor-kappaB (NF-kappaB). Furthermore, 15d-PGJ(2) stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis. 7. In conclusion, 15d-PGJ(2) reduces the development of experimental colitis.

Background/Aims: Oxidative and nitrosative stress plays important roles in the pathogenesis of renal ischemia/reperfusion (I/R) injury. Here we investigate the effect of EUK-134, a synthetic superoxide dismutase and catalase mimetic, (i) on renal dysfunction and injury caused by I/R in vivo and (ii) on proximal tubular cell (PTC) injury and death caused by oxidative and nitrosative stress. Methods: Rats, subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h), were administered EUK-134 (0.3 and 3 mg/kg, i.v.) prior to and during reperfusion, after which biochemical and histological indicators of renal dysfunction and injury were measured. The expression of poly(ADP-ribose) (PAR) and inducible nitric oxide (NO) synthase (iNOS) and nitrotyrosine formation were determined immunohistochemically and used as indicators of oxidative and nitrosative stress. Primary cultures of rat PTCs, isolated and cultured from the kidney cortex, were incubated with hydrogen peroxide (H2O2; 1 mM for 2 h) in the presence of increasing concentrations of EUK-134 (1–100 µM) after which PTC injury and death were measured. The effects of EUK-134 on serum levels of NO in rats subjected to renal I/R or on NO production by PTCs incubated with interferon-γ (IFN-γ, 100 IU/ml) and bacterial lipopolysaccharide (LPS, 10 µg/ml) in combination for 24 h were also measured. Results: EUK-134 produced a significant reduction in renal dysfunction and injury caused by I/R. Specifically, serum creatinine levels, an indicator of renal dysfunction, were reduced from 227 ± 11 (n = 12, I/R only) to 146 ± 9 µM (n = 12, I/R +3 mg/kg EUK-134). Urinary N-acetyl-β-D-glucosaminidase activity, an indicator of tubular damage, was reduced from 42 ± 5 (n = 12, I/R only) to 22 ± 3 IU/l (n = 12, I/R +3 mg/kg EUK-134). EUK-134 significantly reduced renal injury caused by oxidative stress in vivo (reduction in PAR formation), and in vitro EUK-134 reduced PTC injury and death caused by H2O2. However, EUK-134 also reduced nitrosative stress caused by I/R in vivo (reduction of iNOS expression and nitrotyrosine formation), which was reflected by a significant reduction in serum NO levels in rats subjected to renal I/R. Specifically, serum NO levels were reduced from 57 ± 12 (n = 12, I/R only) to 23 ± 3 mM (n = 12, I/R +3 mg/kg EUK-134). In vitro, EUK-134 significantly reduced NO production by PTCs incubated with IFN-γ/LPS. Conclusion: We propose that EUK-134 reduces renal I/R injury not only via reduction of oxidative stress, but also by reducing nitrosative stress caused by renal I/R.

1. Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy-delta(12,14)-PGJ(2) (15d- PGJ(2)) functions as an early anti-inflammatory signal. 2. The aim of the present paper is to investigate the effects of 15d-PGJ(2) in rats subjected to experimental colitis. 3. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d-PGJ(2) was administered daily as intraperitoneal injection (20 or 40 microg kg(-1)). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. 4. 15d-PGJ(2) significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d-PGJ(2) also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). 5. Furthermore, 15d-PGJ(2) reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP-ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM-1 caused by DNBS in the colon. 6. Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d- PGJ(2) also caused a substantial reduction of the activation of nuclear factor-kappaB (NF-kappaB). Furthermore, 15d-PGJ(2) stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis. 7. In conclusion, 15d-PGJ(2) reduces the development of experimental colitis.

1. The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The thiazolidinedione rosiglitazone and the endogenous cyclopentenone prostaglandin (PG)D2 metabolite, 15-deoxy-Delta12,14-PGJ2 (15d-PGJ2), are two PPAR-gamma ligands, which modulate the transcription of target genes. 2. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the tissue injury caused by ischaemia/reperfusion (I/R) of the gut. 3. I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45 min, followed by release of the clamp allowing reperfusion for 2 or 4 h. This procedure results in splanchnic artery occlusion (SAO) shock. 4. Rats subjected to SAO developed a significant fall in mean arterial blood pressure, and only 10% of the animals survived for the entire 4 h reperfusion period. Surviving animals were killed for histological examination and biochemical studies. Rats subjected to SAO displayed a significant increase in tissue myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels, significant increases in plasma tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels and marked injury to the distal ileum. 5. Increased immunoreactivity to nitrotyrosine was observed in the ileum of rats subjected to SAO. Staining of sections of the ileum obtained from SAO rats with anti-intercellular adhesion molecule (ICAM-1) antibody resulted in diffuse staining. 6. Administration at 30 min prior to the onset of gut ischaemia of the two PPAR-gamma agonists (rosiglitazone (0.3 mg kg-1 i.v.) and 15d-PGJ2 (0.3 mg kg-1 i.v.)) significantly reduced the (i) fall in mean arterial blood pressure, (ii) mortality rate, (iii) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (iv) lipid peroxidation (MDA levels), (v) production of proinflammatory cytokines (TNF-alpha and IL-1beta) and (vi) histological evidence of gut injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine formation and the upregulation of ICAM-1 during reperfusion. 7. In order to elucidate whether the protective effects of rosiglitazone and 15d-PGJ2 are related to the activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone and 15d-PGJ2. BADGE (1 mg kg-1 administered i.v. 30 min prior to the treatment of rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists and thus abolished the protective effect against gut I/R. 8. These results demonstrate that the two PPAR-gamma agonists, rosiglitazone and 15d-PGJ2, significantly reduce I/R injury of the intestine.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-gamma receptor subtype seems to play a pivotal role in the regulation of cellular proliferation and inflammation. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxyDelta(12,14)-PGJ(2) (15d-PGJ(2)), which is a metabolite of prostaglandin D(2), functions as an endogenous ligand for PPAR-gamma. We postulated that 15d-PGJ(2) would attenuate inflammation. In the present study, we have investigated the effects of 15d-PGJ(2) of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis, respectively) in animal models. We report for the first time, to our knowledge, that 15d-PGJ(2) (given at 10, 30, or 100 microg/kg i.p. in the pleurisy model or at 30 microg/kg i.p every 48 h in the arthritis model) exerts potent anti-inflammatory effects (e.g., inhibition of pleural exudate formation, mononuclear cell infiltration, delayed development of clinical indicators, and histological injury) in vivo. Furthermore, 15d-PGJ(2) reduced the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase and the expression of inducible nitric-oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated mice and in the joints from collagen-treated mice. Thus, 15d-PGJ(2) reduces the development of acute and chronic inflammation. Therefore, the cyclopentenone prostaglandin 15d-PGJ(2) may be useful in the therapy of acute and chronic inflammation.

This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ(2) and PGA(1)) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-gamma (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta(12,14)-prostagalndin J(2) (15D- PGJ(2)). The mechanisms of the cardioprotective effects of 15D- PGJ(2) may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D- PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D- PGJ(2) was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D- PGJ(2) reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ(2), however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ(2), but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.

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Reactive oxygen species contribute to the multiple organ failure in endotoxic shock. Here, we investigate the effects of a salen-manganese complex, which exhibits both superoxide dismutase and catalase activity (EUK-8), on the circulatory failure, renal and liver injury and dysfunction caused by endotoxin in the anaesthetised rat. Endotoxaemia (6 mg/kg i.v., Escherichia coli lipopolysaccharide) for 6 h caused hypotension, renal dysfunction and liver injury. Treatment of rats with EUK-8 (0.3 or 1 mg/kg bolus injection followed by an infusion of 0.3 or 1 mg/kg/h) attenuated the renal and liver injury and dysfunction in a dose-related fashion. In addition, the higher dose of EUK-8 attenuated the delayed hypotension caused by endotoxin in the rat. Thus, an enhanced formation of reactive oxygen species importantly contributes to the circulatory failure, as well as the organ injury and dysfunction associated with endotoxic shock. We propose that small molecules, which have the catalytic activity of both superoxide dismutase and catalase, may represent a novel therapeutic approach for the therapy of endotoxic shock.

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n=40) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD. Plasma levels of LBP were significantly higher in the overweight group compared with the lean group (P=0.005). The levels of CRP were also significantly higher in overweight subjects (P=0.01), as were IL-6 (P=0.02) and leptin (P=0.002), pro-inflammatory mediators associated with cardiovascular risk. Levels of adiponectin, an adipokine with anti-inflammatory and anti-atherogenic functions, were significantly lower in the overweight group (P=0.002). The leptin/adiponectin ratio, a preferential atherogenic marker was significantly increased in women who are overweight (P=0.02). LBP, CRP, leptin, and adiponectin levels significantly correlated with BMI, but not with age and there was a significant correlation between LBP and IL-6 levels. These results reveal the presence of subclinical endotoxemia and a pro-inflammatory state in overweight women and are of interest for further studies with the goal for improved understanding of cardiovascular health risks in women., Competing Interests: Declaration of interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.