Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR-gamma regulates gene expression by forming a heterodimer with the retinoid X receptor (RXR) before binding to sequence-specific PPAR response elements (PPREs) in the promoter region of target genes, thereby regulating several metabolic pathways, including lipid biosynthesis and glucose metabolism. Thiazolidinediones (TZDs, i.e. rosiglitazone, pioglitazone), which are synthetic PPAR-gamma agonists, act as insulin sensitizers and are used in the treatment of type 2 diabetes. In the last few years, it has, however, become evident that the therapeutic effects of PPAR-gamma ligands reach far beyond their use as insulin sensitizers. Recently, PPAR-gamma has been implicated as a regulator of cellular inflammatory and ischemic responses. PPAR-gamma agonists may exert their anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced during macrophage differentiation and activation, by either PPAR-gamma-dependent or -independent mechanisms. Several lines of evidence suggest that TZDs protect the heart and other organs against the tissue injury caused by ischemia/reperfusion (I/R) injury and shock. This review discusses the anti-inflammatory signalling pathways activated by PPAR-gamma, as well as the potential therapeutic effects of PPAR-gamma agonists in animal models of ischemia/reperfusion, inflammation and shock.

Here we investigate the effects of erythropoietin (EPO) on the tissue/organ injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized with thiopental sodium (85 mg/kg i.p.) and subjected to hemorrhagic shock (HS; i.e., mean arterial blood pressure reduced to 45 mmHg for 90 min, followed by resuscitation with shed blood for 4 h), endotoxemia (for 6 h), or left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). HS and endotoxemia resulted in renal dysfunction and liver injury. Administration of EPO (300 IU/kg i.v., n = 10) before resuscitation abolished the renal dysfunction and liver injury in hemorrhagic, but not endotoxic, shock. HS also resulted in significant increases in the kidney of the activities of caspases 3, 8, and 9. This increase in caspase activity was not seen in HS rats treated with EPO. In cultured human proximal tubule cells, EPO concentration-dependently reduced the cell death and increase in caspase-3 activity caused by either ATP depletion (simulated ischemia) or hydrogen peroxide (oxidative stress). In the heart, administration of EPO (300 IU/kg i.v., n = 10) before reperfusion also caused a significant reduction in infarct size. In cultured rat cardiac myoblasts (H9C2 cells), EPO also reduced the increase in DNA fragmentation caused by either serum deprivation (simulated ischemia) or hydrogen peroxide (oxidative stress). We propose that the acute administration of EPO on reperfusion and/or resuscitation will reduce the tissue injury caused by ischemia-reperfusion of the heart (and other organs) and hemorrhagic shock.

1 Poly (ADP-ribose) synthetase (PARP) is a nuclear enzyme activated by strand breaks in DNA, which are caused inter alia by reactive oxygen species (ROS). Here we report on (i) a new synthesis of a water-soluble and potent PARP inhibitor, 5-aminoisoquinolinone (5-AIQ) and (ii) investigate the e ects of 5-AIQ on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat. 2 Exposure of human cardiac myoblasts (Girardi cells) to hydrogen peroxide (H 2 O 2 , 3 mM for 1 h, n=9) caused a substantial increase in PARP activity. Pre-treatment of these cells with 5-AIQ (1 mM ± 1 mM, 10 min prior to H 2 O 2 ) caused a concentration-dependent inhibition of PARP activity (IC 50 : *0.01 mM, n=6). 3 Haemorrhage and resuscitation resulted (within 4 h after resuscitation) in a delayed fall in blood pressure (circulatory failure) as well as in rises in the serum levels of (i) urea and creatinine (renal dysfunction), (ii) aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gammaglutamyl-transferase (g-GT) (liver injury and dysfunction), (iii) lipase (pancreatic injury) and (iv) creatine kinase (CK) (neuromuscular injury) (n=10). 4 Administration (5 min prior to resuscitation of 5-AIQ) (0.03 mg kg 71 i.v., n=8, or 0.3 mg kg 71 i.v., n=10) reduced (in a dose-related fashion) the multiple organ injury and dysfunction, but did not a ect the circulatory failure, associated with haemorrhagic shock. 5 Thus, 5-AIQ abolishes the multiple organ injury caused by severe haemorrhage and resuscitation.

There is limited evidence that inhibition of the activity of the cytosolic cysteine protease calpain reduces ischemia/reperfusion injury. The multiple organ injury associated with hemorrhagic shock is due at least in part to ischemia (during hemorrhage) and reperfusion (during resuscitation) of target organs. Here we investigate the effects of calpain inhibitor I on the organ injury (kidney, liver, pancreas, lung, intestine) and dysfunction (kidney) associated with hemorrhagic shock in the anesthetized rat. Hemorrhage and resuscitation with shed blood resulted in an increase in calpain activity (heart), activation of NF-kappaB (kidney), expression of iNOS and COX-2 (kidney), and the development of multiple organ injury and dysfunction, all of which were attenuated by calpain inhibitor I (10 mg/kg i.p.), administered 30 min prior to hemorrhage. Chymostatin, a serine protease inhibitor that does not prevent the activation of NF-kappaB, had no effect on the organ injury/failure caused by hemorrhagic shock. Pretreatment (for 1 h) of murine macrophages or rat aortic smooth muscle cells (activated with endotoxin) with calpain inhibitor I attenuated the binding of activated NF-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon. Selective inhibition of iNOS activity with L-NIL reduced the circulatory failure and liver injury, while selective inhibition of COX-2 activity with SC58635 reduced the renal dysfunction and liver injury caused by hemorrhagic shock. Thus, we provide evidence that the mechanisms by which calpain inhibitor I reduces the circulatory failure as well as the organ injury and dysfunction in hemorrhagic shock include 1) inhibition of calpain activity, 2) inhibition of the activation of NF-kappaB and thus prevention of the expression of NFkappaB-dependent genes, 3) prevention of the expression of iNOS, and 4) prevention of the expression of COX-2. Inhibition of calpain activity may represent a novel therapeutic approach for the therapy of hemorrhagic shock.

Background and purpose: Glycogen synthase kinase-3 (GSK-3) is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and has recently been implicated in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3b inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD-8, a potent and selective GSK-3b inhibitor, in a mouse model of carrageenan-induced pleurisy. Experimental approach: Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E 2 (PGE 2 ), tumour necrosis factor-a, (TNF-a) and interleukin-1b (IL-1b). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, iNOS, COX-2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues. Key results: Administration of TDZD-8 (1, 3 or 10 mg kg À1 , i.p.), 30 min prior to injection of carrageenan, caused a dosedependent reduction in all the parameters of inflammation measured. Conclusions and Implications: Thus, based on these findings we propose that inhibitors of the activity of GSK-3b, such as TDZD-8, may be useful in the treatment of various inflammatory diseases.