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C Thiemermann

Publications and source records attributed to C Thiemermann.

At least 19 recordsLinked to original sources
PubMed2006

Inhibition of glycogen synthase kinase-3beta attenuates the development of carrageenan-induced lung injury in mice.

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-3beta inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD-8, a potent and selective GSK-3beta 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 E2 (PGE2), tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). 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(-1), i.p.), 30 min prior to injection of carrageenan, caused a dose-dependent 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-3beta, such as TDZD-8, may be useful in the treatment of various inflammatory diseases.

Animals↗
PubMed2006

The production of hydrogen sulfide limits myocardial ischemia and reperfusion injury and contributes to the cardioprotective effects of preconditioning with endotoxin, but not ischemia in the rat.

We investigated whether (endogenous) hydrogen sulfide (H2S) protects the heart against myocardial ischemia and reperfusion injury. Furthermore, we investigated whether endogenous H2S is involved in the protection afforded by (1) ischemic preconditioning and (2) the second window of protection caused by endotoxin. The involvement of one of the potential (end) effectors of the cardioprotection afforded by H2S was investigated using the mitochondrial KATP channel blocker, 5-hydroxydecanoate (5-HD; 5 mg/kg). Animals were subjected to 25 min regional myocardial ischemia followed by reperfusion (2 h) and were pretreated with the H2S donor, sodium hydrosulfide (3 mg/kg i.v.). Animals were also subjected to shorter periods of myocardial ischemia (15 min) and reperfusion (2 h) and pretreated with an irreversible inhibitor of cystathionine-gamma-lyase, dl-propargylglycine (PAG; 50 mg/kg i.v.). Animals were also pretreated with PAG (50 mg/kg) and subjected to either (1) ischemic preconditioning or (2) endotoxin (1 mg/kg i.p.) 16 h before myocardial ischemia. Myocardial infarct size was determined by p-nitroblue tetrazolium staining. Administration of sodium hydrosulfide significantly reduced myocardial infarct size, and this effect was abolished by 5-HD. Administration of PAG (50 mg/kg) or 5-HD significantly increased infarct size caused by 15 min of myocardial ischemia. The delayed cardioprotection afforded by endotoxin was abolished by 5-HD or PAG. In contrast, PAG (50 mg/kg) did not affect the cardioprotective effects of ischemic preconditioning. These findings suggest that (1) endogenous H2S is produced by myocardial ischemia in sufficient amounts to limit myocardial injury and (2) the synthesis or formation of H2S by cystathionine-gamma-lyase may contribute to the second window of protection caused by endotoxin.

Alkynes↗
PubMed2006

Cytokine responses to CpG DNA in human leukocytes.

Previous studies have implicated a role of bacterial DNA, containing unmethylated cytosine-phosphate-guanosine (CpG) motifs, in the initiation of systemic inflammation. This is based on the ability of CpG-DNA to act in synergy with lipopolysaccharide (LPS) to trigger tumor necrosis factor alpha (TNFalpha) production in murine monocytes and to enhance LPS toxicity in rodents. In this study we investigated the capacity of CpG-DNA to trigger and modulate cytokine responses in human leukocytes. A human blood assay, as well as isolated cultures of monocytes and neutrophils, was exposed to the synthetic oligodeoxynucleotides (ODNs) CpG ODN (2006) and GpC ODN (2006-GC), alone or in combination with peptidoglycan or LPS. Plasma or supernatants were isolated and analyzed for TNFalpha, interleukin-1 beta (IL-1beta), IL-6 and IL-8 by ELISA. In the blood, 2006 (but not 2006-GC) induced the release of TNFalpha (P < 0.05) and possibly IL-1beta and IL-6. IL-8 was induced in a CpG-independent manner. When co-administered with peptidoglycan, both ODNs enhanced the release of cytokines, but not consistently CpG dependent. When co-administered with LPS, only IL-8 values were enhanced, whereas IL-6 was suppressed at early time points. In monocyte and neutrophil cultures, CpG dependent induction of cytokine release was not observed. However, both ODNs inhibited LPS-induced IL-6. In conclusion, the capacity of CpG DNA to trigger the release of TNFalpha and to enhance LPS-induced release of this cytokine is confirmed in human whole blood, but not in adherent human monocytes. Most effects of the ODNs on cytokine release in human leukocytes were CpG independent.

CpG Islands↗
PubMed2006

Anti-inflammatory properties of enamel matrix derivative in human blood.

BACKGROUND AND OBJECTIVE: Enamel matrix derivative (EMD), extracted from porcine tooth buds, has been shown to promote periodontal healing in patients with severe periodontitis. This involves modulation of the inflammatory response followed by the onset of periodontal regeneration. Based on these observations, we examined the ability of EMD to modulate the release of a pro-inflammatory cytokine [tumor necrosis factor (TNF)-alpha], an anti-inflammatory cytokine (interleukin-10) and a chemokine (interleukin- 8) in whole human blood challenged by bacterial cell wall components. MATERIAL AND METHODS: Whole blood from healthy donors was challenged by lipopolysaccharide or peptidoglycan and incubated with different concentrations of EMD or a cAMP analogue 8-(4-chlorophenyl)thio-cAMP (8-CPT-cAMP). TNF-alpha, interleukin-8 and interleukin-10 were analysed from plasma by enzyme-linked immunosorbent assay (ELISA) while cAMP levels of peripheral blood mononuclear cell lysates were analysed by enzyme immunoassay (EIA). RESULTS: We found that EMD attenuated the release of TNF-alpha and interleukin-8 in whole blood from healthy donors challenged by lipopolysaccharide or peptidoglycan, while the release of interleukin-10 was unchanged. Enamel matrix derivative also produced a four-fold increase in the cAMP levels of peripheral blood mononuclear cell lysates. Like EMD, 8-CPT-cAMP attenuated the formation of TNF-alpha, but not of interleukin-10, in blood challenged by lipopolysaccharide. CONCLUSION: Enamel matrix derivative limits the release of pro-inflammatory cytokines induced by lipopolysaccharide or peptidoglycan in human blood, suggesting that it has anti-inflammatory properties. We propose that this effect of EMD is, at least partly, secondary to an increase in the intracellular levels of cAMP in peripheral blood mononuclear cells.

Animals↗
PubMed2005

Peptidoglycan of Staphylococcus aureus upregulates monocyte expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 in human blood: possible implications for priming of lipopolysaccharide signaling.

Previous studies have indicated that peptidoglycan (PepG) from gram-positive bacteria can exert a priming effect on the innate immune response to lipopolysaccharide (LPS) from gram-negative bacteria. Here, we hypothesized that this priming effect may be preceded by enhanced expression of monocyte CD14, Toll-like receptor 2 (TLR2), and TLR4. In an ex vivo whole human blood model, we observed a substantial synergy between LPS and PepG in the release of tumor necrosis factor alpha and interleukin-1beta (IL-1beta) over the 24-h experimental period, whereas the effect on IL-8 and IL-10 release was more time dependent. The priming effect of PepG on cytokine release was preceded by a rapid upregulation of CD14, TLR2, and TLR4 expression on monocytes: at 3 hours there was a twofold increase in CD14 expression (P < 0.03), a fivefold increase in TLR2 expression (P < 0.03), and a twofold increase in TLR4 expression (P < 0.03). CD14 and TLR2 remained upregulated throughout the experimental period following exposure to PepG (P < 0.05). Only a transient upregulation of these monocyte receptors was observed following treatment with LPS or LPS plus PepG. In conclusion, the synergistic effect of LPS and PepG on cytokine release is preceded by a reciprocal upregulation of TLR2 and TLR4 by both bacterial cell wall components.

Cytokines↗
PubMed2005

Effect of rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 on bleomycin-induced lung injury.

Thiazolidinedione rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), are two peroxisome proliferator-activated receptor (PPAR)-gamma ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice. Administration of the two PPAR-gamma agonists rosiglitazone (10 mg x kg(-1) i.p.) and 15d-PGJ2 (30 microg x kg(-1) i.p.) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-gamma antagonist bisphenol A diglycidyl ether (1 mg x kg(-1) i.p. 30 min before the rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists. These results demonstrate that the two peroxisome proliferator-activated receptor-gamma agonists, rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, significantly reduce lung injury induced by bleomycin in mice.

Analysis of Variance↗
PubMed2004

Tempol, an intracelullar free radical scavenger, reduces liver injury in hepatic ischemia-reperfusion in the rat.

Liver ischemia is of clinical interest because of its role in liver failure and also hepatic graft rejection. The generation of reactive oxygen species contributes to the injury that follows ischemia-reperfusion. One therapy utilizes the administration of antioxidants; however, only limited experience suggests a potential benefit of systemic administration of these compounds. To overcome the limitations of these compounds, small molecules with improved cell membrane permeability characteristics and higher potency, such as tempol, are being tested in vivo. Tempol, a membrane-permeable radical scavenger, interferes with the formation or the effects of many radicals, including superoxide anions, hydroxyl radicals, and peroxynitrite. The aim of this study was to investigate the effects of tempol in an in vivo rat model of liver ischemia-reperfusion injury. Male Wistar rats were pretreated with tempol (30 mg/kg, i.v.) 5 minutes prior to liver ischemia (for 30 minutes) and reperfusion (for 2 hours). The liver injury was assessed by measuring serum levels of transaminases, lactate dehydrogenase, and gamma-glutamyl transferase. Tempol significantly mitigated the increase in transaminases, lactate dehydrogenase, and gamma-glutamyl transferase following liver ischemia-reperfusion, suggesting an improvement in liver function and resistance to injury.

Animals↗
PubMed2003

Ligands of the peroxisome proliferator-activated receptor-gamma and heart failure.

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 subfamily comprises of three members, PPAR-alpha, PPAR-beta and PPAR-gamma. There is good evidence that ligands of PPAR-gamma, including certain thiazolinediones, reduce myocardial tissue injury and infarct size. The use of PPAR-gamma agonists in the treatment of heart failure is, however, controversial.

Animals↗
PubMed2002

The tyrosine kinase inhibitor tyrphostin AG 126 reduces the multiple organ failure induced by zymosan in the rat.

OBJECTIVE: To investigate the effects of tyrphostin AG 126, a tyrosine kinase inhibitor, on the multiple organ failure (MOF) caused by zymosan in the rat. DESIGN: Zymosan (500 mg/kg, suspended in saline solution, i.p.) causes an enhanced formation of reactive oxygen species, which contribute to the pathophysiology of MOF. After zymosan or saline administration, animals were monitored for 12 days. MEASUREMENTS AND RESULTS: Treatment of rats with tyrphostin AG 126 (10 mg/kg, 3 mg/kg or 1 mg/kg intraperitoneally, 1 h and 6 h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Tyrphostin AG 126 also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in the levels of myeloperoxidase and malondialdehyde caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine, poly (ADP-ribose) polymerase (PAR), iNOS, and COX-2 revealed a positive staining in lung, liver and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine, PAR, iNOS, and COX-2 were markedly reduced in tissue sections obtained from zymosan-treated rats which had received tyrphostin AG 126. Furthermore, treatment of rats with tyrphostin AG 126 significantly reduced the production of peroxynitrite and of pro-inflammatory cytokines TNF-alpha and IL-1beta. CONCLUSIONS: This study provides the first evidence that the protein kinase inhibitor tyrphostin AG 126 attenuates the degree of MOF associated with zymosan-induced peritonitis in the rat.

Animals↗
PubMed2002

A novel, potent and selective inhibitor of the activity of inducible nitric oxide synthase (GW274150) reduces the organ injury in hemorrhagic shock.

An enhanced formation of nitric oxide (NO) by the inducible NO synthase (iNOS) may contribute to the pathophysiology of hemorrhagic shock. This study investigates the effect of a novel, potent and selective inhibitor of iNOS activity (GW274150) on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock in the anesthetised rat. Hemorrhage (sufficient to lower mean arterial blood pressure to 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure, renal and liver injury and dysfunction as well as the pancreatic injury. Pre-treatment of rats with GW274150 (5 mg/kg at 30 min prior to the onset of hemorrhage) attenuated the renal dysfunction as well as the liver and pancreatic injury caused by hemorrhage and resuscitation. Interestingly, GW274150 did not reduce the delayed fall in blood pressure associated with hemorrhagic shock. We propose that an enhanced formation of NO from iNOS contributes to the organ injury and dysfunction in hemorrhagic shock, and that highly selective inhibitors of iNOS activity, such as GW274150, may represent a novel therapeutic approach for the therapy of hemorrhagic shock.

Animals↗
PubMed2001

5-aminoisoquinolinone, a potent inhibitor of poly (adenosine 5'-diphosphate ribose) polymerase, reduces myocardial infarct size.

This study investigates the effects of a novel, water-soluble inhibitor of the activity of poly (adenosine 5'-diphosphate ribose) polymerase, 5-aminoisoquinolinone [5-aminoisoquinolin-1(2H)-one], on (i) poly (adenosine 5'-diphosphate ribose) polymerase activity in rat cardiac myoblasts and (ii) the infarct size caused by regional myocardial ischaemia and reperfusion in the rat. Exposure of H9c2 cells to hydrogen peroxide (H2O2, 1 mM) caused a significant increase in poly (adenosine 5'-diphosphate ribose) polymerase activity and an 80-90% reduction in mitochondrial respiration (cellular injury). Pretreatment of these cells with 5-aminoisoquinolinone (0.003-1 mM) caused a concentration-dependent inhibition of poly (adenosine 5'-diphosphate ribose) polymerase activity (IC50: approximately 4.5 microM, n=6-9) and cell injury (EC50: approximately 4.45 microM, n=9). In a rat model of myocardial infarction, left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h) resulted in an infarct size of 50+/-3%. Administration (1 min before reperfusion) of 5-aminoisoquinolinone reduced myocardial infarct size in a dose-related fashion. Thus, 5-aminoisoquinolinone is a potent inhibitor of poly (adenosine 5'-diphosphate ribose) polymerase activity in cardiac myoblasts and reduces myocardial infarct size in vivo.

Animals↗
PubMed2001

Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat.

Ranolazine reduces cellular acetyl-CoA content via inhibition of fatty acid beta-oxidation and activates pyruvate dehydrogenase. This metabolic switch increases ATP production per mole of oxygen consumed, reduces the rise in lactic acid and acidosis, and maintains myocardial function under conditions of reduced myocardial oxygen delivery. It is still unclear whether ranolazine causes a reduction of (i) infarct size and (ii) cardiac troponin T release, in a male Wistar rat model of left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). Rats were subjected to saline infusion (n=12) or ranolazine (bolus injection: 10 mg/kg plus infusion: 9.6 mg/kg/h, n=12), 30 min prior to left anterior descending coronary artery occlusion-reperfusion, respectively. Ranolazine caused a significant reduction in myocardial infarct size of approximately 33% compared to saline control (P<0.05). In addition, infusion of ranolazine significantly attenuated the release of cardiac troponin T into the plasma from 65+/-14 (controls) to 12+/-2 ng/ml. This study demonstrates for the first time that ranolazine significantly reduces (i) infarct size and (ii) cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion.

Acetanilides↗
PubMed2001

Procalcitonin does not influence the surface expression of inflammatory receptors on whole blood leukocytes.

The plasma levels of procalcitonin (PCT) are increased in patients with severe bacterial infections. Its cellular origin and potential pathophysiological function in sepsis is, however, unclear. White blood cells have recently been described to express both PCT mRNA and protein. The aim of this study was to determine whether PCT has any influence on the surface expression of receptors, relevant in inflammation, on human whole blood leukocytes under normal and septic conditions. Venous blood from healthy donors was incubated with PCT (40 ng/ml or 1200 ng/ml) alone or in combination with lipopolysaccharide (LPS, 10 ng/ml) or peptidoglycan (PepG, 10 micrograms/ml) for 6 h. The surface expression of CD14, CD54, CD64, CD80, CD86 and HLA-DR was determined by flow cytometry. We could not detect any influence of PCT on the expression of these receptors. Further studies on potential effects on other cell types during infection seem warranted.

Analysis of Variance↗
PubMed2001

Sirolimus interferes with the innate response to bacterial products in human whole blood by attenuation of IL-10 production.

Current immunosuppressive strategies are aimed at abrogating the allospecific T-cell response against donor tissues or organs. However, little information is yet available on the potential influences of these drugs on innate immune responses. In order to address this, we have employed a whole blood model. Human whole blood was pretreated with sirolimus, cyclosporine A or tacrolimus in therapeutic as well as supra therapeutic doses, and subsequently stimulated with lipopolysaccharide (LPS), peptidoglycan (PepG) or lipoteichoic acid (LTA). Plasma cytokine analyses revealed a potent inhibitory effect of sirolimus on interleukin(IL)-10 production induced by all bacterial products tested. In contrast, cyclosporine A and tacrolimus inhibited the tumour necrosis factor (TNF)-alpha production in response to LPS, but not to PepG and LTA. Using a quantitative mRNA analyses, we also observed that sirolimus significantly decreased the IL-10 mRNA accumulation to sub-basal levels in peripheral blood mononuclear cells (PBMC). This suggests that the sirolimus inhibits IL-10 production by interfering with the IL-10 gene transcription. However, the molecular mechanism of this inhibition remains unclear. Based on the present study and observations by others, we postulate that the clinical use of the sirolimus may be associated with a dysregulated innate immune response to bacterial infection and thus an increased risk of hyperinflammation and sepsis.

Adult↗
PubMed2001

Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat.

BACKGROUND: Activation of the cysteine protease calpain has been implicated in renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of calpain inhibitor-1 (Cal I-1) in an in vivo model of renal I/R injury. METHODS: Male Wistar rats were administered Cal I-1 (10 mg/kg, IP) 30 minutes before undergoing bilateral renal ischemia (45 minutes) followed by reperfusion (6 hours). Plasma concentrations of urea, creatinine, Na(+), gamma-glutamyl transferase (gamma GT), aspartate aminotransferase (AST) and urinary Na(+), glutathione S-transferase (GST), and N-acetyl-beta-D-glucosaminidase (NAG) were measured for the assessment of renal dysfunction and I/R injury. Creatinine clearance (C(Cr)) and fractional excretion of Na(+) (FE(Na)) were used as indicators of glomerular and tubular function, respectively. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured for assessment of neutrophil infiltration and lipid peroxidation, respectively. Renal sections were used for histologic grading of renal injury and for immunohistochemical localization of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). RESULTS: Cal I-1 significantly reduced I/R-mediated increases in urea, creatinine, gamma GT, AST, NAG, and FE(Na) and significantly improved C(Cr). Cal I-1 also significantly reduced kidney MPO activity and MDA levels. Cal I-1 also reduced histologic evidence of I/R-mediated renal damage and caused a substantial reduction in the expression of iNOS and COX-2, both of which involve activation of nuclear factor-kappa B (NF-kappa B). CONCLUSIONS: : These results suggest that Cal I-1 reduces the renal dysfunction and injury associated with I/R of the kidney. We suggest that the mechanism could involve the inhibition of I/R-mediated activation of NF-kappa B.

Acetylglucosaminidase↗
PubMed2001

High density lipoproteins reduce organ injury and organ dysfunction in a rat model of hemorrhagic shock.

High density lipoproteins (HDLs) inhibit the cytokine-induced expression of endothelial cell adhesion molecules both in vitro and in vivo. We examined the ability of HDLs to mediate a functional anti-inflammatory effect by measuring their ability to prevent neutrophil adhesion and transmigration in vitro. Treatment of human endothelial cell cultures with physiologic concentrations of HDLs inhibited neutrophil binding by 68 +/- 5.9% (mean and se, n=6, P<0.05) and neutrophil transmigration by 48.7 +/- 6.7% (n=8, P<0.05). We then examined the effect of HDLs on inflammatory infiltration and subsequent multiple organ dysfunction syndrome (MODS), associated with trauma in a rat model of hemorrhagic shock. Rats given human HDLs (80 mg apo A-I/kg, i.v.) 90 min after hemorrhage (which reduced mean arterial pressure to 50 mmHg) and 1 min before resuscitation showed attenuation of the increases in the serum levels of markers of MODS normally observed in this model. Severe disruption of the architecture of tissues and the extensive cellular infiltration into those tissues were also largely inhibited in animals that received HDLs. Human HDLs attenuate the MODS associated with ischemia and reperfusion injury after hemorrhagic shock in rats.

Adult↗
PubMed2001

Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock.

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.

Animals↗