The role of hepatic type 1 plasminogen activator inhibitor (PAI‐1) during murine hemorrhagic shock†

Abstract

Hemorrhagic shock (HS) followed by resuscitation (HS-R) is characterized by profound physiological changes. Even if the patient survives the initial blood loss, these poorly understood changes can lead to morbidity. One of the tissues most often affected is liver. We sought to recognize specific hepatic changes induced by this stressor to identify targets for therapeutic intervention. Gene array analyses using mouse liver mRNAs were used to identify candidate genes that contribute to hepatic damage. To verify the role of one of the genes identified using the arrays, mice were subjected to HS-R, and multiple parameters were analyzed. A profound increase in plasminogen activator inhibitor type 1 (PAI-1) mRNA was observed using hepatic mRNAs from C57Bl/6 mice after HS, both with and without resuscitation. Constitutive loss of PAI-1 resulted in notable tissue preservation and lower (P < .05) alanine aminotransferase (ALT) levels. Fibrin degradation products (FDPs) and interleukins 6 and 10 (IL-6 and IL-10) were unaffected by loss of PAI-1; however, enhanced urokinase activity, an elevation of active hepatocyte growth factor (HGF), an increase in unprocessed transforming growth factor-␤1 (TGF-␤1), and retention of ERK phosphorylation after HS-R were associated with improved hepatic function. In conclusion, PAI-1 protein is a negative effector of hepatic damage after HS-R through its influence on classic regulators of hepatic growth, as opposed to its role in fibrinolysis. (HEPATOLOGY 2005;42: 390-399.)H emorrhagic shock (HS) is characterized by a diverse range of physiological changes. 1,2 The body's exact response to shock depends on the type and severity of the original insult, combined with the host's genetic factors. These act in concert to determine the sequence of inflammatory events, degree of end-organ damage, and patient fate. Unfortunately, despite successful resuscitation and surgical intervention, HS often results in complications, leading to increased mortality. 3 We have previously demonstrated the upregulation of inducible nitric oxide synthase during shock. This increase precedes significant pro-inflammatory events such as nuclear factor-kappaB activation, cytokine expression, and neutrophil infiltration. 4 We also have demonstrated the importance of interleukin-6 (IL-6) in posthemorrhage inflammation and organ damage/dysfunction. 5,6 Nevertheless, knowledge regarding the pathogenesis of HS is limited.DNA microarray analysis provides a rapid, efficient method for identifying global changes in mRNA transcription. 7 We carried out DNA microarray analyses on mouse livers using an array capable of interrogating ϳ12,000 genes. In accordance with previous findings in rat, 8 examination of hepatic mRNAs from mice subjected to HS or HS followed by resuscitation (HS-R) indicated a potential role for plasminogen activator type 1 (PAI-1), an appealing candidate for therapeutic intervention after shock. Hence, we designed studies to verify the role of PAI-1 after HS-R.PAI-1 inhibits plasmin generation, playing a ...

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