Serine Proteases Are Involved in the Pathogenesis of Trauma-Hemorrhagic Shock-Induced Gut and Lung Injury

Deitch, Edwin A.; Shi, Han; Lu, Quan; Feketeova, Eleonora; Xu, Dakang

doi:10.1097/01.shk.0000048899.46342.f6

Cited by 84 publications

(68 citation statements)

References 28 publications

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“…It has been observed that plasma from male rats subjected to trauma-hemorrhage primes neutrophil respiratory burst, but plasma from proestrus females subjected to traumahemorrhage does not (79). Intraluminal nafamostat (serine protease inhibitor) reduced trauma-hemorrhage-induced gut and lung injury as well as neutrophilactivating ability, demonstrating that neutrophil-derived serine proteases play an important role in traumahemorrhage-induced gut and lung injury (80). Ischemic gut is a major source of factors that lead to neutrophil activation (81).…”

Section: Neutrophilsmentioning

confidence: 99%

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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ESTROGEN, MECHANISM OF ACTIONE2, the female hormone, is mainly produced by the ovaries and the placenta. The three major estrogens in women are estradiol, estriol, and estrone ( Figure 1). Estrogens are synthesized from androgens by the loss of C-19 angular methyl group and the formation of an aromatic A ring. Whereas estradiol is derived from testosterone, estrone is derived from androstenedione. The main form of E2 in women Trauma-hemorrhage leads to prolonged immune suppression, sepsis, and multiple organ failure. The condition affects all compartments of the immune system, and extensive studies have been carried out elucidating the immunological events following trauma-hemorrhage. The immune alteration observed following trauma-hemorrhage is gender dependent in both animal models and humans, though some studies in humans are contradictory. Within 30 min after trauma-hemorrhage, splenic and peritoneal macrophages, as well as T-cell function, are depressed in male animals, but not in proestrus females. Studies have also shown that the survival rate and the induction of subsequent sepsis following trauma-hemorrhage are significantly higher in males and ovariectomized females compared with proestrus females. These and other investigations show that sex hormones form the basis of this gender dichotomy, and administration of estrogen can ameliorate the immune depression and increase the survival rate after trauma-hemorrhage. This review specifically elaborates the studies carried out thus far demonstrating immunological alteration after trauma-hemorrhage and its modulation by estrogen. Also, estrogen was shown to produce its salutary effects through nuclear as well as extranuclear receptors. Estrogen rapidly activates several protein kinases and phosphatases, as well as the release of calcium in different cell types. The results of the studies exemplify the promise of estrogen as a therapeutic adjunct in treating adverse pathophysiological conditions following trauma-hemorrhage.

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Section: Neutrophilsmentioning

confidence: 99%

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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“…The production of inflammatory mediators in mesenteric I/R can be inhibited by blockade of digestive proteases in the lumen of the intestine, a procedure that attenuates many symptoms of experimental shock. 1,10,40,41,57,58 Inflammatory mediators are readily produced in vitro from intestinal tissue in the presence of digestive enzymes, among which pancreatic trypsin serves as a particularly potent producer of mediators for leukocyte activation. 13 The inflammatory mediators produced by proteolytic digestion of the intestinal wall consist of both peptide and lipid components, many of which with molecular weight below 10 kd.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Trypsin Increases Matrix Metalloproteinase-9 Accumulation and Activation during Acute Intestinal Ischemia-Reperfusion in the Rat

Rosario¹,

Waldo²,

Becker³

et al. 2004

The American Journal of Pathology

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Ischemia-reperfusion of the intestine produces a set of inflammatory mediators, the origin of which has recently been shown to involve pancreatic digestive enzymes. Matrix metalloproteinase-9 (MMP-9) participates in a variety of inflammatory processes including myocardial, hepatic, and pancreatic ischemiareperfusion. In the present study, we explore the role of neutrophil-derived MMP-9 in acute intestinal ischemia-reperfusion and its interaction with pancreatic trypsin. Male Sprague-Dawley rats were subjected to 45 minutes of superior mesenteric arterial occlusion followed by 90 minutes of reperfusion. In situ zymography of the proximal jejunum reveals increased gelatinase activity in the intestinal wall after ischemiareperfusion. Gel electrophoresis zymography and immunofluorescence co-localization suggests that this gelatinase activity is derived from MMP-9 released from infiltrating neutrophils. The role of intraluminal trypsin in this process was investigated using an in vivo isolated jejunal loop model of intestinal ischemia-reperfusion. Trypsin increased the inflammatory response after reperfusion, with an augmented neutrophil infiltration of the intestinal wall. Furthermore, trypsin stimulated a rapid conversion of neutrophil-released proMMP-9 into the lower molecular weight enzymatically active MMP-9. This process represents a powerful in vivo pathophysiological mechanism for trypsin-induced MMP-9 activation and is likely to play a central role in the development of acute intestinal inflammation and shock. Intestinal ischemia-reperfusion (I/R) is a localized pathology that often leads to multi-organ dysfunction and shock.

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“…These studies have largely focused on the splanchnic circulation and systemic host factors because it is well recognized that shock or major trauma leads to a decrease in mesenteric perfusion, resulting in an ischemia-reperfusion injury as well as an ischemia-reperfusion-induced gut inflammatory response (1). This work has led to the recognition of the important roles of inflammatory cells, proinflammatory molecules, intraluminal proteases, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI) in the pathogenesis of ischemiareperfusion-related gut injury and dysfunction (1,7,8,13,15,22). However, very little attention has been paid to the role of the unstirred mucus layer as a critical component of the gut barrier or the consequences of damage to this mucus layer.…”

mentioning

confidence: 99%

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure

Fishman

Levy

Alli

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure. Am J Physiol Gastrointest Liver Physiol 304: G57-G63, 2013. First published November 1, 2012; doi:10.1152/ajpgi.00170.2012.-Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radicalmediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS-and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.intestinal mucus layer; gut-mediated sepsis IN CERTAIN CLINICAL SCENARIOS, including major trauma and hemorrhage, gut injury and the subsequent loss of the gut barrier function have been implicated in the development of the acute respiratory distress syndrome, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome (8). Thus prevention or amelioration of gut injury in conditions associated with intestinal ischemia would be a key therapeutic strategy. Several such strategies, including early enteral nutrition, have been identified and instituted into clinical practice (1,20). However, the development of successful new clinical therapies is based on a complete knowledge of the mechanisms of the injuries they are being developed to treat. Consequently, a considerable amount of investigative attention has been committed to elucidating the pathogenesis of stress-and trauma/ shock-induced gut injury and gut barrier failure. These studies have largely focused on the ...

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Serine Proteases Are Involved in the Pathogenesis of Trauma-Hemorrhagic Shock-Induced Gut and Lung Injury

Cited by 84 publications

References 28 publications

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Pancreatic Trypsin Increases Matrix Metalloproteinase-9 Accumulation and Activation during Acute Intestinal Ischemia-Reperfusion in the Rat

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure

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