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

Abstract

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.

Early Anastomotic Repair in the Rat Intestine is Affected by Transient Preoperative Mesenteric Ischemia

“…Immediately after anastomotic construction (day 0) in the ileum, MMP-9 and active MMP-2 activities are greater in the IR groups, which is consistent with earlier findings in the rat intestine after a 90-min reperfusion. 25 However, this effect does not persist, and at later time points, active MMP-9 is even reduced in the IR groups. Remarkably, in the colonic anastomoses, MMP-2 activities after IR are enhanced at days 1 and 2 but reduced at day 3.…”

TNF-α Regulated MAdCAM-1 Expression in Pancreatic Microvessel Endothelium: A Possible Role for MAdCAM-1 in Pancreatitis?

“…Activated pancreatic macrophages may release inflammatory cytokines (e.g., IL-1, IL-6 and TNF-) as a response to local tissue injury [39]. These cytokines would be anticipated to aggravate local pancreatitis, and systemically may increase capillary permeability, recruit leukocytes and stimulate their extravasation [40]. Another important activity of macrophages is the presentation of antigens to T lymphocytes.…”

A journey with Tony Hugli up the inflammatory cascade towards the auto-digestion hypothesis

“…An ischemic intestine is associated with elevated permeability [37,38,39,40,41] and therefore the usual compartmentalization of digestive enzymes in the lumen of the intestine may no longer be preserved. The question arises whether products generated during inadvertent entry of digestive enzymes into the wall of the intestine may cause an inflammatory reaction.…”