Removal of luminal content protects the small intestine during hemorrhagic shock but is not sufficient to prevent lung injury

Abstract

The small intestine plays a key role in the pathogenesis of multiple organ failure following circulatory shock. Current results show that reduced perfusion of the small intestine compromises the mucosal epithelial barrier, and the intestinal contents (including pancreatic digestive enzymes and partially digested food) can enter the intestinal wall and transport through the circulation or mesenteric lymph to other organs such as the lung. The extent to which the luminal contents of the small intestine mediate tissue damage in the intestine and lung is poorly understood in shock. Therefore, rats were assigned to three groups: No-hemorrhagic shock (HS) control and HS with or without a flushed intestine. HS was induced by reducing the mean arterial pressure (30 mmHg; 90 min) followed by return of shed blood and observation (3 h). The small intestine and lung were analyzed for hemorrhage, neutrophil accumulation, and cellular membrane protein degradation. After HS, animals with luminal contents had increased neutrophil accumulation, bleeding, and destruction of E-cadherin in the intestine. Serine protease activity was elevated in mesenteric lymph fluid collected from a separate group of animals subjected to intestinal ischemia/reperfusion. Serine protease activity was elevated in the plasma after HS but was detected in lungs only in animals with nonflushed lumens. Despite removal of the luminal contents, lung injury occurred in both groups as determined by elevated neutrophil accumulation, permeability, and lung protein destruction. In conclusion, luminal contents significantly increase intestinal damage during experimental HS, suggesting transport of luminal contents across the intestinal wall should be minimized.

Peptidomic Analysis of Rat Plasma

“…D’Alessandro and coworkers [22] reported that the upregulation of such proteins is accompanied by an impaired homeostasis of the balance between proteases and anti-proteases, especially serine proteases and MMPs, and that this could entail an activation of neutrophils following extracellular matrix metalloproteinase involvement. These observations are consistent with the evidence that digestive enzymes can promote “autodigestion” [2–5]. Hence, we took the next step in this investigation, the analysis of peptides in plasma, with the goal of looking for evidence of proteolytic processes in shock, which could prove impactful in future clinical studies.…”

“…The intestinal mucosal barrier may become severely damaged due to hypoperfusion in hemorrhage and sepsis. As a consequence, its function as a barrier between the intestinal lumen and the interstitial tissue and vasculature may become compromised, and digestive enzymes, such as proteases and lipases may exit the intestinal lumen and reach the systemic circulation, resulting in global cellular and organ dysfunction [2–5]. Digestive proteases contribute to malfunction of important transmembrane receptors, such as the insulin receptor, possibly through cleavage [4], but they are also known to activate matrix metalloproteinases (MMPs) in vivo , and could therefore act as mediators of secondary cell and tissue injury.…”

Diagnosis biomarkers in acute intestinal ischemic injury: so close, yet so far

“…Aside from its barrier function, the gut contains growth factors, adenosine and hormones, which are potential mediators of the modulation of intestinal inflammation and repair, due to their roles in cellular proliferation, differentiation, migration, apoptosis and autophagy [18][19][20][21][22]. Physiologically, the gut could initiate and propagate sepsis due to the ability of bacteria, endotoxins, and other antigens to translocate, along with the production of pro-inflammatory cytokines and toxins [11].…”

“…The action of these enzymes would involve degradation of inter-enterocytic tight junction's proteins such as E-cadherin. Moreover, these enzymes would also induce a cleavage of the prometalloproteinases into active metalloproteinases [22].…”

Is Matrix Metalloproteinase-8 Activity in the Mucosal Barrier a Requirement for Leakage of Cecal Material in Peritonitis?*

“…A typical cecal slurry consists of a mixture of fully or partially digested food items, the powerful digestive enzymes, enteral bacteria and viruses, each needs to be contained in the cecum and the intestine to avoid peritoneal cell injuries and inflammation. The containment of these cytotoxic and proinflammatory materials in the cecum or in the lumen of the intestine requires an intact mucosal epithelial barrier (5) and therefore there is a possibility that MMP-8 may be involved in the maintenance of barrier properties.…”