Recent studies indicate that the stomach and intestine are target organs injured during sepsis-induced multiple organ failure. Under these conditions, organs are injured in response to systemically-released inflammatory mediators and cytokines. Studies from our laboratory during the current funding period have shown that activation of circulating leukocytes plays an important role in the pathogenesis of gastric microvascular injury induced by several inflammatory mediators (i.e., PAF, TNF-alpha, FMLP). This microcirculatory injury includes changes in gastric vascular resistance, increased vascular permeability, and altered vascular reactivity to vasoactive agents. These studies were performed in acute experiments using exogenous administration of inflammatory mediators. The proposed studies of this application are a natural extension of our acute studies to a chronic animal model of sepsis. The central goal of the proposed studies of this application is to examine microvascular changes and to identify the underlying mechanisms following sepsis produced by cecal ligation-puncture in rats. Using intravital microcopy which provides a direct visualization of adhesive interactions between circulating leukocytes and the intestinal microcirculation, the mechanisms of leukocyte-dependent microvascular injury will be more clearly defined. In addition, we will examine several potential interventions to reduce microvascular injury and organ dysfunction during sepsis. Utilizing recent advances in molecular biology, these interventions include: 1) prevention of host immune responses by inhibition of endotoxin or lipopolysaccharide (a component of gram negative bacterial cell membrane), and 2) blockade of adhesion of circulating leukocytes with vascular endothelium. We postulate that the microcirculatory changes during sepsis will be similar to our previous observations using exogenously administered inflammatory mediators. Furthermore, adhesion of activated leukocytes to vascular endothelium represents a critical step in microvascular injury under these conditions. Of the proposed interventions described above, we hypothesize that blockade of adhesion of circulating leukocytes with vascular endothelium will have the greatest potential in reducing microvascular injury in multiple organs during sepsis. The proposed studies of this application will provide new information regarding the role of leukocytes in gastrointestinal microvasculalr injury during sepsis. Since the gastrointestinal tract is one of the organ systems adversely affected during sepsis, a better understanding of the pathophysiology and the prevention of the microcirculatory injury in the small intestine should also be beneficial to our knowledge regarding other organ dysfunctions under these conditions.
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