A long-term objective of the studies outlined in this proposal is to determine how leukocyte adherence and emigration in postcapillary venules influence microvascular fluid and protein exchange during an acute inflammatory response. Three experimental maneuvers will be used to elicit an acute inflammatory response in cat mesenteric venules, ie., local intra-arterial infusion of either 1) leukotriene B4 or 2) platelet activating factor, and 3) one hour ischemia (blood flow reduced to 20% of baseline) followed by one hour of reperfusion. The rolling velocity, adherence and emigration of leukocytes as well as venular blood flow will be monitored in the three models of acute inflammation.
One specific aim will focus on the relative contributions of the three alpha-subunits (CD11a, CD11b, CD11c) and the common beta-subunit (CD18) of the CD11/CD18 leukocyte adhesion glycoprotein as well as the endothelial cell adhesion molecules, ICAM-1 and ELAM-1, in mediating the leukocyte-endothelial cell adhesive interactions elicited during acute inflammation. Specific monoclonal antibodies will be used to define the contributions of the different adhesive glycoproteins to leukocyte adhesion in vivo. The second specific aim is to determine whether the products of neutrophil activation (reactive oxygen metabolites and granule-associated proteins) modulate leukocyte adherence and emigration in mesenteric venules exposed to an acute inflammatory stimulus. Studies are proposed to assess the contributions of superoxide and hydrogen peroxide in modulating leukocyte adherence in vivo. Antibodies directed against either lactoferrin, elastase or myeloperoxidase, and specific inhibitors of the latter two enzymes will be used to determine whether neutrophilic granule-associated proteins also contribute to the leukocyte-endothelial cell adhesive interactions during inflammation. The third specific aim is to define the relative contributions of leukocyte and endothelial cell adhesion molecules to the increased intestinal vascular permeability associated with acute inflammation. These studies will involve measurements of vascular permeability in the acutely inflamed intestine of animals pretreated with monoclonal antibodies directed against specific subunits of the CD11/CD18 adhesive glycoproteins, ICAM-1 and ELAM-1. The results obtained should extend our understanding of the mechanisms underlying the enhanced vascular fluid and protein leakage and interstitial edema that accompanies an acute inflammatory response.
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