Distant organ injury following intestinal ischemia-reperfusion (I-R) is associated with the entrapment and activation of leukocytes within several organs, including the lung, which promote increased salute permeability across the microvasculature and the major causes of morbidity and mortality associated with reperfusion injury are pulmonary edema and impaired lung function. Recently, we have reported that the solute barrier created and maintained by the endothelium involves cell-cell adhesion mediated by a class of cell surface proteins called 'cadherins' which help form the endothelial adherens junction. The endothelial junction forms the solute barrier, and is associated with the cortical actin cytoskeleton which regulates junctional structure and barrier. Although several different in vivo and in vitro approaches have been explored to understand the etiology of reperfusion injury following ischemia, junctional mechanisms through which the microvascular barrier is altered following I-R remain less well characterized. Many studies suggest that PMN derived oxidants and proteases significantly modify the microvascular barrier, and it is highly likely that the endothelial adherens junctions is an important target of these agents. The studies outlined in this proposal will test the hypothesis that PMN-derived mediators promote increased microvascular permeability in reperfusion injury by disrupting the normal organization and integrity of the cadherin cytoskeletal complex. Based on several lines of preliminary results, we will determine; 1) which PMN-derived oxidants and proteases alter the barrier created by the adherens junction, 2) determine how the translocation (endocytosis), cytoskeletal association and surface organization of cadherins within the endothelial adherens junction are affected by PMN oxidants and proteases, and 3) determine how PMN oxidants and proteases promote destructive (proteolytic) changes in endothelial cadherins to increase solute permeability. The proposed experiments should allow us to gain important insights into the junctional mechanisms of increased permeability in I-R injury and aid in the development of therapies for edema which target the endothelial junction.

Project Start
2000-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Type
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
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Yan, Serena L S; Russell, Janice; Harris, Norman R et al. (2013) Platelet abnormalities during colonic inflammation. Inflamm Bowel Dis 19:1245-53

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