Intestinal ischemia-reperfusion, as a primary event or as an adaptive response to systemic hypotension, is a common clinical problem which can activate a systemic inflammatory response. Systemic inflammation is characterized by neutrophil entrapment in the lung, increased pulmonary microvascular permeability and clinical evidence of non-cardiogenic pulmonary edema, commonly termed the acute respiratory distress syndrome (ARDS). There are over 150,000 cases of ARDS annually in the United States and 50% of these patients will die. Although systemic inflammation and ARDS are characterized by neutrophil retention in the lung, the mechanism by which these inflammatory cells are trapped in athe lung microvasculature and contribute to permeability edema formation following intestinal ischemia-reperfusion is not clear. However, we have recently developed a new animal model which allows us to distinguish the events in the gut which initiate systemic inflammation from the locally medicated pulmonary injury response to the systemic insult. Using this new technique, we will test the overall hypothesis that intestinal ischemia-reperfusion induced alterations in reactive oxygen metabolites and nitric oxide elicit the activation and subsequent sequestration of leukocytes in the pulmonary microvessels. The entrapped leukocytes diminish the barrier function of pulmonary endothelial cells by releasing elastase.
The specific aims of the work outlined in this proposal are: 1) To define the contribution of reactive oxygen metabolites generated in the lung or in the intestine to the disruption of pulmonary microvascular barrier integrity elicited by intestinal ischemia-reperfusion; 2) To define the role of alterations in lung and intestinal nitric oxide availability in the pulmonary injury elicited by intestinal ischemia- reperfusion; 3) To define the contributions of platelet activating factor, leukotriene B4 and complement activation in the lung or in the intestine to the pulmonary dysfunction elicited by intestinal ischemia-reperfusion; and 4) To define the role of neutrophil elastase ina the lung or in the intestine in the pulmonary dysfunction elicited by intestinal ischemia- reperfusion. The results of this work will significantly enhance our understanding of the mechanisms responsible for lung neutrophil retention and pulmonary microvascular barrier disruption following intestinal ischemia-reperfusion and may provide a means for the development of therapeutic interventions in ARDS.

Project Start
2000-09-01
Project End
2002-07-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2000
Total Cost
$74,357
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Type
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Ma, Yuxiang; Okazaki, Yasumasa; Glass, Jonathan (2018) A fluorescent metal-sensor study provides evidence for iron transport by transcytosis in the intestinal epithelial cells. J Clin Biochem Nutr 62:49-55
Hozumi, Hideaki; Russell, Janice; Vital, Shantel et al. (2016) IL-6 Mediates the Intestinal Microvascular Thrombosis Associated with Experimental Colitis. Inflamm Bowel Dis 22:560-8
Souza, Daniele G; Senchenkova, Elena Y; Russell, Janice et al. (2015) MyD88 mediates the protective effects of probiotics against the arteriolar thrombosis and leukocyte recruitment associated with experimental colitis. Inflamm Bowel Dis 21:888-900
Yan, Serena L S; Russell, Janice; Granger, D Neil (2014) Platelet activation and platelet-leukocyte aggregation elicited in experimental colitis are mediated by interleukin-6. Inflamm Bowel Dis 20:353-62
Senchenkova, Elena Y; Komoto, Shunsuke; Russell, Janice et al. (2013) Interleukin-6 mediates the platelet abnormalities and thrombogenesis associated with experimental colitis. Am J Pathol 183:173-81
Yan, Serena L S; Russell, Janice; Harris, Norman R et al. (2013) Platelet abnormalities during colonic inflammation. Inflamm Bowel Dis 19:1245-53
Singer, Georg; Stokes, Karen Y; Neil Granger, D (2013) Reactive oxygen and nitrogen species in sepsis-induced hepatic microvascular dysfunction. Inflamm Res 62:155-64
Watts, Megan N; Eshaq, Randa S; Carter, Patsy R et al. (2013) Decreased retinal blood flow in experimental colitis; improvement by eye drop administration of losartan. Exp Eye Res 115:22-6
Watts, Megan N; Leskova, Wendy; Carter, Patsy R et al. (2013) Ocular dysfunction in a mouse model of chronic gut inflammation. Inflamm Bowel Dis 19:2091-7
Carter, Patsy R; Watts, Megan N; Kosloski-Davidson, Melissa et al. (2013) Iron status, anemia, and plasma erythropoietin levels in acute and chronic mouse models of colitis. Inflamm Bowel Dis 19:1260-5

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