Ischemia and reperfusion is a regional circulatory disorder that elicits microvascular and immune responses that are characteristic of acute inflammatory conditions, such as multiple organ system failure and organ transplantation. The overall objective of this Program Project Grant (program project) is to define the mechanisms that underlie the inflammatory responses, microvascular dysfunction, and parenchymal cell injury that result when the intestine and/or liver are exposed to ischemia and reperfusion. The program formalizes and extends existing collaborations among thirteen investigators with an active interest in the pathobiology of ischemia/reperfusion (I/R) injury. Support is requested for five projects, three scientific cores, and an administrative core. The molecular, biochemical, structural, and functional responses of microvascular endothelial cells to I/R is a major focus of the work outlined in this program project. Project 0004 will address the potential roles of superoxide and nitric oxide (NO), as well as reduced shear rates, in mediating I/R-induced platelet-endothelial cell adhesion in intestinal venules and define the importance of platelets in modulating the recruitment of leukocytes and endothelial barrier dysfunction in postischemic venules. Project 0007 will focus on the mechanisms whereby acute ethanol consumption promotes the development of a sustained defensive (or protected) phenotype in the intestine such that the gut exhibits enhanced resistance to the deleterious consequences of I/R for 24 to 48 hrs after ingestion. Project 0006 will determine the mechanisms by which hepatic I/R-induced oxidative stress creates an imbalance between NF-kB-dependent expression of potentially injurious cytokines and protective proteins in favor of the former resulting in liver injury. Project 0010 will examine the mechanisms that allow Kupffer cells and hepatocytes to modulate the responses of hepatic endothelial cells to hypoxia-reoxygenation, including NF-kB activation, inflammatory cytokine expression, and E-selectin upregulation. Project 0009 will determine how matrix metalloprotease (MMPs) synthesis and activation are regulated in posthypoxic endothelial cells, and how MMPs contribute to the endothelial barrier dysfunction that is associated with I/R. These projects will be supported by services provided by an, Cell Biology/Morphology Core (9001), Molecular Biology/Biochemistry Core (9002) and a Mutant Mouse Resource Facility (9003). This coordinated effort involves a multidisciplinary approach aimed at elucidating the mechanisms responsible for I/R-induced inflammation and microvascular dysfunction at the molecular, cellular, single microvessel and organ levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK043785-11A1
Application #
6535452
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M1))
Program Officer
Hamilton, Frank A
Project Start
1997-05-01
Project End
2007-06-30
Budget Start
2002-08-07
Budget End
2003-06-30
Support Year
11
Fiscal Year
2002
Total Cost
$1,486,250
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Physiology
Type
Schools of Medicine
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
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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
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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
Cromer, Walter E; Ganta, Chaitanya V; Patel, Mihir et al. (2013) VEGF-A isoform modulation in an preclinical TNBS model of ulcerative colitis: protective effects of a VEGF164b therapy. J Transl Med 11:207
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

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