Intestinal ischemia and reperfusion is a common condition in the critically ill and it has been implicated as an important factor in the etiology of a variety of pathologic conditions, including multiple organ failure, necrotizing enterocolitis, and inflammatory bowel disease. The overall objective of this Program Project Grant is to define the events that ultimately lead to the mucosal dysfunction that is observed during ischemia and following reperfusion of the adult and neonatal intestine. This program will formalize and extend existing collaborative efforts among nine investigators with an active interest in the pathobiology of intestinal ischemia. The Program will employ a multidisciplinary approach to elucidate the mechanisms underlying the structural, biochemical and physiological responses of the mucosal epithelium, interstitial matrix, vascular smooth muscle and microvascular endothelium to ischemia and reperfusion. The proposed work will focus on both the early (minutes to hours) and late events (days) associated with ischemia and reperfusion, including tissue hypoxia, leukocyte adhesion and emigration from the microvasculature, epithelia cell dysfunction, endothelial and epithelial cell injury, interstitial matrix and basement membrane degradation, decreased sensitivity of arterioles to circulating vasoconstrictors, increased mucosal permeability, mucosal ulceration, and finally mucosal regeneration and repair. Project 1 will characterize the decrement and recovery of mucosal function (lipid absorption) and its relation to the morphological changes that occur during the first few days following a brief period of mesenteric ischemia. Project 2 will assess the responses of the intestinal vasculature and mucosal permeability to ischemia- reperfusion in the developing intestine during feeding. Project 3 will study the mechanisms underlying the altered responsiveness of the intestinal microvasculature to vasoconstrictors following ischemia- reperfusion. Project 4 will determine how the variations in vascular shear forces that occur during ischemia and reperfusion influence leukocyte adhesion and emigration in mesenteric venules. Project 5 will focus on the mechanisms by which neutrophils adhere to and injure cultured vascular endothelium exposed to anoxia-reoxygenation. Project 6 will examine how interstitial fluid protects the interstitial matrix, basement membrane, and epithelial cells from the products of neutrophil activation. These projects will be supported by facilities in the Administrative Core, (Core A) Cell Culture Core (Core B), Biochemistry Core (Core C), and Morphology COre (Core D). This coordinated effort is aimed at elucidating the mechanisms that are responsible for the mucosal dysfunction and injury associated with intestinal ischemia and reperfusion, with the ultimate goal of providing the fundamental knowledge needed to improve the diagnosis and treatment of ischemic disorders of the bowel.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK043785-04
Application #
2143284
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1991-06-01
Project End
1996-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
4
Fiscal Year
1994
Total Cost
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
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
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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