This project is designed to test the hypothesis that bacterial products, which produce acute and chronic systemic inflammation and inflammatory changes in the distal small intestine of susceptible hosts, act in part through activation of the kallikrein-kinin system. further, this study will determine if the kallikrein-kinin system is involved in the pathogenesis of experimentive inflammatory bowel disease (IBD). This plasma proteolytic enzyme system is a source of excellent candidate mediators since the reactions release bradykinin from high molecular weight kininogen (HK) which can produce edema, vascular permeability and pain, and generate kallikrein, which can cause neutrophil activation and chemotaxis.
The specific aims are: 1) To ascertain whether acute inflammation induced by systemically injected PG-PS is mediated by activation of the kallikrein- kinin system in rats by investigating the ability of contact system inhibitors to prevent the arthritis and the biochemical changes. 2) To ascertain whether activation of the kallikrein-kinin system accompanies indicators of acute inflammation by PG-PS and/or LPS and whether inhibitors will prevent pathologic and biologic changes. 3) To investigate whether the induction and reactivation of experimental granulomatous enterocolitis in rats is accompanied by activation of the kallikrein-kinin system and whether inhibition will prevent the pathologic and biochemical changes. 4) To determine if contact activation occurs with reactivation and colonic injury models. These models in rats mimic the extraintestinal manifestations and bowel changes of IBD and will evaluate the participation of the kallikrein-kinin system and therapeutic potential of specific inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043735-02
Application #
3245193
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1992-09-30
Project End
1995-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Isordia-Salas, Irma; Pixley, Robin A; Parekh, Hemant et al. (2003) The mutation Ser511Asn leads to N-glycosylation and increases the cleavage of high molecular weight kininogen in rats genetically susceptible to inflammation. Blood 102:2835-42
Stadnicki, Antoni; Mazurek, Urszula; Gonciarz, Maciej et al. (2003) Immunolocalization and expression of kallistatin and tissue kallikrein in human inflammatory bowel disease. Dig Dis Sci 48:615-23
Isordia-Salas, Irma; Pixley, Robin A; Li, Fengling et al. (2002) Kininogen deficiency modulates chronic intestinal inflammation in genetically susceptible rats. Am J Physiol Gastrointest Liver Physiol 283:G180-6
Isordia-Salas, Irma; Pixley, Robin A; Li, Fengling et al. (2002) Chronic intestinal inflammation and angiogenesis in genetically susceptible rats is modulated by kininogen deficiency. Int Immunopharmacol 2:1895-905
Uknis, A B; DeLa Cadena, R A; Janardham, R et al. (2001) Bradykinin receptor antagonists type 2 attenuate the inflammatory changes in peptidoglycan-induced acute arthritis in the Lewis rat. Inflamm Res 50:149-55
Selim, T E; Ghoneim, H R; Abdel Ghaffar, H A et al. (2001) High molecular mass kininogen inhibits cathepsin G-induced platelet activation by forming a complex with cathepsin G. Hematol J 2:371-7
Colman, R W (1999) Plasma and tissue kallikrein in arthritis and inflammatory bowel disease. Immunopharmacology 43:103-8
DeLa Cadena, R A; Kunapuli, S P; Walz, D A et al. (1998) Expression of thrombospondin 1 on the surface of activated platelets mediates their interaction with the heavy chains of human kininogens through Lys 244-Pro 254. Thromb Haemost 79:186-94
Stadnicki, A; Sartor, R B; Janardham, R et al. (1998) Kallikrein-kininogen system activation and bradykinin (B2) receptors in indomethacin induced enterocolitis in genetically susceptible Lewis rats. Gut 43:365-74
Blais Jr, C; Couture, R; Drapeau, G et al. (1997) Involvement of endogenous kinins in the pathogenesis of peptidoglycan-induced arthritis in the Lewis rat. Arthritis Rheum 40:1327-33

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