and specific aims): Interleukin-8 (IL-8) is a potent neutrophil attractant and activator. IL-8 has been reported to be involved in the pathogenesis of several diseases including idiopathic dilated cardiomyopathy, sepsis, rheumatoid arthritis, psoriasis and the acute respiratory distress syndrome (ARDS). ARDS affects more than 150,000 people each year in the USA, and the mortality of severe cases remains at 50-80 percent of autoantibodies to IL-8 in lung fluids from patients with ARDS. The purpose of this research is to test two hypotheses: HYPOTHESIS 1: IL-8 function in the lung is regulated by IL-8-binding proteins, including alpha-2-macroglobulin and anti-IL-8 autoantibodies. HYPOTHESIS 2: Interaction between IL-8 and IL-8-binding proteins affects the outcome of IL-8-dependent lung inflammation.
The specific aims are: 1a) to determine how alpha-2-macroglobulin affects IL-8 function in the lung; 1b) to determine if the autoantibodies to IL-8 modulate IL-8 activity in the lung; 2a) to determine if antibodies against IL-8 prevent the development of IL-8-dependent lung inflammation in rabbits; 2b) to establish if alpha-macroglobulin affects the course of IL-8-dependent lung inflammation in rabbits; 2c) to determine if antibodies to IL-8 and alpha-macroglobulin act in synergy to regulate IL-8 in vivo; and 2d) to establish if the presence of alpha-2-macroglobulin and anti-IL-8 autoantibodies at different stages of the acute lung injury correlates with the improved survival rate in patients with ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL056768-03
Application #
6030761
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1997-08-15
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
City
Tyler
State
TX
Country
United States
Zip Code
75708
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Kurdowska, Anna; Noble, James M; Grant, Ian S et al. (2002) Anti-interleukin-8 autoantibodies in patients at risk for acute respiratory distress syndrome. Crit Care Med 30:2335-7
Kurdowska, A; Noble, J M; Griffith, D E (2001) The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages. J Antimicrob Chemother 47:867-70
Kurdowska, A; Alden, S M; Noble, J M et al. (2000) Involvement of alpha-2-macroglobulin receptor in clearance of interleukin 8-alpha-2-macroglobulin complexes by human alveolar macrophages. Cytokine 12:1046-53
Kurdowska, A; Fujisawa, N; Peterson, B et al. (2000) Specific binding of IL-8 to rabbit alpha-macroglobulin modulates IL-8 function in the lung. Inflamm Res 49:591-9
Kurdowska, A; Noble, J M; Steinberg, K P et al. (1999) Anti-IL-8 autoantibodies in alveolar fluid from patients at risk for ARDS and with well-defined ARDS. Chest 116:9S
Fujisawa, N; Hayashi, S; Kurdowska, A et al. (1999) Inhibition of GROalpha-induced human endothelial cell proliferation by the alpha-chemokine inhibitor antileukinate. Cytokine 11:231-8
Fujisawa, N; Hayashi, S; Kurdowska, A et al. (1998) Staphylococcal enterotoxin A-induced injury of human lung endothelial cells and IL-8 accumulation are mediated by TNF-alpha. J Immunol 161:5627-32