Bacterial pneumonia is the second most common cause of hospital-acquired infection, and is leading cause of death among all nosocomial infections. Innate, or natural immunity, is the principal pathway for effective elimination of bacterial organisms from the lung. While ELR-CXC chemokines have been shown to be expressed during the generation of Th1 cell-mediated immune responses against intracellular microbial pathogens, the contribution of this family of chemokines to innate immunity against common gram-positive and gram-negative bacterial pathogens is unknown. We have focused this competitive renewal on ELR-CXC chemokines, as our preliminary observations indicate that the in-vivo depletion of selected ELR-CXC chemokines substantially impairs bacterial clearance and survival of mice with pneumonia due to Klebsiella pneumoniae. It is the hypothesis of this proposal that ELR-CXC chemokines are integral components of the innate neutrophil-dependent immune response against gram-negative bacterial infection of the lung. A murine model of Klebsiella pneumonia will be employed to achieve the following specific aims: 1) to determine the time course of expression and cellular sources of ELR-CXC chemokines and their common receptor (CXCR3) during the evolution of gram-negative bacterial pneumonia; 2) to determine the contribution of ELR-CXC chemokines and their receptor to leukocyte recruitment, proinflammatory cytokine expression, bacterial clearance, survival in Klebsiella pneumonia using specific neutralizing antibodies or knockout mice; 3) to determine the effect of IP-10 or MIG administration/transgenic expression on proinflammatory cytokine expression, bacterial clearance, and survival in murine Klebsiella pneumonia in-vivo and on alveolar macrophage effector cell function in-vitro; and 4) to identify endogenous signals that regulate the expression of ELR-CXC chemokines during the evolution of Klebsiella pneumonia in-vivo and in isolated lung cells in-vitro. Elucidation of specific cellular and molecular mechanisms of lung antibacterial host defense, in conjunction with the use of novel gene therapy approaches will provide important insights into the treatment of patients with serious multi-drug resistant bacterial infections of the lung.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057243-07
Application #
6621715
Study Section
Special Emphasis Panel (ZRG1-RAP (01))
Program Officer
Harabin, Andrea L
Project Start
1996-12-01
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
7
Fiscal Year
2003
Total Cost
$302,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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