Lung inflammation contributes to morbidity and mortality in many critically ill patients. The major goals of this proposal are to understand the mechanisms that regulate cell traffic during inflammatory processes in the lungs and to develop strategies that could be used to limit some types of lung inflammation. Chemotactic factors generated by alveolar macrophage and other cells in the lung airspaces recruit leukocytes from the bloodstream into the lungs. These leukocytes amplify inflammatory reactions and their products may contribute to lung injury in some circumstances. Because the alveolar macrophage is a primary cell that recognizes bacteria and foreign particulate in the airspaces, we hypothesize that alveolar macrophage products are important in initiating and sustaining inflammatory responses in the lungs.
The Specific Aims of this proposal are: 1) to identify the major peptide chemoattractants for neutrophils (PMN) and monocytes (MN) that are produced by alveolar macrophage; 2) to develop specific approaches to inhibit the function of these peptides; 3) to define the regulation of these products in response to bacterial products; and 4) to compare the potency of these endogenous chemoattractants with the potency of chemoattractants produced by Gram negative and Gram positive bacteria. In the studies proposed, we will determine the relative contribution of peptide chemoattractants to the chemotactic activity for PMN and MN produced by stimulated alveolar macrophage; we will clone the receptors for IL-8 and MCP-1, two major PMN and MN chemoattractants, respectively; we will raise monoclonal antibodies to these receptors that inhibit receptor-ligand interactions and test these antibodies for their ability to block leukocyte migration in vitro and in vivo; and we will compare the relative potency of the alveolar macrophage derived peptides with the products of Gram positive and Gram negative bacteria in order to determine whether inhibition of endogenous chemotactic signals poses a potential risk to the host during bacterial infections. These studies will identify strategies to limit inflammation in the lungs that could lead to improved therapy in critically ill patients with diffuse lung injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029103-07
Application #
2390336
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1990-07-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Mou, Zhirong; Muleme, Helen M; Liu, Dong et al. (2013) Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating programmed cell death-1-mediated CD4+ T cell exhaustion. J Immunol 190:3380-9
Muleme, Helen M; Reguera, Rosa M; Berard, Alicia et al. (2009) Infection with arginase-deficient Leishmania major reveals a parasite number-dependent and cytokine-independent regulation of host cellular arginase activity and disease pathogenesis. J Immunol 183:8068-76
Kurahashi, Kiyoyasu; Sawa, Teiji; Ota, Maria et al. (2009) Depletion of phagocytes in the reticuloendothelial system causes increased inflammation and mortality in rabbits with Pseudomonas aeruginosa pneumonia. Am J Physiol Lung Cell Mol Physiol 296:L198-209
Frevert, Charles W; Goodman, Richard B; Kinsella, Michael G et al. (2002) Tissue-specific mechanisms control the retention of IL-8 in lungs and skin. J Immunol 168:3550-6
Kurdowska, A; Noble, J M; Steinberg, K P et al. (2001) Anti-interleukin 8 autoantibody: interleukin 8 complexes in the acute respiratory distress syndrome. Relationship between the complexes and clinical disease activity. Am J Respir Crit Care Med 163:463-8
Matute-Bello, G; Winn, R K; Jonas, M et al. (2001) Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation. Am J Pathol 158:153-61
Sittipunt, C; Steinberg, K P; Ruzinski, J T et al. (2001) Nitric oxide and nitrotyrosine in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 163:503-10
Park, W Y; Goodman, R B; Steinberg, K P et al. (2001) Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 164:1896-903
Matute-Bello, G; Frevert, C W; Kajikawa, O et al. (2001) Septic shock and acute lung injury in rabbits with peritonitis: failure of the neutrophil response to localized infection. Am J Respir Crit Care Med 163:234-43
Matute-Bello, G; Liles, W C; Radella 2nd, F et al. (2000) Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med 28:7-Jan

Showing the most recent 10 out of 36 publications