Pneumocystis carinii pneumonia is a major cause of mortality in immunosuppressed subjects with and without the acquired immune deficiency syndrome (AIDS). Although much has been learned in recent years regarding the microbiologic aspects of P. carinii, the mechanisms underlying P. carinii pneumonia are poorly understood. For example, prior ultrastructural studies suggest the successful attachment of P. carinii to target lung cells is critical to the growth of the organisms and the development of pneumonia; yet, the biochemical mechanisms of attachment of P. carinii are virtually unstudied. Furthermore, alveolar epithelial cell damage in P. carinii pneumonia is well recognized, but no studies have yet attempted to examine the mechanism of this adverse effect. The normal host response to invading microorganisms is the development of an inflammatory or immune response within the lung. In contrast, P. carinii pneumonia in immunosuppressed animals or human subjects is generally characterized by a poor but variable inflammatory response. The ability of P. carinii (via cell attachment) to directly induce lung cells to release proinflammatory mediators is unstudied, and may provide important insight into the mechanisms of the pneumonia and the host response to the organism. We propose an entirely different approach to the study of P. carinii pneumonia with a focus on the in vitro interaction of P. carinii with cultured lung cells as a model of P. carinii pneumonia. We propose the following Specific Aims: 1) to determine the mechanism(s) of attachment of P. carinii to target lung cells, 2) to determine if P. carinii adversely affects lung cell function, 3) to determine if P. carinii induces target lung cells to generate proinflammatory mediators, 4) to determine if proinflammatory mediators or inflammatory cells inhibit P. carinii viability or growth and 5) to determine if a """"""""cause-effect"""""""" relationship exists between P. carinii attachment and impairment of lung cell function or release of proinflammatory mediators. Such studies will likely provide new insight into P. carinii pneumonia and potentially suggest novel therapeutic strategies for this devastating lung disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043524-04
Application #
3362156
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Davis, Ian C; Zhu, Sha; Sampson, Jacinda B et al. (2002) Inhibition of human surfactant protein A function by oxidation intermediates of nitrite. Free Radic Biol Med 33:1703-13
Pasula, Rajamouli; Wisniowski, Paul; Martin 2nd, William J (2002) Fibronectin facilitates Mycobacterium tuberculosis attachment to murine alveolar macrophages. Infect Immun 70:1287-92
Spech, R W; Wisniowski, P; Kachel, D L et al. (2000) Surfactant protein A prevents silica-mediated toxicity to rat alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 278:L713-8
Perry, D G; Daugherty, G L; Martin 2nd, W J (1999) Clathrin-coated pit-associated proteins are required for alveolar macrophage phagocytosis. J Immunol 162:380-6
Pasula, R; Wright, J R; Kachel, D L et al. (1999) Surfactant protein A suppresses reactive nitrogen intermediates by alveolar macrophages in response to Mycobacterium tuberculosis. J Clin Invest 103:483-90
Zhu, S; Kachel, D L; Martin 2nd, W J et al. (1998) Nitrated SP-A does not enhance adherence of Pneumocystis carinii to alveolar macrophages. Am J Physiol 275:L1031-9
Pasula, R; Downing, J F; Wright, J R et al. (1997) Surfactant protein A (SP-A) mediates attachment of Mycobacterium tuberculosis to murine alveolar macrophages. Am J Respir Cell Mol Biol 17:209-17
Perry, D G; Wisniowski, P; Daugherty, G L et al. (1997) Nonimmune phagocytosis of liposomes by rat alveolar macrophages is enhanced by vitronectin and is vitronectin-receptor mediated. Am J Respir Cell Mol Biol 17:462-70
Weaver, T; Hall, C L; Kachel, D L et al. (1996) Assessment of in vivo attachment/phagocytosis by alveolar macrophages. J Immunol Methods 193:149-56
Williams, M D; Wright, J R; March, K L et al. (1996) Human surfactant protein A enhances attachment of Pneumocystis carinii to rat alveolar macrophages. Am J Respir Cell Mol Biol 14:232-8

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