Several lines of evidence support the concept that important alterations in the pulmonary parenchyma occur in a substantial number of HIV- seropositive individuals prior to the development of recognized pulmonary complications. Although the pathogenesis of these abnormalities remains obscure, recent evidence has suggested an important role for an HIV-associated lymphocytic alveolitis and critical alveolar lymphocyte-alveolar macrophage interactions. The goal of the present project is to extend these observations by rigorously examining the significance of a lymphocytic alveolitis both with respect to physiologic and morphologic evidence of lung injury as well as with respect to dysregulation of cytokine production by alveolar macrophages. The following specific aims will be examined in an effort to reach this goal.
Specific Aim 1 addresses this question: Is the in vivo presence of an HIV-associated lymphocytic alveolitis a critical determinant of parenchymal lung injury and proinflammatory cytokine upregulation? This aim will prospectively delineate the importance of a lymphocytic alveolitis with respect to physiologic, radiographic, and morphometric evidence of parenchymal lung damage as well as with respect to in vivo proinflammatory cytokine induction. The question in Specific Aim 2 addresses: Is the in vitro presence of alveolar cytoxic T- lymphocytes an important regulatory factor in the production of TNF alpha and IL-1 beta by alveolar macrophages? This aim will examine basic mechanisms of proinflammatory cytokine regulation and will focus primarily on the effects of CD8+ cytotoxic lymphocytes on IL-beta processing and release by alveolar macrophages. Because this study addresses the significance of one of the most common of the inflammatory events occurring in the alveolar environment in HIV, it may greatly advance knowledge of HIV- related lung disease. Perhaps more importantly, it focuses on the role of the alveolar lymphocyte as a central player in orchestrating pulmonary parenchymal damage through interactions with alveolar macrophages. As such, this project represents an opportunity to elucidate novel mechanisms of lung injury and to better understand factors of potentially fundamental importance to the regulation of inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL053229-01
Application #
2231042
Study Section
Special Emphasis Panel (ZHL1-CSR-C (M1))
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Wewers, Mark D; Lemeshow, Stanley; Lehman, Amy et al. (2005) Lung CD4 lymphocytes predict survival in asymptomatic HIV infection. Chest 128:2262-7
Diaz, Philip T; Wewers, Mark D; Pacht, Eric et al. (2003) Respiratory symptoms among HIV-seropositive individuals. Chest 123:1977-82
Fahy, R J; Diaz, P T; Hart, J et al. (2001) BAL and serum IgG levels in healthy asymptomatic HIV-infected patients. Chest 119:196-203
Diaz, P T; King, M A; Pacht, E R et al. (2000) Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers. Ann Intern Med 132:369-72
Fahy, R J; Doseff, A I; Wewers, M D (1999) Spontaneous human monocyte apoptosis utilizes a caspase-3-dependent pathway that is blocked by endotoxin and is independent of caspase-1. J Immunol 163:1755-62
Diaz, P T; King, M A; Pacht, E R et al. (1999) The pathophysiology of pulmonary diffusion impairment in human immunodeficiency virus infection. Am J Respir Crit Care Med 160:272-7
Wewers, M D; Diaz, P T; Wewers, M E et al. (1998) Cigarette smoking in HIV infection induces a suppressive inflammatory environment in the lung. Am J Respir Crit Care Med 158:1543-9
Marsh, C B; Wewers, M D (1996) The pathogenesis of sepsis. Factors that modulate the response to gram-negative bacterial infection. Clin Chest Med 17:183-97