Abstract

The goal of this proposal is to determine the roles of alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN) in the development of emphysema. RATIONALE: Emphysema is an important clinical problem. The mechanisms responsible for the development of emphysema are not known. However, it is known that: 1) Phagocytes are strategically located at the site of the primary lesions of emphysema, 2) Phagocytes produce enzymes and reactive oxygen species that can cause tissue destruction and 3) Cigarette smoking appears to alter the numbers and activities of AM and PMN in such a way to increase their potential toxicity for lung tissue. Hypothesis: The working hypothesis is that AM and/or PMN release proteolytic enzymes and reactive O2 species which participate in the development of emphysema. RESEARCH PLAN: A model of emphysema has been developed which involves intratracheal administration of CdCL2 to hamsters fed the lathyrogen Beta-adminoproprionitrile. Using this model, experiments have been designed that will: 1) Determine the time course relationships between the number of AM and/or PMN in the lung, their metabolic and enzymatic activities and the development of emphysema and 2) To determine the effect of selective depletion of AM and/or PMN on the development of emphysema. SIGNIFICANCE: The findings of the proposed research will provide a better understanding of lung injury so that methods of interrupting the process can be designed and tested.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001308-04
Application #
3073744
Study Section
Pathology A Study Section (PTHA)
Project Start
1983-09-01
Project End
1987-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163

  Publications

Port, J D; Debellis, C C; Klein, J et al. (1992) Pharmacological characterization of chick and frog beta adrenergic receptors in primary cultures of myocardial cells. J Pharmacol Exp Ther 262:217-24
Rao, N V; Kennedy, T P; Rao, G et al. (1990) Sulfated polysaccharides prevent human leukocyte elastase-induced acute lung injury and emphysema in hamsters. Am Rev Respir Dis 142:407-12
Port, J D; Gilbert, E M; Larrabee, P et al. (1990) Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart. Circulation 81:929-38
McCusker, K; Hoidal, J (1990) Selective increase of antioxidant enzyme activity in the alveolar macrophages from cigarette smokers and smoke-exposed hamsters. Am Rev Respir Dis 141:678-82
Kennedy, T P; Rao, N V; Hopkins, C et al. (1989) Role of reactive oxygen species in reperfusion injury of the rabbit lung. J Clin Invest 83:1326-35
Kao, R C; Wehner, N G; Skubitz, K M et al. (1988) Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. J Clin Invest 82:1963-73
Hibbs, M S; Hoidal, J R; Kang, A H (1987) Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages. J Clin Invest 80:1644-50
McLaughlin, M E; Kao, R; Liener, I E et al. (1986) A quantitative in vitro assay of polymorphonuclear leukocyte migration through human amnion membrane utilizing 111in-oxine. J Immunol Methods 95:89-98
Hoidal, J R; Niewoehner, D E; Rao, N V et al. (1985) The role of neutrophils in the development of cadmium chloride-induced emphysema in lathyrogen-fed hamsters. Am J Pathol 120:22-9
Gudapaty, S R; Liener, I E; Hoidal, J R et al. (1985) The prevention of elastase-induced emphysema in hamsters by the intratracheal administration of a synthetic elastase inhibitor bound to albumin microspheres. Am Rev Respir Dis 132:159-63

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