Abstract

To function as a gas exchanging organ, the lung must be free of inhaled particulates and microbes. The alveolar macrophage (AM) acts as a roving protector of alveolar surfaces. To perform this task, the AM evolved into a specialized cell markedly different from macrophages in other tissues. Novel major peptide components of rabbit AM, the macrophage cationic peptides MCP-1 and 2, were recently discovered and chemically characterized. These peptides together comprise up to 2% of the total AM protein and demonstrate microbicidal activity in vitro towards many types of bacteria, several fungi and herpes simplex virus. The MCPs also show opsonic activity towards several species of bacteria. Remarkably, these or similar peptides appear to be absent from adult rabbit monocytes, and peritoneal or splenic macrophages, and present in only small amounts in newborn rabbit AM. We hypothesize that MCPs are a specific product of rabbit AM, are contained in their lysosomal granules, and are employed for microbicidal and opsonic purposes. They are likely to be secreted into the lung fluids and into the phagosomes of AM. It is postulated that local pulmonary factors regulate the production of these peptides by AM. The known presence of homologous peptides in rabbit and human neutrophils makes it likely that related peptides will be found in AM of other species, including man. To test these hypotheses the following studies will be performed: 1. Immunohistochemical determination of the distribution of MCP in the lung 2. Measurement of the concentration of MCP in lung wash fluids 3. Electron microscopic determination of the intracellular location of MCP in AM 4. Measurement of secretion of MCP by AM in vitro 5. A search for regulatory and developmental signals for MCP synthesis by AM, using recombinant DNA methods. 6. Tests of the microbicidal role of MCP in AM in vitro and in vivo using resistant strains of bacteria 7. Measurements of opsonic activity of MCP towards organic and inorganic dusts 8. Analysis of human AM for the presence of MCP homologues. The MCPs are likely to endow the lungs of rabbit and man with a defensive capability. The understanding of their role may facilitate the fortification of these defenses in disease states.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035640-04
Application #
3349716
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1985-12-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Porter, E M; Bevins, C L; Ghosh, D et al. (2002) The multifaceted Paneth cell. Cell Mol Life Sci 59:156-70
Valore, E V; Park, C H; Quayle, A J et al. (1998) Human beta-defensin-1: an antimicrobial peptide of urogenital tissues. J Clin Invest 101:1633-42
Quayle, A J; Porter, E M; Nussbaum, A A et al. (1998) Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract. Am J Pathol 152:1247-58
Porter, E M; Liu, L; Oren, A et al. (1997) Localization of human intestinal defensin 5 in Paneth cell granules. Infect Immun 65:2389-95
Liu, L; Zhao, C; Heng, H H et al. (1997) The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry. Genomics 43:316-20
Porter, E M; van Dam, E; Valore, E V et al. (1997) Broad-spectrum antimicrobial activity of human intestinal defensin 5. Infect Immun 65:2396-401
Lehrer, R I; Ganz, T (1996) Endogenous vertebrate antibiotics. Defensins, protegrins, and other cysteine-rich antimicrobial peptides. Ann N Y Acad Sci 797:228-39
Valore, E V; Martin, E; Harwig, S S et al. (1996) Intramolecular inhibition of human defensin HNP-1 by its propiece. J Clin Invest 97:1624-9
Martin, E; Ganz, T; Lehrer, R I (1995) Defensins and other endogenous peptide antibiotics of vertebrates. J Leukoc Biol 58:128-36
Liu, L; Ganz, T (1995) The pro region of human neutrophil defensin contains a motif that is essential for normal subcellular sorting. Blood 85:1095-103

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