The central role of airway mucus in obstructive lung diseases such as chronic bronchitis and bronchial asthma is well appreciated in clinical and pathologic investigations. Abnormalities in mucus secretion and composition are felt to contribute to the morbidity and mortality in these diseases. But the mechanisms controlling the composition of mucus as well as the amount of this secretion remain poorly understood. In previous studies we described a novel molecule, synthesized and released by pulmonary macrophages (PM), peripheral blood monocytes (PMN), and currently from human macrophage hybridoma cell line number 13, which is able to cause human airways to release increased amounts of biosynthetically radiolabeled mucous glycoproteins (MGP). This molecule was termed macrophage (or monocyte) derived mucus secretagogue (MMS). The role of MMS in health and disease forms the basis of this proposal. MMS has been chemically characterized and purified. Initial effort of this proposal will be directed towards the development of immunological assay (ELISA) for the specific and sensitive detection of MMS. This would allow us to investigate the clinical relevance of MMS. Our clinical objectives are to clarify the mechanisms underlying enhanced mucus secretion in patients with bronchitis and chronic obstructive pulmonary disease (COPD). Specifically, we will examine if MMS is important in regulating mucus secretion under these clinical conditions. In vivo and in vitro measurements of MMS activity in PM, PMN and bronchoalveolar lavage fluid (BALF), will be performed in patients with bronchitis and COPD to 1) demonstrate that airway mucus hypersecretion in these clinical conditions is associated with detectable MMS activity; 2) demonstrate that mucus hypersecretion in these patients is associated with macrophage activation leading to facilitated release of MMS; 3) determine the possible mechanisms underlying prolonged mucus secretion in patients with bronchitis and COPD; 4) establish a relation between the hypersecretion of mucus in the airways and MMS activity. We expect that the information derived from these studies will contribute to the understanding of the mechanisms controlling the secretion of airway mucus, especially in patients with mucus hypersecretion. The obtained results may help to identify individuals at risk of developing chronic bronchitis, may provide us with a marker for patients with COPD and will form the basis for pharmacologic intervention in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL037254-01A2
Application #
3352780
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-01-01
Project End
1991-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Sperber, K; Chanez, P; Bousquet, J et al. (1995) Detection of a novel macrophage-derived mucus secretagogue (MMS-68) in bronchoalveolar lavage fluid of patients with asthma. J Allergy Clin Immunol 95:868-76
Gollub, E G; Waksman, H; Goswami, S et al. (1995) Mucin genes are regulated by estrogen and dexamethasone. Biochem Biophys Res Commun 217:1006-14
Goswami, S; Gollub, E; Weiss, D J et al. (1994) Characterization of a unique mucin-like glycoprotein secreted by a human endometrial adenocarcinoma cell line (Ishikawa). Exp Lung Res 20:85-100
Gollub, E G; Goswami, S; Kouba, D et al. (1993) Regulation of mucin gene expression in secretory epithelial cells. Biochem Biophys Res Commun 197:667-73
Sperber, K; Sylvester, C; Gollub, E et al. (1993) In vivo detection of a novel macrophage-derived protein involved in the regulation of nasal mucus-like glycoconjugate secretion. J Allergy Clin Immunol 92:581-8
Gollub, E G; Goswami, S K; Sperber, K et al. (1992) Isolation and characterization of a macrophage-derived high molecular weight protein involved in the regulation of mucus-like glycoconjugate secretion. J Allergy Clin Immunol 89:696-702
Amin, D N; Goswami, S; Klein, T et al. (1991) Functional antagonism between hormone receptor systems: modulation of glycoprotein secretion in secretory epithelial cells. Am J Respir Cell Mol Biol 4:135-9
Goswami, S K; Kivity, S; Marom, Z (1990) Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. Am Rev Respir Dis 141:72-8
Bernstein, J M; Goswami, S; Marom, Z (1990) Macrophage (monocyte)-derived mucous secretagougue (MMS) is released into the fluid of the middle ear of patients with otitis media with effusion. Otolaryngol Head Neck Surg 103:1-9