The major objective of this project is to gain an understanding of the presently undefined relationship between pulmonary macrophages, lung inflammation and respiratory mucus secretion. Our approach towards achieving this objective will make use of the novel mucus secretagogue, MMS, which is elaborated by pulmonary macrophages, peripheral blood monocytes and a human macrophage hybridoma cell line, (HB63). MMS has been demonstrated to be a mediator of lung inflammation and a regulator of mucus secretion. A further in-depth study of this secretagogue at the molecular level is proposed which will lead to a clearer understanding of the regulatory mechanisms in the biosynthesis and secretion of MMS.
The specific aims are 1) to isolate and sequence the cDNA coding for the MMS protein and to study the pattern of gene expression in cultured cells in response to various inducers and inhibitors of mMS formation and secretion. Gene expression will be studied by measuring steady state mRNA levels in the cells to ascertain whether cellular mRNA is modulated under conditions which exhibit modulation of secreted MMS. Results of these studies will help to elucidate the relationship between MMS secretion and mucus secretion/hypersecretion. Another major objective is to better understand the clinical role that MMS plays in lung diseases associated with mucus hypersecretion as well as to gain an understanding to the mechanism of action of MMS in the secretory cells.
Specific aims two and three are proposed to achieve these goals: 2) to correlate the in-vitro studies with clinical studies by using peripheral blood monocytes from normal volunteers and from patients with inflammatory lung diseases, especially asthmatics, steroid dependent asthmatics and bronchitics and to determine whether there is any relationship between the disease state, levels of MMS and the levels of MMS-mRNA in these cells. 3) to study the mechanism of MMS activity by investigating membrane, transmembrane and cellular signaling pathways associated with MMS stimulation of mucus secretion from the secretory cells. This multifaceted approach should provide new insights into the mechanisms regulating MMS synthesis and secretion, its possible mechanism of action, as well as provide new information about the regulation of mucus secretion in inflammatory lung diseases. In the future, this proposed research may also help in the possible development of diagnostic tools (e.g. RFLP analysis for potential familial predisposition for the development of asthma or steroid dependent asthma), and/or therapeutic agents (e.g. development of new drugs or new use of existing ones) for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL037254-04A1
Application #
3352782
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1989-01-01
Project End
1996-06-30
Budget Start
1992-08-26
Budget End
1993-06-30
Support Year
4
Fiscal Year
1992
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