Chronic obstructive airway diseases such as cystic fibrosis are characterized by mucin overproduction. Over time, this can lead to the formation of mucus plugs, infection, bronchiectasis, respiratory insufficiency, and death. An understanding of how this sequence of events is triggered would help in the design of methods to inhibit it. During the last period, our experiments confirmed the hypothesis that an early event in experimentally induced hypersecretion is the upregulation of steady state mucin (MUC 2) mRNA (induced by endotoxin instillation in rat airways). Our experiments also revealed a phasic upregulation of MUC 2 early in tracheal development. The goal of the proposed studies is to gain information about how these events are triggered and controlled. Studies listed under Specific Aim l will determine, using in situ hybridization, the time course of MUC 2 activation in the developing trachea. In addition, they will identify relevant protein-DNA interactions by gel shift and footprinting assays, isolate footprinted proteins and map the time and place of their expression during development. They will also attempt to identify genes controlling the mucous cell phenotype as a whole and identify mesenchymal induction factors activating their expression. Studies listed under Specific Aim 2 will determine, using epithelial cell cultures, whether the endotoxin upregulation of MUC 2 previously observed in vivo is a direct effect or is mediated by neutrophil products. Other studies will determine the extent to which mucin induction by endotoxin is transcriptional or post-transcriptional and identify protein-DNA interactions mediating this induction. Because recent experiments have revealed MUC 2 upregulation by Pseudomonas (PA) products, additional studies will analyze the PA-MUC 2 induction by methods similar to those used to analyze the endotoxin-MUC 2 induction and attempt to identify the active component in PA supernatant. The information gained from these studies will hopefully suggest pharmacological interventions to inhibit excessive mucin production in human airways.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043762-09
Application #
2750340
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1990-07-01
Project End
1999-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sidhu, Sukhvinder S; Mengistab, Aklilu T; Tauscher, Andrew N et al. (2004) The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene 23:956-63
Gensch, Erin; Gallup, Marianne; Sucher, Anatol et al. (2004) Tobacco smoke control of mucin production in lung cells requires oxygen radicals AP-1 and JNK. J Biol Chem 279:39085-93
McNamara, Nancy; Gallup, Marianne; Khong, Amy et al. (2004) Adenosine up-regulation of the mucin gene, MUC2, in asthma. FASEB J 18:1770-2
Lemjabbar, Hassan; Li, Daizong; Gallup, Marianne et al. (2003) Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J Biol Chem 278:26202-7
McNamara, Nancy; Basbaum, Carol (2002) Mechanism by which bacterial flagellin stimulates host mucin production. Adv Exp Med Biol 506:269-73
McNamara, N; Khong, A; McKemy, D et al. (2001) ATP transduces signals from ASGM1, a glycolipid that functions as a bacterial receptor. Proc Natl Acad Sci U S A 98:9086-91
Longphre, M; Li, D; Li, J et al. (2000) Lung mucin production is stimulated by the air pollutant residual oil fly ash. Toxicol Appl Pharmacol 162:86-92
Longphre, M; Li, D; Gallup, M et al. (1999) Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J Clin Invest 104:1375-82
Nogami, H; Ohmori, H; Li, J D et al. (1997) Sp1 protein contributes to airway-specific rat MUC 2 mucin gene transcription. Gene 198:191-201
Kai, H; Takeuchi, K; Ohmori, H et al. (1996) Transcriptional regulation of the lysozyme gene in airway gland serous cells. J Cell Biochem 61:350-62

Showing the most recent 10 out of 18 publications