Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations in the content and composition of the lung extracellular matrix, and we believe this "altered" matrix has the ability to promote lung carcinoma cell growth. One extracellular matrix molecule shown to be altered in these lung diseases is fibronectin (Fn). We previously reported increased growth and survival of non-small cell lung carcinoma (NSCLC) cells exposed to Fn. Thus Fn may serve as a mitogen/survival factor for NSCLC and therefore represents a novel target for anti-cancer strategies. To this end, we studied the effects of the PPARgamma ligands 15d-PGJ(2), rosiglitazone (BRL49653), and troglitazone on Fn expression in NSCLC cells and found that they were able to inhibit Fn gene transcription. Inhibition of Fn expression by BRL49653 and troglitazone, but not by 15d-PGJ(2), was prevented by the specific PPARgamma antagonist GW-9662 and by PPARgamma small interfering RNA. Working with Fn deletion and mutated promoter constructs, we found that the region between -170 and -50 bp downstream from the transcriptional start site of the promoter was involved in PPARgamma ligand inhibition. PPARgamma ligands also diminished the phosphorylation of CREB, diminished Sp1 nuclear protein expression, and prevented the binding of these transcription factors to CRE and Sp1 sites, respectively, within the Fn promoter. In summary, our results demonstrate that PPARgamma ligands inhibit Fn gene expression in NSCLC cells through PPARgamma-dependent and -independent pathways that affect both CREB and Sp1.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1. 1590 79

Chronic obstructive pulmonary disease is a major health problem and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular, cigarette smoke (CS), causes the progressive airflow limitation, in which macrophages and neutrophils are attracted by chemokines, leading to oxidative stress, emphysema, small airways fibrosis, and mucus hypersecretion. Smoking is also associated with an increase in mast cell numbers in bronchial mucosa. This study was conducted to determine the direct effects of CS on mast cell function, using murine bone marrow-derived mast cells (BMMC) as an in vitro model. BMMC were cultured from BALB/cBy mice for 3 weeks. Cells were treated with CS medium (CSM) for 30 min or 16 h. The effects of CSM on mast cell degranulation and chemokine production were measured. Moreover, we investigated the effect of CSM on IkappaB-alpha degradation and p38, Erk1/2, p65, and CREB expression by Western blotting. We found that CSM stimulated the release of chemokines in a noncytotoxic manner but did not induce mast cell degranulation. CSM induced phosphorylation of Erk1/2, p38, and CREB and increased translocation of p65 without degradation of IkappaB-alpha NF-kappaB in mast cells. The induction of chemokine production by CSM in mast cells could promote and prolong the inflammatory process. Our observations suggest that mast cells may contribute to the pathogenesis of emphysema through a direct effect of CS on the production of proinflammatory chemokines.
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PMID:Cigarette smoke stimulates the production of chemokines in mast cells. 1815 85