591. CIGARETTE SMOKE ALTERS TISSUE INHIBITOR OF METALLOPROTEINASE 1 AND MATRIX METALLOPROTEINASE 9 LEVELS IN THE BASOLATERAL SECRETIONS OF HUMAN ASTHMATIC BRONCHIAL EPITHELIUM IN VITRO.

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Watson^1,2, A.M., Benton¹, A.S., Rose^1,3,4,5, M.C. and Freishtat^1,4,5,6, R.J. ¹Research Center for Genetic Medicine, Children’s National Medical Center; ²Institute of Biomedical Sciences, and Departments of ³Biochemistry and Molecular Biology, ⁴Integrative Systems Biology, and ⁵Pediatrics, School of Medicine and Health Sciences, The George Washington University; and ⁶Division of Emergency Medicine, Children’s National Medical Center, Washington, DC. J Investig Med, 58, 725-729, 2010.

Summary:
Background: Asthma, a major cause of chronic lung disease worldwide, has increased in prevalence in all age and ethnic groups, particularly in urban areas where cigarette smoking is common. Cigarette smoke (CS) significantly impacts the development of asthma and is strongly associated with increased asthma-related morbidity.
Purpose: To evaluate bioinformatic analyses predicting that CS would alter expression of tissue inhibitor of metalloproteinase (TIMP) 1 and matrix metalloproteinase (MMP) 9 in asthmatic epithelium.
Methods: Primary differentiated normal (n = 4) and asthmatic (n = 4) human respiratory epithelia on collagen-coated Transwells at air-liquid interface were exposed for 1 hour to CS condensate (CSC) or hydrogen peroxide (H2O2). Tissue inhibitor of metalloproteinase 1 and MMP-9 protein levels were measured at 24 hours by enzyme-linked immunosorbent assay in cell lysates and in apical and basolateral secretions.
Results: Tissue inhibitor of metalloproteinase 1 and MMP-9 levels in the apical secretions of normal and asthmatic epithelia were unchanged after exposure to CSC and H2O2. However, CSC increased TIMP-1 levels in the basolateral secretions of both normal and asthmatic epithelia, but decreased MMP-9 levels only in asthmatic basolateral secretions, resulting in a 2.5-fold lower MMP-9/TIMP-1 ratio that corresponded to decreased MMP-9 activity in CS-exposed asthmatic basolateral secretions. Conclusions: These data validate our prior bioinformatic analyses predicting that TIMP-1 plays a role in the stress response to CS and indicate that asthmatics exposed to CS may be more susceptible to MMP-9Ymediated airway remodeling. This is in agreement with the current paradigm that a reduction in the MMP-9/TIMP-1 ratio is a milieu that favors subepithelial airway remodeling in chronic asthma.
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Keywords: AIR-606, AIR-606-Asthma, Apical secretions, Asthma, Basolateral secretions, Chronic obstructive pulmonary diseases, Cigarette smoke, Environmental air pollutants, Human bronchial epithelial cells, Matrix Metalloproteinase (MMP) 9, TIMP-1/MMP-9, Tissue inhibitor of Metalloproteinase (TIMP) 1, Tobacco smoke

Materials Tested: Cigarette smoke, Dimethyl sulfoxide (DMSO), Hydrogen peroxide

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