Chronic obstructive pulmonary disease (COPD) is marked physiologically by airflow limitations and pathologically by mucosal injury and inappropriate repair in the airway (bronchitis) and parenchyema (emphysema). COPD is currently the fourth leading cause of death in the United States and has long been associated with certain occupations. These include mining, chemical manufacturing, farming, food preparation, and farming. A common feature of COPD, airway mucus hypersecretion is due to excessive production of mucins. These proteins provide the characteristic viscosity, adhesiveness, and elasticity to the mucus lining the airways. To date, nine human mucin genes have been identified and partially characterized in lung disease. This study seeks to use a potent aldehyde, acrolein, to induce mucus hypersecretion in a laboratory species. This aldehyde is a member of a chemical class, the low molecular weight aldehydes, that have excessive use in industry and can result in wide industral exposures. Acrolein is also produce by a number of combustion processes and can be found in diesel, wood, and cigarette smoke in high concentrations. The overall hypothesis of this study is that occupational aldehyde exposures can induce mucus hypersecretion by direct and indirect inflammatory mechanisms.
Specific aims i nclude: (1) To develop a mouse model for the study of acrolein-induced COPD, (2) To further investigate the role of macrophage/monocyte or neutrophil infiltration in mucus hypersecretion, and (3) To begin to investigate the genetic determinants of individual susceptibility.
These aims will be completed using novel research approaches (including normal, transgenic, and knockout mice with deficient or enhanced leukocyte migratory capacities). Genetic analyses will include strain distribution pattern, mode of inheritance, recombinant inbred, and quantitative trai locus analysis. The well-characterized mouse model generated by this proposal will be useful in the further understanding of the relationship between occupational exposures, genetic markers, inflammatory responses, and COPD.
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