Effect of smoke and gender on bronchiolar injury and repair
Initial Award Abstract
Environmental tobacco smoke (ETS) is causally associated with pulmonary diseases of both men and women. However, risk of cancer of the peripheral lung as well as risk of COPD is higher in women exposed to smoke. This suggests that there are gender differences in epithelial responses in the airways. However the cellular mechanisms involved in these differences, before tumors develop, are largely unknown. Metabolic activation of compounds found in tobacco smoke is associated with the formation of tumors. Epidemiologic studies suggest that women with increased expression of certain P450s and alterations in detoxifying pathways have an increased risk of cancer. What is not known is the relation of the status of these enzyme systems at time of exposure, the role of subsequent co-exposures and the association with the early epithelial changes that may be precursors of later airway disease. Because ETS-induced changes are focal within the lung, it is necessary to use site-specific experimental approaches to study the cellular changes in distal vs. proximal airways. Our previous studies have shown that: 1) the potential for acute injury following ETS exposure is different between male and female mice, 2) prior ETS exposure differentially affects xenobiotic metabolizing systems in males and females and 3) we have the methods to study cellular changes on an airway level specific basis.
The central hypothesis of the proposed research is that a history of prior ETS exposure alters the airway epithelium in a gender specific manner and that this in turn alters both epithelial injury and repair. We further hypothesize that injury is greater in males because ETS induces tolerance in males but not in females. In addition, we hypothesize that impaired repair caused by ETS exposure will decrease clearance of particles and will also result in pre-neoplastic lesions in long-term studies and that impaired repair will be greater in female mice. We will address this hypothesis with two specific aims. In the first aim we will determine whether a history of prior ETS exposure will result in greater susceptibility to bronchiolar injury in female mice vs male mice by examining 4 different potential mechanisms. In specific aim 2 we will define whether a history of prior exposure to ETS impairs repair to a greater extent in female mice vs. male mice and will also define the effect of prior ETS exposure on clearance of particles and persistence of pre-neoplastic lesions.
This research has potential impact for women who smoke or are exposed to ETS and who live in urban areas with high levels of air pollution. These studies have direct relevance to understanding the causes of tobacco-related diseases. We expect these studies will benefit the general population by defining the mechanisms that make females more susceptible and relating susceptibility to expression of precancerous markers on lung epithelium. Once mechanisms have been defined, strategies can be devised that will afford sensitive populations some protection (including appropriate air quality standards). Further, identification of key pathways involved in susceptibility will enable identification of individuals most at risk. These studies are highly relevant to TRDRP research primary priorities on the pathogenesis, susceptibility and progression of lung cancer in an under-researched and sensitive population, females. |