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Cigarette smoking is the single major cause of chronic fibrosis affecting lungs, heart, kidney, and gums in the United States. Chronic fibrosis is associated with long-term ill health and it contributes to hundreds of thousands of premature deaths each year. Further, although the prevalence of smoking during pregnancy is decreasing, an unacceptably large percentage of women still smoke while pregnant. The mechanism(s) underlying predisposition to fibrosis in different organs in response to smoke/nicotine exposure either before or after birth is (are) poorly understood. However, there is now strong evidence to support that a break-down in cell-cell cross talk, i.e., how cells talk to each other molecularly, in different organs may be playing a crucial role in fibrosis in various organs. We have identified a specific protein that is essential in maintaining this cell-cell communication in the lung under normal conditions of good health. If, however, the levels of this protein go down, it sets the stage for lung fibrosis. Indeed we have seen that nicotine exposure does decrease the levels of this protein in the lung significantly. Further, maintaining normal levels of this protein in the lung during exposure to conditions that would otherwise cause lung fibrosis, e.g., exposure to nicotine, a normal lung health was maintained, and fibrosis could be prevented. This is a huge step in designing treatment strategies against lung fibrosis. However, we feel that the mechanism, which helps in maintaining normal lung health, is not restricted only to the lung, but is likely to a fundamental mechanism in many other organs systems as well. Therefore, now we propose to look at whether nicotine exposure also adversely affects the levels of the relevant protein essential for cell-cell communication in other organs, such as the kidney, liver, brain, and long bones, as well. Incidentally, all of these organs are already known to express this protein, but how exposure to nicotine affects the levels of this protein it is not known. The proposed studies are likely to provide us a novel understanding that for the first time might open up the possibility of preventing nicotine-induced organ damage in almost all organ systems simultaneously. In fact, we will look at not only the prevention but also the possibility of reversibility of nicotine-induced injury in various organs. Our hypothesis and proposed studies will unravel the molecular mechanisms of fibrosis in general, enabling us to better understand, prevent, treat, or even reverse this process through more rationale and focussed interventions. In line with Tobacco-Related Disease Research Program goals, this has an enormous potential of opening up novel interventional strategies to tackle not only the nicotine-induced fibrosis, but also all chronic diseases characterized by fibrosis in general. |
