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Tobacco smoke inflicts tremendous damage to the health and well-being of Americans. Nearly 450,000 individuals in the US die prematurely each year from smoking or exposure to secondhand smoke, and more than 8.5 million more suffer serious injury and disease from smoking. The harm does not end with the smoker: an estimated 88 million Americans who do not smoke, including more than half of young children, are exposed to secondhand smoke, which is now known to cause serious injury and death. The cost of all this is staggering: tobacco use exacts a toll of close to $200 billion annually in medical costs and considerable loss of productivity. The most obvious and blatant case of passive exposure to smoke where an innocent by-stander is affected is exposure of a fetus to maternal smoke during pregnancy. Despite being known for decades that this exposure to tremendously harmful to the developing fetus, unfortunately, >10% of U.S. women smoke during pregnancy, resulting in at least 400,000 smoke-exposed infants/year. It is unlikely that smoking during pregnancy will dissipate any time soon since tobacco industry continues to spend billions of dollars to attract young smokers. In fact, with the recent introduction of a multitude of Modified Risk Tobacco Products, (MRTPs), under the pretext of being less harmful and safer alternatives to traditional cigarettes, this problem is worse than it has ever been. Furthermore, some MRTPs are targeted to be particularly appealing to adult female smokers, increasing the possibility of an even more exposure to fetuses. Very little research has been done on the safety or harm of these products. Based on strong epidemiologic and experimental evidence, it is well-established that environmental exposure of the developing offspring to cigarette smoke increases the susceptibility to chronic diseases of the lung and other organs, even when the offspring does not smoke later in life. Exposure to smoking is an independent risk factor for adult chronic lung disease (CLD). Though the mechanism (s) underlying this increased proclivity to CLD is not exactly known, with the support of the TRDRP and the NIH, work from our laboratory, over the years, has provided seminal contributions of the field, and has brought us much closer to designing effective targeted preventive and therapeutic interventions than we were a decade earlier. One of our fundamental discoveries has revealed that infant's lung has crucial fat containing cells that on exposure to tobacco smoke during pregnancy transform to muscle like cells, which are the hallmark of a damaged lung. Once this change has occurred, a normal functioning cell, which is essential for good lung function, is converted to a cell that has the potential to cause serious lung damage, resulting in impaired oxygenation to the body in the short term, and CLD in the long-term. Furthermore, we have teased out complex molecular pathways that determine the fate of these crucial cells in the lung, i.e., what makes them to behave as 'Good and Beneficial' cells and what makes them 'Bad and Harmful' cells. Now we propose that following exposure to tobacco smoke during pregnancy, whether from traditional cigarettes or from MRTPs, the 'Bad and Harmful' cells in the lungs are produced not only locally, but these also originate from stem cells derived from the bone marrow of the affected individuals. This proposal is aimed at demonstrating this phenomenon, understanding the molecular mechanisms involved, and discovering the ways to prevent and revert it. We are confident that based on our previous TRDRP and NIH funded work, and the work proposed in this application, we will discover novel and effective molecular techniques that will make 'Bad and Harmful' cells behave as 'Good and Beneficial' cells. Furthermore, the work proposed here can turn out to be pivotal in tackling not only the menace of lung damage following perinatal tobacco exposure, but also damage to many other organ systems, potentially opening up novel interventional strategies to tackle a wide spectrum of tobacco smoke-induced chronic diseases in the exposed offspring. |
