Mechanisms of Persistent Immune Dysregulation Following Early Life Tobacco Smoke Exposure
Abstracts
Initial Award Abstract |
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Environmental tobacco smoke (ETS) exposure studies focus on chronic obstructive pulmonary disease (COPD), while cigarette smoke mediated changes in immune responses in children, the most susceptible population, remain understudied. ETS exposure in early life has been associated with increased risk of respiratory diseases and infections such as, asthma, pneumonia, sinusitis, and allergies. Our laboratory has extensively reported that in a nonhuman primate model of childhood development, normal growth of the airways during early life is highly vulnerable to environmental exposures. Previous studies in humans and animal models have indicated altered monocyte/macrophage function to be linked with antecedent cigarette smoke exposure. Monocytes are bone marrow derived macrophage and dendritic cell precursors that reside in the circulatory system, with relatively short half-lives and high turnover rates. Recent investigations suggest that these changes in physiological function are the result of ETS exposure-induced alterations in gene expression that can persist well past the lifespan of a circulating monocyte. These changes can manifest as improper or skewed activation of monocyte/macrophage populations. Previous studies in adult patients with COPD reported a shift from inflammatory to alternative macrophage activation. However, to date, there is no direct experimental evidence that describes how early life ETS exposure induces long-term changes in immune response. We hypothesize that neonatal ETS exposure can persistently modulate a bone marrow derived stem cell population that manifests as altered monocyte/macrophage function later in life, which ultimately results in increased microbial vulnerability. We will test this hypothesis by exposing neonatal mice to ETS and then monitoring the subsequent inflammatory response in a time course study on through adulthood. We also propose to transfer bone marrow cells from ETS or filtered air exposed mice and assess their response to infectious challenges. The rationale for this proposal is based upon our very limited understanding of immune system development in the context of environmental challenges. Ultimately we hope to elucidate a progenitor population of bone marrow derived stem cells that can become a target for therapeutic intervention. |
