Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Understudied polycyclic aromatic hydrocarbons involved in pulmonary inflamation

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? DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs) are major environmental contaminants of air, water and soil as well as secondhand (SHS) and thirdhand smoke, thus the human health concern is evident. Most research has focused on high molecular weight PAHs while little is known about the non-genotoxic 2-4 ring low molecular weight (LMW) PAHs (e.g. fluoranthene) despite their far greater concentration in SHS and thirdhand smoke, the environment, and occupationally, and their potential role in inflammatory lung diseases. Our novel preliminary data in lung epithelial cells demonstrates that LMW PAHs activate p38 MAP kinase (MAPK) followed by induction of inflammatory mediators associated with early events in several lung diseases and dysregulation of gap junctional intercellular communication (GJIC, a crucial mechanism to maintain tissue homeostasis). Further, p38 MAPK activation, which is critical to lung inflammation, is a current target for respiratory disease therapy (eg. asthma and COPD). Thus a gap exists in our current knowledge of these understudied yet prevalent LMW PAHs, their roles in pulmonary inflammation and the mechanisms driving these effects. We hypothesize that these LMW PAHs, both SHS-abundant and environmental toxicants, exert their effects in the pulmonary epithelial cells by eliciting an oxidative stress response that activates p38 MAPK leading to reduced cell-cell communication that is linked to specific inflammatory pathways (i.e. NALP3 inflammasome). We will test this hypothesis in three aims using both in vitro and in vivo models: Aim 1, Determine the involvement of reactive oxygen/nitrogen species (RONS) in p38 MAPK activation, GJIC dysregulation, and inflammation in response to LMW PAHs in pulmonary epithelial cells; Aim 2, Elucidate the role of the NALP3 inflammasome following p38 MAPK activation and GJIC dysregulation in response to LMW PAHs in pulmonary epithelial cells; Aim 3, Validate the translational relevance of these PAHs in a novel lung specifi model using p38 MAPK- deficient (p38+/-) mice. Both Aims 1 and 2 will use mouse and human epithelial cell lines as well as primary alveolar type II (ATII) cells with molecular and pharmacological approaches to address the mechanisms upstream and downstream of p38 MAPK based on novel preliminary data to support these aims. Aim 3 will then validate the importance of p38 MAPK in PAH-induced pulmonary inflammation in vivo using whole lung analysis (e.g. bronchoalveolar lavage, histology) and ATII cells. Collectively, these innovative studies will provide a fundamental understanding of the underlying mechanisms responsible for LMW PAH-induced pulmonary inflammation and their contribution to disease, provide additional data to initiate improved risk assessment, lead to future studies to identify potential new therapeutic targets, and lead to future studies on the influence of developmental exposures and disease initiation and progression. This funding mechanism will also provide essential research training to both undergraduate and graduate students, including minority students, in a novel area important to human respiratory disease development and environmental toxicology.
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