Cigarette smoke and the acute respiratory distress syndrome: mechanisms and the role of alveolar macrophages in priming

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PROJECT SUMMARY/ABSTRACT The acute respiratory distress syndrome (ARDS), also known as acute lung injury, is a major source of morbidity and mortality, with nearly 200,000 cases annually in the US and a mortality of 30-40%. Cigarette smoking has recently been identified as a risk factor for developing ARDS. However, few studies have directly examined the mechanisms that predispose smokers to develop ARDS, including the role of alveolar macrophages, the predominant cellular constituent in the alveolar space. Furthermore, it is unknown if cigarette smokers are simply predisposed to develop ARDS, or whether those that do develop ARDS have differential activation of key pathways of injury compared to non-smokers with ARDS. Further insight into the mechanisms of ARDS, both in smokers and non-smokers, may identify key preventative and therapeutic targets for a disease with no effective treatments. The proposed project aims to study the mechanisms through which cigarette smokers are primed to develop ARDS and to determine whether the pathogenesis of ARDS differs in cigarette smokers compared to non-smokers. In Aim 1, I will study the pathogenesis of ARDS via protein biomarker and transcriptomic approaches in an established cohort of critically ill patients to determine if smokers have differentially activated pathways of injury compared to non-smokers. I hypothesize that cigarette smokers will have differentially activated pathways of inflammation, oxidative stress and injury as measured by protein biomarkers (Hypothesis 1a) as well as increased pro-inflammatory and oxidative stress gene-expression in the BAL transcriptome (Hypothesis 1b). In Aim 2, I will use a human experimental model of acute lung injury using inhaled lipopolysaccharide (LPS) to investigate mechanisms through which cigarette smokers are primed to develop ARDS. I hypothesize that in the presence of a “second hit,” modeled by LPS, alveolar macrophages from cigarette smokers will have an exaggerated release of inflammatory cytokines and oxidant/antioxidant imbalance that predisposes smokers to develop ARDS (Hypothesis 2). These studies will provide increased insight into the biology of ARDS in both cigarette smokers and non-smokers, laying the foundation for novel preventative and therapeutic strategies in these subgroups of patients. To accomplish these aims, I have assembled a multidisciplinary mentoring team whose expertise spans the relevant disciplines needed including 1) Dr. Carolyn Calfee, my primary mentor and expert on using translational techniques in human cohorts to study ARDS 2) Dr. Michael Matthay, my co-mentor with expertise in using basic science laboratory approaches to study ARDS pathogenesis 3) Dr. Prescott Woodruff, a scientific advisor with expertise in a) genomics b) human bronchoscopy research studies and c) alveolar macrophages and 4) Dr. Daniel McAuley, a scientific advisor with expertise in safely using inhaled LPS in a human model of acute lung injury. This mentorship, along with a training plan designed to address key training gaps, will allow me to complete the projects proposed in this application and prepare me for a career as an independent investigator.