Sexual dimorphism in susceptibility to emphysematous tissue injury

Abstract Chronic Obstructive Pulmonary Disease (COPD) is a leading chronic disease worldwide, causing significant healthcare utilization, morbidity, and mortality. Irreversible airflow obstruction alone can establish the diagnosis of COPD. However, a diagnosis of COPD includes a heterogeneous collection of lung diseases. This proposal will focus on one form of COPD, emphysema (EM). Past studies suggest that sex may significantly impact the EM severity. However, we do not have a clear mechanistic understanding of how sexual dimorphism drives smokers’ lung tissue injury toward or award from EM. Our preliminary studies identified a gene module from Weighted Gene Correlation Network Analysis (WGCNA) that highly correlated with emphysematous tissue remodeling related to sex differences. These Green module genes were significantly expressed in monocyte lineage cells. Sex differences significantly correlate with changes in monocyte/macrophage clusters of the lung tissue single-cell RNA sequencing (scRNA-seq). In a preliminary study collaborating with the Multi-Ethnic Study of Atherosclerosis (MESA), we concluded that emphysema severity in 1,346 subjects’ chest CT was significantly worse in male smokers than in female smokers. These completed studies led us to hypothesize that sex differences cause greater susceptibility for males to develop emphysematous lung injury during chronic cigarette smoke exposure by altering the monocyte clusters enriched with the Green module genes. The primary goal of this study is to identify sex-dependent biomolecular factors that drive the divergent changes in monocyte-lineage cells during emphysematous pulmonary tissue injury. We will also determine how these changes in monocyte- lineage cells cause pathology in lung structures (epithelium and endothelium). To achieve these goals, we propose three aims. (1). Aim 1 - Determine monocyte-lineage cells’ composition, differentiation, functions, and their downstream effects on the alveolar epithelium and endothelium, using the “Green” module as a target gene set in the C57B/6 murine model over chronic cigarette smoke exposure with gain or loss of female or male gonadal functions. (2). Aim 2 - Determine the correlation between monocyte-lineage cells’ composition in lung scRNA-seq and emphysema severity by chest CT from UVa cohorts balanced in sex and presence or absence of COPD (n=60) using the “Green” module as a target gene set. (3). Aim 3 - Test the Green module as a longitudinal mediator of sexual dimorphism during the evolution of emphysema from longitudinal MESA Exams 5 to Exam 6. Emphysema is mainly resistant to all available therapies except lung volume reduction strategy and lung transplant. To date, little is known about the functions of monocytes at the level of single cells in the lungs undergoing emphysematous damage. Therefore, our proposal can provide critical biomolecular information between females and males to assess the risk, identify the dysregulated processes, and help develop strategies to mitigate and treat emphysematous COPD tailored by sexual dimorphism and monocyte biology.