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.