Genetic susceptibility, terminal bronchiole pathology, and inflammation: An integrated mechanisms of the pathogenic process in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) remains a leading cause of mortality yet understanding of disease initiation and progression is incomplete. Current therapeutic agents provide symptomatic relief but fail to halt disease progression, highlighting the urgent need to elucidate underlying pathogenic mechanisms, particularly in the preclinical and early stages before irreversible lung damage becomes established. COPD exhibits profound heterogeneity in clinical presentation and disease trajectories, even among patients with similar spirometric measures, indicating that divergent pathogenic mechanisms arise from distinct interactions among genetic, environmental, and temporal factors throughout the lifespan. This review integrates three mechanistically distinct yet biologically interconnected pathogenic processes underlying the progression of COPD. First, we synthesize evidence that genetic susceptibility and developmental trajectories shaped by cumulative early-life exposures determine individual disease risk and phenotypes. Genome-wide association studies have identified more than 80 COPD-associated loci, with polygenic risk scores capturing a substantially greater proportion of genetic liability and enabling identification of high-risk individuals amenable to early intervention. Second, we establish the terminal bronchioles as the primary anatomical site of obstruction, characterized by loss of radial alveolar attachments and aberrant extracellular matrix remodeling that precedes emphysematous tissue destruction. Third, we synthesize emerging single-cell transcriptomic and proteomic evidence revealing that interferon-γ-mediated epithelial-stromal-lymphocyte crosstalk perpetuates tissue destruction through complementary mechanisms: augmented matrix metalloproteinase production overwhelming anti-protease defenses, and direct reprogramming of alveolar epithelial and stromal cells toward apoptosis and senescence. Together, these mechanistic insights provide a unified framework for understanding disease heterogeneity and identifying stage-specific therapeutic targets before irreversible damage becomes established.