Combined exposure to cigarette smoke and hypoxia in mice significantly increased right ventricular systolic pressure by 30.3% and Fulton index by 25.8% at 6 weeks compared to controls (p<0.01).
Does combined exposure to cigarette smoke and hypoxia accelerate the development of pulmonary hypertension in a murine model of COPD?
Combined cigarette smoke and hypoxia exposure effectively accelerates the COPD-PH phenotype in mice, providing a robust model for studying underlying mechanisms and potential therapeutic targets.
p-value: p=< 0.01
Abstract Rationale The severity of chronic obstructive pulmonary disease (COPD) is increased by the development of pulmonary hypertension (PH), a complication with an incompletely understood pathogenesis. Bridging this knowledge gap requires elucidation of the underlying mechanisms using effective animal models. Traditional chronic (6 months) cigarette smoke (CS) exposure models are cumbersome and produce only modest PH phenotypes. We hypothesize that concurrent exposure to CS with hypoxia (Hx) will accelerate PH development. Methods C57BL/6 mice were exposed to CS (5 hours/day) and normobaric hypoxia (12% FiO2) for 6 weeks or for 9 weeks (CS-Hx), or for 6 weeks followed by recovery for 3 weeks in ambient air (CS-HxR). Right ventricular (RV) hypertrophy was assessed via Fulton index, wheat germ agglutinin and glycosphingolipid lectin imaging using fluorescence. RV systolic pressure (RVSP) and pulmonary function parameters were measured via right heart catheterization and FlexiVent, respectively. Pulmonary artery (PA) remodeling was assessed with α-smooth muscle actin (α-SMA) immunofluorescence. Markers of autophagy, apoptosis, and proliferation were analyzed by western blotting; Transcriptomic changes in the lungs were analyzed by bulk RNA sequencing. Results Compared to unexposed control mice, CS-Hx exposure caused significant (p 0.01 for each) increases in RVSP (30.3%), Fulton index (25.8%), and static compliance (Cst, 35.9%) at 6 weeks, all of which persisted after recovery. CS-Hx exposure showed further increases in RVSP (36.8%) and Cst (3.5%) at 9 weeks, with no further change in the Fulton index. The phenotype exhibited sexual dimorphism, with males being more severely affected (p 0.001). Both the CS-Hx and CS-HxR groups showed PA remodeling with significant increase in α-SMA thickness compared with controls (by 30.7% and 25.1%, respectively; p 0.001). The cross-sectional area of cardiomyocytes increased by 145.5 and 122.8 µm² in CS-Hx and CS-HxR mice, respectively (p 0.0001). CS-Hx exposure enhanced autophagy while decreasing apoptosis and proliferation (p 0.05) in both the RV and the lung tissue. Bulk RNA sequencing revealed upregulation of cellular stress adaptation pathways and marked suppression of immune signaling. Interestingly, both the decreased proliferation and transcriptional changes were significantly restored in CS-HxR mice. Conclusion Combined CS-Hx effectively models and accelerates the COPD-PH phenotype, with males being more affected than females. Although full recovery of the phenotype was not observed, cellular mechanisms suggest that a longer observation period may be required to study loss of repair capacity. Altered autophagy, apoptosis, proliferation, and transcriptomic shifts reveal potential molecular targets for therapeutic development. This abstract is funded by: AHA 25POST1363837 (TP), Carson Family Foundation and Wollowick Chair in COPD research (IP); NIH R01: NIH 5R01HL144727 (TL), VA Merit Review Award 7I01 BX002042 (TL), NIH 1P01 HL158507 (TL)
Palmo et al. (Fri,) conducted a other in Chronic obstructive pulmonary disease with pulmonary hypertension (COPD-PH). Combined exposure to cigarette smoke (CS) and normobaric hypoxia (Hx) vs. Unexposed control mice was evaluated on Right ventricular systolic pressure (RVSP), Fulton index, and static compliance (p=< 0.01). Combined exposure to cigarette smoke and hypoxia in mice significantly increased right ventricular systolic pressure by 30.3% and Fulton index by 25.8% at 6 weeks compared to controls (p<0.01).