Bronchopulmonary dysplasia (BPD) is a major complication of prematurity frequently accompanied by life-threatening pulmonary hypertension (PH). Pirfenidone (PFD), an anti-fibrotic drug approved for adults, exhibits multimodal properties but its therapeutic efficacy and underlying mechanisms in neonatal BPD-associated PH(BPD-PH) remain to be elucidated. This study aimed to evaluate the therapeutic potential of PFD and its underlying mechanisms in a hyperoxia-induced mouse model of BPD. We found that PFD treatment enhanced alveolarization, reduced pulmonary fibrosis, attenuated pulmonary vascular remodeling and right ventricular hypertrophy. These protective effects were accompanied by decreased expression of inflammatory cytokines, improved oxidative stress profiles, and concomitant suppression of Wnt5A signaling and TGF-β1/Smad pathway activation. Collectively, these findings identify PFD as a potential modulator of lung injury and vascular remodeling in experimental BPD. However, as these observations are derived from a preclinical model, further studies are required to define safety, dosing, and efficacy prior to clinical translation.

Pulmonary vascular remodeling is increasingly recognized as an important yet underappreciated component of smoking-related lung disease and may contribute to the early development of pulmonary hypertension (PH) in susceptible individuals. This systematic review examined human studies evaluating the association between cigarette smoking and quantitative measures of pulmonary vascular remodeling assessed through histologic analysis or computed tomography (CT). A comprehensive search of PubMed, Embase, and Scopus covering publications from 1990 to 2024 identified eight eligible studies, including cross-sectional and cohort designs. Histologic investigations demonstrated thickening of the intimal and medial layers, reduction in small arterial numbers, and altered elastin deposition in smokers and individuals with mild to moderate chronic obstructive pulmonary disease (COPD). CT-based studies consistently showed distal vascular pruning, reflected by reduced blood vessel volume in vessels less than 5 mm[2] (BV5) to total blood vessel volume (TBV) ratios and decreased percentage of cross-sectional area in vessels under 5 mm[2] (%CSA<5). These findings correlated with airflow limitation, functional impairment, or hemodynamic markers relevant to PH. Across study designs, a coherent pattern emerged indicating that vascular remodeling can appear early in smoking-exposed populations and may be disproportionate to parenchymal disease. These insights suggest that quantitative CT metrics may serve as noninvasive indicators of early pulmonary vascular pathology and support the recognition of a vascular-predominant phenotype in some smokers. Further longitudinal studies integrating smoking exposure, imaging, and hemodynamic assessment are needed to clarify causality and improve risk stratification for PH in this population.

Pulmonary hypertension (PH) and diabetes frequently coexist, and metabolic dysregulation plays a role in PH pathogenesis. While preclinical studies indicate that certain antidiabetic therapies may beneficially impact the pulmonary vasculature and right heart function in PH, clinical data remain limited. We conducted a retrospective cohort study of veterans with PH and diabetes using Veterans Health Affairs data (2003-2015). The associations between exposure to antidiabetic medications at the time of PH diagnosis and survival were analyzed using Cox proportional hazards regression. We identified 41,670 veterans with PH and diabetes, largely older men (median age 69, 97% male). Average survival from PH diagnosis was 3.5 years. After adjustment for demographics, comorbid conditions, renal function, and hemoglobin A1c, metformin and thiazolidinedione (TZD) exposure were associated with lower mortality (HR 0.828, 95% CI 0.799-0.857 and HR 0.838, 95% CI 0.793-0.885, respectively). Conversely, insulin use was associated with higher mortality. These associations remained consistent across multiple analytical approaches and were independent of baseline hemoglobin A1c levels. Interactions were observed between drug effects and both renal function and PH comorbidities, with metformin's protective effect enhanced in patients with lower eGFR but attenuated in those with lung disease. In conclusion, metformin and TZD use were associated with improved survival in veterans with PH and diabetes, while insulin use was associated with reduced survival. These findings suggest that metabolic modulation may represent a viable therapeutic strategy in PH, though could be context dependent. Prospective trials are needed to evaluate therapeutic approaches targeting the metabolic pathobiology of PH.

Long-term oxygen therapy (LTOT) is a cornerstone of management for chronic hypoxemic respiratory diseases, such as chronic obstructive pulmonary disease, yet its physiological impact as a potent modulator of cardiovascular function remains a subject of ongoing investigation. While oxygen is primarily prescribed to correct arterial desaturation, its role as a regulator of vascular tone and cellular metabolism suggests it can exert significant, and sometimes contrasting, effects on the heart and systemic circulation. This review evaluates the evidence for LTOT in heart failure and pulmonary hypertension, 2 conditions where oxygen is frequently utilized despite varying levels of baseline hypoxemia. In heart failure, LTOT has not been shown to improve key hemodynamic variables and relevant endpoints, such as exercise capacity, in normoxemic patients. Some studies suggest that supplemental oxygen may even impose hemodynamic strain in this population by increasing systemic vascular resistance and reducing cardiac output. On the other hand, LTOT shows promise in improving relevant hemodynamic variables in pulmonary hypertension, such as mean pulmonary arterial pressure, as well as exercise capacity and other clinical measures across various baseline oxygen saturation levels. These findings suggest that the cardiovascular response to LTOT is highly dependent on the specific underlying pathology.