Gene signature profiles in lung tissues of wild type mice or Has2 heterozygous deficient mice stimulated with porcine pancreatic elastase

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition primarily caused by prolonged exposure to harmful substances, such as cigarette smoke. Hyaluronic acid synthase 2 (HAS2) synthesizes high-molecular-weight hyaluronic acid (HMW-HA), believed to have anti-inflammatory properties. Previous studies have suggested that HAS2 dysfunction may exacerbate COPD. However, the specific impact of HAS2 on pulmonary emphysema progression remains unclear. In this study, we tested the hypothesis that HAS2 dysfunction worsens airway inflammation and emphysema in mouse COPD model. Has2 heterozygous-deficient (Has2+/-) mice and their wild-type (WT) littermates have been evaluated in a porcine pancreatic elastase (PPE)-induced COPD model. Following PPE administration, Has2+/- mice exhibited a significant increase in total cell and neutrophil counts in BALF samples compared to WT mice. Has2+/- mice demonstrated enhanced emphysema development on histological analyses, with higher values of mean linear intercept relative to wild-type mice. Elastase-stimulated Has2+/- mice also demonstrated increased G-CSF level and TGF-β attenuation in lung. RNA-seq analysis suggested that PPE stimulation promotes HMW-HA synthesis and TGF-β signaling. GO analysis using Has2+/- mice-specific DEGs showed that genes associated with pathways that "negative regulation of transforming growth factor beta receptor signaling pathway" were activated after PPE administration. This study demonstrates that Has2 dysfunction exacerbates neutrophilic airway inflammation and emphysema, underscoring the protective role of HAS2 in a PPE induced emphysema model. The exacerbated response appears to involve G-CSF and TGF-β-related signaling pathways. These findings may contribute to the development of novel therapeutic strategies for COPD management.