Targeting heparanase-associated epithelial glycocalyx remodeling attenuates Akt/NF-κB-related barrier dysfunction in experimental COPD.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation, epithelial barrier dysfunction, and progressive structural remodeling. Although glycocalyx impairment has been implicated in COPD pathogenesis, the mechanisms linking glycocalyx degradation to epithelial barrier injury remain incompletely understood. Heparanase (HPSE), the only mammalian endoglycosidase capable of degrading heparan sulfate, may contribute to COPD progression by regulating epithelial glycocalyx integrity. Methods: HPSE expression was evaluated in serum samples from patients with COPD, a murine COPD model induced by cigarette smoke exposure combined with lipopolysaccharide (LPS), and cigarette smoke extract (CSE)-stimulated human bronchial epithelial BEAS-2B cells. The therapeutic effects of CV122, a small-molecule heparanase inhibitor previously developed by our group, were investigated Results: HPSE abundance, including the mature 50-kDa HPSE form, was increased in serum from patients with COPD, lung tissues of COPD mice, and CSE-stimulated epithelial cells. In the murine COPD model, CV122 treatment significantly improved pulmonary function, reduced inflammatory cytokine production, and attenuated emphysematous and fibrotic remodeling. Mechanistically, CV122 preserved epithelial glycocalyx integrity, restored the expression and localization of ZO-1, occludin, and E-cadherin, and reduced epithelial and vascular permeability. In addition, CV122 inhibited Akt and NF-κB pathway activation, accompanied by decreased levels of TNF-α, IL-1β, and IL-6. Consistently, CV122 protected BEAS-2B cells against CSE-induced apoptosis, cytotoxicity, inflammatory responses, and barrier dysfunction. Conclusion: This study identifies HPSE-associated glycocalyx remodeling as an important contributor to epithelial barrier dysfunction in COPD. Pharmacological inhibition of HPSE with CV122 preserves glycocalyx integrity, restores epithelial barrier function, and attenuates inflammatory signaling, at least in part through suppression of the Akt/NF-κB pathway. These findings advance our understanding of glycocalyx remodeling in COPD and support HPSE as a promising therapeutic target for disease modification.