W3D ameliorates COPD lung injury by regulating macrophage polarization via glycolysis inhibition

Chronic obstructive pulmonary disease (COPD) remains a major global health challenge, characterized by persistent inflammation and progressive lung damage. Current therapies often fall short in fully addressing the underlying inflammatory processes and lung remodeling. Emerging research highlights the critical role of macrophage polarization and metabolic reprogramming, specifically glycolysis, in driving COPD pathogenesis. Targeting these pathways offers a promising avenue for developing novel therapeutic strategies beyond conventional anti-inflammatory approaches.

Researchers investigated the therapeutic potential of 4-(5'-Dimethylamino)-Naphthalenesulfonyl-2(3H)-Benzoxazolone (W3D) in both in vivo COPD lung injury models and in vitro cigarette smoke extract (CSE)-induced macrophages. In vivo, W3D's effects on airway inflammation and lung function were assessed. In vitro, the study examined W3D's impact on inflammatory cytokine expression (IL-6, IL-1β, TNF-α, MMP-9), tight junction protein levels (claudin-1, occludin), TLR4/NF-κB pathway activation, and glycolytic enzyme expression (LDHA, PKM2, HK2). The role of glycolysis was further confirmed using the glycolytic inhibitor 2-deoxy-d-glucose (2-DG).

W3D consistently demonstrated significant anti-inflammatory and protective effects across both in vivo and in vitro models. It effectively down-regulated inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and MMP-9, leading to reduced airway inflammation and improved lung function in COPD models. Furthermore, W3D increased the expression of tight junction proteins claudin-1 and occludin, thereby attenuating the activation of the Toll-like receptor 4/nuclear factor kappa B (TLR4)/NF-κB signaling pathway to maintain bronchial epithelial cell integrity. A key finding was W3D's ability to restore the expression of glycolytic enzymes LDHA, PKM2, and HK2, which modulated lactate levels and corrected glycolytic pathway dysregulation. W3D also decreased intracellular lactate content, down-regulated global Kla levels and H3K18la expression, and regulated macrophage polarization in CSE-induced macrophages.

Importantly, these therapeutic effects of W3D were compromised in the presence of the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), strongly indicating that W3D regulates macrophage polarization by inhibiting glycolysis.