Exploring the Role of WISP1 in Redox Homeostasis in COPD

Oxidative stress plays a central role in the pathogenesis of COPD. This study delves into the interplay between two pivotal regulators of cellular redox homeostasis, p62 and nuclear redox-related factor 2 (NRF2) in COPD. Primary airway smooth muscle cells (ASMCs) sourced from endobronchial biopsies of COPD patients were treated with WISP1 (100 ng/mL) along with inhibitors of macrophage migration inhibitory factor (MIF) or Src kinases. Subcellular localization of Nrf2 was assessed via immunofluorescence. Gene expression of antioxidant enzymes (NQO1 and HO-1) was evaluated by qPCR. The role of Nrf2 in mediating WISP1-induced effects was investigated using the Nrf2 inhibitor ML385. The expression of MMP-1, p62, and STAT3 was assessed by qPCR, ELISA and Western blotting. WISP1 downregulated p62 expression and inactivated NRF2. Immunofluorescence analysis revealed cytoplasmic sequestration of NRF2, which was alleviated in the presence of MIF or Src kinases inhibitors. Furthermore, WISP1 treatment significantly suppressed MMP-1 expression and mitigated STAT3 phosphorylation. Conversely, inhibition of MIF reversed the WISP1-induced downregulation of p62 expression. Moreover, WISP1 upregulated NQO1 expression albeit without affecting HO-1, an effect eliminated by NRF2 inhibition. These findings hint the potential contribution of WISP1 to airway remodeling, oxidative stress, and inflammation in COPD. Unraveling the intricate interplay between p62 and NRF2 sheds light on the elaborate regulatory networks orchestrating redox balance in COPD. Moreover, these insights may pave the way for therapeutic avenues aimed at bolstering antioxidant defense mechanisms, thus alleviating oxidative stress-induced pulmonary damage in COPD patients.