Introduction
Asthma and COPD are chronic inflammatory diseases characterized by oxidative stress leading to airway remodeling. Nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of cellular defense against oxidative stress and inflammation. We investigated the effect of WISP-1, a Wnt-1 agonist, on the activation of NRF2 in human primary airway smooth muscle cells (ASMC) from patients with asthma and COPD.

Methods
Primary cultures of ASMC were established from endobronchial biopsies from patients with asthma (A-ASMC) and COPD (C-ASMC) and stimulated with WISP-1 (10-1000ng/ml), PP2, an inhibitor of the Src kinases, or ISO-1, an inhibitor of macrophage migration inhibitory factor (MIF). Gene expression of NRF2 was assessed by real time PCR and subcellular localization of NRF2 by immunofluorescence.

Results
WISP-1 upregulated gene expression of NRF2 in A-ASMC in a dose-dependent manner but not in C-ASMC. In A-ASMC, NRF2 was mainly localized in the cytoplasm and in C-ASMC in the cytoplasm and in the nucleus. WISP-1 stimulated the accumulation of NRF2 in the cytoplasm and its translocation to the nucleus both in A-ASMC and C-ASMC. This effect was abolished in the presence of PP2 and of ISO-1, indicating the involvement of Src kinases and MIF.

Conclusion
These results suggest that in asthma and in COPD, WISP-1 modulates the cytosolic and nuclear accumulation of NRF2 by activating Src kinases and MIF, highlighting the molecular mechanisms underlying inflammation in these diseases and offering potential alternative targets for therapeutic intervention.