The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which
pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced
acute lung injury (ALI). hUCMSCs with
pyrogallol treatment increased expression of HO-1 at both
mRNA and
protein levels, accompanied by
Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2
protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by
pyrogallol was reversed by pretreatment with
N-acetylcysteine (NAC) and a P38
kinase inhibitor (
SB203580). Whereas, NAC pretreatment abrogated
pyrogallol-mediated activation of P38
kinase, indicating that
pyrogallol-derived ROS led to P38
kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the
pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in
pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P-P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with
pyrogallol-primed hUCMSCs
transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with
pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based
therapy for treating LPS-associated ALI.