ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

Abstract

Pulmonary fibrosis is a grave diagnosis with insidious progression, generally considered as a consequence of aberrant epithelial wound healing and excessive scarring. This process is commonly modeled in animals by local bleomycin administration, resulting in peribronchial inflammation and subsequent fibrosis. We have previously described initiation and early development of distal pulmonary fibrosis following repeated subcutaneous bleomycin injections (systemic administration). The aim of this study was to identify mechanisms for the development of pulmonary fibrosis, which we hypothesize is related to endothelial stress and activation. Bleomycin was administered subcutaneously 3 times/ week during 0.33-4w, and parenchymal alterations were studied. In addition, we used microvascular endothelial cells to investigate effects of bleomycin in vitro. Our results confirmed that systemic administration of bleomycin exerts oxidative stress indicated by an increase in Sod1 at 0.33, 1, and 4w (Po0.05). Endothelial cells were activated (increased CD106 expression) from 1w and onwards (Po0.05), and p21 expression was increased 2-3 times throughout the study (Po0.05) as were the number of β-catenin-positive nuclei (Po0.001). Wnt3a was increased at 0.33, 1, and 4w (Po0.01) and Wnt5a from 1w and onwards (Po0.001). The present study suggests that bleomycin-induced reactive oxygen species (ROS) causes DNA stress affecting the endothelial niche, initiating repair processes including Wnt signaling. The repeated systemic administrations disrupt a normally fine-tuned balance in the Wnt signaling. In addition, pericyte differentiation was affected, which may have significant effects on fibrosis due to their ability to differentiate into myofibroblasts. We conclude that the endothelial niche may have an important role in the development of pulmonary fibrosis and warrants further investigations.

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells

“…In particular, depletion of ROS reverses the EndMT process in HAECs [44]. LIPUS has been documented to reduce ROS accumulation via protein kinase A-mediated inhibition of NAD(P)H oxidases [45].…”

5‐HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo

“…; Andersson‐Sjoland et al. ). The 5‐HT 2B receptors have been associated with tissue remodeling caused by platelet activation and vascular damage (Dees et al.…”

“…; Andersson‐Sjoland et al. ), in contrast to most studies that use local (intra‐tracheal) administration. Local administration results in extensive epithelial damage, acute inflammation, and subsequent heterogeneous pulmonary fibrosis.…”

Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice

“…Oxidative stress is considered a prominent mechanism associated with the pathogenesis of PF (30,31). The decline in antioxidant capacity and the elevated oxidant burden contribute to the progression of lung fibrosis via the activation of inflammation and growth regulatory cytokines, the regulation of related enzymes essential to the induction of antioxidants, and the stimulation of the production of myofibroblasts and ECM (32).…”