Resolvin D1 attenuates mechanical stretch-induced pulmonary fibrosis via epithelial-mesenchymal transition

Abstract

Mechanical ventilation-induced pulmonary fibrosis plays an important role in the high mortality rate of acute respiratory distress syndrome (ARDS). Resolvin D1 (RvD1) displays potent proresolving activities. Epithelial-mesenchymal transition (EMT) has been proved to be an important pathological feature of lung fibrosis. This study aimed to investigate whether RvD1 can attenuate mechanical ventilation-induced lung fibrosis. Human lung epithelial (BEAS-2B) cells were pretreated with RvD1 for 30 min and exposed to acid for 10 min before being subjected to mechanical stretch for 48 h. C57BL/6 mice were subjected to intratracheal acid aspiration followed by mechanical ventilation 24 h later (peak inspiratory pressure 22 cmH2O, positive end-expiratory pressure 2 cmH2O, and respiratory rate 120 breaths/min for 2 h). RvD1 was injected into mice for 5 consecutive days after mechanical ventilation. Treatment with RvD1 significantly inhibited mechanical stretch-induced mesenchymal markers (vimentin and α-smooth muscle actin) and stimulated epithelial markers (E-cadherin). Tert-butyloxycarbonyl 2 (BOC-2), a lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) antagonist, is known to inhibit ALX/FPR2 function. BOC-2 could reverse the beneficial effects of RvD1. The antifibrotic effect of RvD1 was associated with the suppression of Smad2/3 phosphorylation. This study demonstrated that mechanical stretch could induce EMT and pulmonary fibrosis and that treatment with RvD1 could attenuate mechanical ventilation-induced lung fibrosis, thus highlighting RvD1 as an effective therapeutic agent against pulmonary fibrosis associated with mechanical ventilation.

Transient receptor potential canonical 1 channel mediates the mechanical stress‑induced epithelial‑mesenchymal transition of human bronchial epithelial (16HBE) cells

“…Significant EMT has been demonstrated in the airway epithelial cells of patients with cOPd (14)(15)(16), and EMT has been suggested as an important factor for airway remodeling in cOPd (17,18). Previous studies have demonstrated that primary airway epithelial cells subjected to mechanical stretch acquire EMT phenotypes (19)(20)(21). However, the specific molecular mechanisms of EMT in response to mechanical stress remain poorly understood.…”

Diet in Intestinal Fibrosis: A Double-Edged Sword

“…It is in accordance with a study from Zeng et al, showing that DHA inhibits TGF-β-induced rat renal fibroblast activation at a dose and time-dependent manner [ 85 ]. DHA derivative such as resolvin D1 was also evaluated in extra-intestinal fibrosis model [ 86 ]. Resolvin D1 treatment was able to reduce mechanical stretch-induced EMT and SMAD signaling in a murine model of lung fibrosis [ 86 ].…”

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine

“…Maresins have organ protective effects, decrease edema, improve lung mechanics and tissue hypoxia (75). RvD1 decreases pulmonary edema, leukocyte infiltration and the release of pro-inflammatory cytokines and alleviates lung injury (76)(77)(78)(79) and RvE1 can restore mitochondrial function in human alveolar epithelial cells and accelerates the resolution of experimental lung inflammation (80)(81)(82). Moreover, protectin D1 has beneficial effects in influenza-infected mice (83) and 15-epiLXA4 inhibits neutrophil infiltration and enhances pathogen clearance (84,85).…”