BML-111 accelerates the resolution of inflammation by modulating the Nrf2/HO-1 and NF-κB pathways in rats with ventilator-induced lung injury.

Abstract

The timely resolution of pulmonary inflammation coordinated by endogenous pro-resolving mediators helps limit lung tissue injury, but few endogenous pro-resolving mediators that are normally operative during acute inflammation. The protective effects of BML-111 (5(S)-6(R)-7-trihydroxyheptanoic acid methyl ester), a potent commercially available anti-inflammatory and pro-resolving mediator, on ventilation-induced lung injury (VILI) have been extensively studied, but its characteristics as a pro-resolving mediator have not. Here, anesthetized Sprague-Dawley rats were ventilated with a high tidal volume (20 mL/kg, HVT) for 1 h and randomly allocated to recover for 6, 12, 24, 48, 72, 96 or 168 h; BML-111 was administered at the peak of inflammation to evaluate its pro-resolving effect on VILI. The one-hour HVT induced a maximal pulmonary inflammatory response at 12 h that was largely resolved by 72 h. BML-111 largely resolved the maximal inflammatory response at 48 h; the resolution interval (Ri) was shortened by 26 h. Similarly, HVT elicited a time course of changes in histopathology and pulmonary edema, and BML-111 alleviates these changes. Mechanistically, neutrophil apoptosis was significantly increased in BML-111-treated rats subjected to HVT. The apoptosis inhibitor z-VAD-fmk partially reversed the proapoptotic actions of BML-111 on neutrophil and the resolving effects of BML-111 on VILI but had no effect alone. Importantly, the HVT treatment activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) and NF-κB signaling pathways in the lung tissue, and BML-111 further induced Nrf2 and HO-1 expression but inhibited the NF-κB pathway. Intriguingly, when we inhibited the Nrf2/HO-1 pathway with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), Nrf2 expression was further increased, but the inhibitory effects of BML-111 on the NF-κB pathway and on the subsequent inflammatory response, and the proapoptotic actions on neutrophil were reversed. The results suggest that BML-111 promotes the resolution of HVT-induced inflammation to mitigate VILI in rats, perhaps by modulating the Nrf2/HO-1 and NF-κB pathways and subsequently increasing neutrophil apoptosis.

• Authors: Jiqian Xu, Hong-Bin Li, Lin Chen, Ya-Xin Wang, Shengzhong Lu, Sheng-Nan Li, Shu-Nan Cui, Hai-Rong Xiao, Lu Qin, Houxiang Hu, Shanglong Yao, You Shang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 69 Pg. 289-298 (Apr 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 30753968 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
• Heptanoic Acids
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, rat
• Protoporphyrins
• zinc protoporphyrin
• Heme Oxygenase-1

Topics

• Animals
• Apoptosis
• Cells, Cultured
• Disease Models, Animal
• Heme Oxygenase-1 (metabolism)
• Heptanoic Acids (therapeutic use)
• Humans
• Inflammation (drug therapy)
• Lung (drug effects, pathology)
• Male
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Neutrophils (pathology)
• Protoporphyrins (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Ventilator-Induced Lung Injury (drug therapy)