Lipoxin A₄attenuates LPS-induced acute lung injury via activation of the ACE2-Ang-(1-7)-Mas axis

Abstract

Previous studies have reported that lipoxin A4 (LXA4) and the angiotensin I-converting enzyme 2 (ACE2), angiotensin-(1-7) [Ang-(1-7)], and its receptor Mas [ACE2-Ang-(1-7)-Mas] axis play important protective roles in acute lung injury (ALI). However, there is still no direct evidence of LXA4-mediated protection via the ACE2-Ang-(1-7)-Mas axis during ALI. This work was performed using an LPS-induced ALI mouse model and the data indicated the following. First, the animal model was established successfully and LXA4 ameliorated LPS-induced ALI. Second, LXA4 could increase the concentration and activity of ACE2 and the levels of Ang-(1-7) and Mas markedly. Third, LXA4 decreased the levels of TNF-α, IL-1β, and reactive oxygen species while increasing IL-10 levels. Fourth, LXA4 inhibited the activation of the NF-κB signal pathway and repressed the degradation of inhibitor of NF-κB, the phosphorylation of NF-κB, and the translocation of NF-κB. Finally, and more importantly, BOC-2 (LXA4 receptor inhibitor), MLN-4760 (ACE2 inhibitor), and A779 (Mas receptor antagonist) were found to reverse all of the effects of LXA4. Our data provide evidence that LXA4 protects the lung from ALI through regulation of the ACE2-Ang-(1-7)-Mas axis.

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…Prostaglandins prevent hypertension and upregulate renal ACE2 protein expression in adult male rats exposed either prenatally to dexamethasone plus postnatally to high fat diet (P. C. Lu et al, 2016 ) or prenatally to high fructose intake ( Tain, Lee, Wu, Leu, & Chan, 2016 ). Lipoxin A4, another product of arachidonic acid metabolism, attenuates lung injury and increases lung ACE2 levels and protein expression in a lipopolysaccharide-induced lung injury model (Q. F. Chen et al, 2018 ). Similarly, the lipoxin receptor agonist BML-111 also decreases lung and liver injuries, which are associated with increased ACE2 levels and protein expression in these tissues ( Q. F. Chen et al, 2019 ; Hu et al, 2017 ).…”

Lipoxin A4 Reduces Ventilator-Induced Lung Injury in Rats with Large-Volume Mechanical Ventilation

“…Despite the application of lung protective strategies and other pharmacological treatments, VILI remains the major cause of death of individuals with ARDS [ 7 ]. Lipoxin A4 is an endogenous anti-inflammatory lipid mediator that is synthesised from arachidonic acid, and it attenuates different organ injuries via its anti-inflammatory, antioxidative, and antiapoptotic effects [ 12 , 18 , 19 ]. However, no study investigated the effect of lipoxin A4 on VILI.…”

“…MV was initiated after injection of 0.6 mg/kg rocuronium. Rats in the sham and VILI groups received 0.5 ml saline simultaneous with MV initiation, and the rats in the LX4 group received lipoxin A4 (100 μ g/kg diluted in 1 ml saline, administered via injection for 30 min) [ 10 , 12 ] (Cayman Chemical, Ann Arbor, MI, USA). The anaesthesia was maintained with pentobarbital sodium (10 mg/kg intraperitoneally) and rocuronium (0.6 mg/kg) via intravenous injection at one-hour intervals.…”

Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2

“…These are yet to gain drug regulatory approval and range from traditional Chinese medicinal products to novel molecules, herbal extracts, and repurposed compounds. A list of these compounds with their effects on ACE/ACE2 is provided in Table 1 (Castardeli et al, 2018;Chang et al, 2018;Q.-F. Chen et al, 2019;Chen et al, 2018;Guo et al, 2010;Haber et al, 2014;Kadakol et al, 2015;Lee et al, 2015;Li et al, 2018;Liao et al, 2019;Lin et al, 2017;Liu et al, 2018;Lv et al, 2017;de Macedo et al, 2015;Martínez-Aguilar et al, 2016;Prata et al, 2017;Qaradakhi et al, 2020;Shi et al, 2013;Syed et al, 2016;Tain et al, 2016;Tikellis and Thomas, 2012;Wang et al, 2016Wang et al, , 2018Wei et al, 2015;Wu et al, 2014;Ye et al, 2008;Zhang et al, 2013;Zhao et al, 2015).…”