Lipoxin A4 receptor agonist BML-111 induces autophagy in alveolar macrophages and protects from acute lung injury by activating MAPK signaling.
BACKGROUND
Acute lung injury (ALI) is a life-threatening lung disease where alveolar macrophages (AMs) play a central role both in the early phase to initiate inflammatory responses and in the late phase to promote tissue repair. In this study, we examined whether BML-111, a lipoxin A4 receptor agonist, could alter the phenotypes of AM and thus present prophylactic benefits for ALI.


METHODS
In vitro, isolated AMs were treated with lipopolysaccharide (LPS) to induce ALI. In response to BML-111 pre-treatment, apoptosis and autophagy of AMs were examined by flow cytometry, and by measuring biomarkers for each process. The potential involvement of MAPK1 and mTOR signaling pathway was analyzed. In vivo, an LPS-induced septic ALI model was established in rats and the preventative significance of BML-111 was assessed. On the cellular and molecular levels, the pro-inflammatory cytokines TNF-α and IL-6 from bronchoalveolar lavage were measured by ELISA, and the autophagy in AMs examined using Western blot.


RESULTS
BML-111 inhibited apoptosis and induced autophagy of AMs in response to ALI inducer, LPS. The enhancement of autophagy was mediated through the suppression of MAPK1 and MAPK8 signaling, but independent of mTOR signaling. In vivo, BML-111 pre-treatment significantly alleviated LPS-induced ALI, which was associated with the reduction of apoptosis, the dampened production of pro-inflammatory cytokines in the lung tissue, as well as the increase of autophagy of AMs.


CONCLUSIONS
This study reveals the prophylactic significance of BML-111 in ALI and the underlying mechanism: by targeting the MAPK signaling but not mTOR pathway, BML-111 stimulates autophagy in AMs, attenuates the LPS-induced cell apoptosis, and promotes the resolution of ALI.
['Liu|Huaizheng|H|', 'Zhou|Kefu|K|', 'Liao|Liangkan|L|', 'Zhang|Tianyi|T|', 'Yang|Mingshi|M|', 'Sun|Chuanzheng|C|']
D055371:Acute Lung Injury D000818:Animals D001343:Autophagy D004789:Enzyme Activation D006538:Heptanoic Acids D008070:Lipopolysaccharides D020935:MAP Kinase Signaling System D016676:Macrophages, Alveolar D008297:Male D051381:Rats D017207:Rats, Sprague-Dawley D044067:Receptors, Lipoxin
Lipoxin BML-111 Autophagy Acute lung injury Apoptosis