Mesencephalic Astrocyte-Derived Neurotrophic Factor Attenuates Acute Lung Injury via Inhibiting Macrophages’ Activation

Background: Acute lung injury (ALI) is an urgent respiratory disease without effective treatment. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been demonstrated to play a suppressive role in some inflammatory conditions. However, the effect of MANF on ALI has not yet been reported. <br><br>Methods: We collected bronchoalveolar lavage fluid (BALF) from the patients with or without pulmonary inflammation, and used lipopolysaccharide (LPS) to induce mice ALI model. Mono-macrophage-specific MANF knockout (MKO) mice was constructed and recombinant human MANF protein was used to ALI mice. <br><br>Findings: We found that the endogenous MANF protein in both human BALF and mice lung tissues was increased in inflammatory conditions. MANF level in the macrophages of inflammatory lung was higher than that in normal controls in both human and mice. MANF deficiency in macrophages induced lung inflammation and aggravated LPS-induced lung injury. MANF lowered LPS-induced lung injury, inhibited macrophage polarization to M1 functional type. Meanwhile, MANF inhibited-LPS induced activation of NF-κB signal pathway by down regulating phosphorylated p65 in lung tissue and macrophages.<br><br>Interpretation: Our findings indicate that MANF acts as a suppressor in ALI, which may be a novel potential target and shed light on ALI therapy.<br><br>Clinical Trial Registration Details: ChiCTR1800017141 (registered at Chinese Clinical Trial Registry).<br><br>Funding Information: This work was supported by the funds from Natural Science Foundation of China (no.81973336, no.81902003, and no.31800702) and funds from Natural Science Foundation of Anhui Province (no.1708085QH173 and no. 1908085QH311).<br><br>Declaration of Interests: The authors declare no competing interests.<br><br>Ethics Approval Statement: ll individuals were recruited under an investigational protocol approved by Ethics Committee of Anhui Medical University (PJ2018-07-27) and written informed consent was obtained.<br><br>All the experiments described in the following research were approved by the Animal Care and Use Committee of Anhui Medical University.<br><br>