Protective effect of combination of anakinra and MCC950 against acute lung injury is achieved through suppression of the NF-κB-mediated-MAPK and NLRP3-caspase pathways

Abstract

Background: It has been uncovered that the interleukin-1 receptor antagonist anakinra and the NLRP3 inflammasome blocker MCC950 can alleviate acute lung injury (ALI). However, the specific mechanism underlying these effects remains unknown. Thus, we sought to investigate the effects of anakinra and MCC950 in ALI as well as the molecular mechanisms.

Methods: We treated C57BL/6 mice with aerosols of anakinra and/or MCC950 along with lipopolysaccharide (LPS), followed by mechanical ventilation (MV) treatment after 1.5 h of inhalation of aforementioned compounds. Lung injury was assessed by determining the level of inflammatory factors in the alveolar lavage fluid and monitoring blood oxygen saturation. We confirmed our findings of regulation of the ALI model through the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK)/nucleotide binding domain and leucine-rich repeat (NLR) pyrin domain containing 3 (NLRP3)-caspase pathway in further studies with RelA^-/- mice.

Results: Combined treatment of anakinra and MCC950 presented the best therapeutic effect on LPS and MV-induced ALI than did treatment with anakinra or MCC950 alone. Combined therapy with anakinra and MCC950 suppressed MAPK and NLRP3-caspase via inhibition of the NF-κB pathway to improve ALI, but the therapeutic pathway was revoked by knockout of NF-κB.

Conclusion: Taken together, combined treatment of anakinra and MCC950 was effective in alleviating ALI in the mouse model, highlighting a new insight into ALI treatment.

Keywords: Acute lung injury; Anakinra; MCC950; Mitogen-activated protein kinase; Nuclear factor-κB; Nucleotide binding domain and leucine-rich repeat (NLR) pyrin domain containing 3.