Acute lung injury (ALI) is characterized by alveolar epithelial damage and uncontrolled
pulmonary inflammation. Mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial
peptides [ N-formyl
peptides (NFPs)], are released during cell injury and death and induce
inflammation by unclear mechanisms. In this study, we have investigated the role of mitochondrial DAMPs (MTDs), especially NFPs, in alveolar epithelial injury and
lung inflammation. In murine models of ALI, high levels of mitochondrial
NADH dehydrogenase 1 in bronchoalveolar lavage fluid (BALF) were associated with
lung injury scores and increased
formyl peptide receptor (FPR)-1 expression in the alveolar epithelium.
Cyclosporin H (CsH), a specific inhibitor of FPR1, inhibited
lung inflammation in the ALI models. Both MTDs and NFPs upon intratracheal challenge caused accumulation of neutrophils into the alveolar space with elevated BALF levels of mouse
chemokine KC, interleukin-1β, and
nitric oxide and increased pulmonary FPR-1 levels. CsH significantly attenuated MTDs or NFP-induced inflammatory
lung injury and activation of MAPK and AKT pathways. FPR1 expression was present in rat primary alveolar epithelial type II cells (AECIIs) and was increased by MTDs. CsH inhibited MTDs or NFP-induced CINC-1/IL-8 release and phosphorylation of p38, JNK, and AKT in rat AECII and human cell line A549. Inhibitors of MAPKs and AKT also suppressed MTD-induced
IL-8 release and NF-κB activation. Collectively, our data indicate an important role of the alveolar epithelium in initiating immune responses to MTDs released during ALI. The potential mechanism may involve increase of
IL-8 production in MTD-activated AECII through FPR-1 and its downstream MAPKs, AKT, and NF-κB pathways.