Mitochondrial peptides cause proinflammatory responses in the alveolar epithelium via FPR-1, MAPKs, and AKT: a potential mechanism involved in acute lung injury
| Autor: | Tao Wang, Luqi Dai, Fuqiang Wen, Ni Zeng, Hao Wang, Lian Liu, Zhicheng Yuan, Xue Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Pulmonary and Respiratory Medicine Physiology Alveolar Epithelium Acute Lung Injury Inflammation Lung injury Formyl peptide receptor 1 Proinflammatory cytokine Rats Sprague-Dawley Epithelial Damage Mice 03 medical and health sciences Physiology (medical) Animals Medicine Phosphorylation Potential mechanism Protein kinase B Mice Inbred BALB C business.industry Interleukin-8 NF-kappa B Pneumonia Cell Biology respiratory system Receptors Formyl Peptide Peptide Fragments Mitochondria Rats respiratory tract diseases 030104 developmental biology Alveolar Epithelial Cells Cancer research Inflammation Mediators Mitogen-Activated Protein Kinases medicine.symptom business Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 315:L775-L786 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00466.2017 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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