Knockout of cytochrome P450 1A1 enhances lipopolysaccharide‐induced acute lung injury in mice by targeting NF‐κB activation

• Published in: FEBS open bio Vol. 10; no. 11; pp. 2316 - 2328
• Main Authors: Tian, Li‐xing, Tang, Xin, Ma, Wei, Wang, Jing, Zhang, Wei, Liu, Kuan, Chen, Tao, Zhu, Jun‐yu, Liang, Hua‐ping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2020; John Wiley and Sons Inc; Wiley
• Subjects: acute lung injury; Alanine; Alanine transaminase; Antibodies; Aspartate aminotransferase; Centrifugation; Chemiluminescence; Creatine; Creatine kinase; Creatinine; Cytochrome; Cytochrome P450; cytochrome P450 1A1; Cytokines; Drug therapy; E coli; Hydrocarbons; Inflammation; Kinases; L-Lactate dehydrogenase; Laboratory animals; Lactic acid; Lipopolysaccharides; LPS; Lung diseases; Lungs; NF‐κB; Proteins; Respiratory distress syndrome; Sepsis; Skim milk; TLR4 protein; Toll-like receptors; United States > US; China; NF-κB; cytochrome P450 1A1; acute lung injury; LPS
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12977

CYP1A1 was induced in lung of mice by LPS treatment with an aryl hydrocarbon receptor‐independent manner, while Toll‐like receptor 4 knockout abolished CYP1A1 overexpression. CYP1A1 deficiency elevated pro‐inflammatory cytokines in lung tissues of septic mice by targeting NF‐κB (p65) and increased lung injury in response to LPS or E. coli challenge. Acute lung injury (ALI) is accompanied by overactivation of multiple pro‐inflammatory factors. Cytochrome P450 1A1 (CYP1A1) has been shown to aggravate lung injury in response to hyperoxia. However, the relationship between CYP1A1 and lipopolysaccharide (LPS)‐induced ALI is unknown. In this study, CYP1A1 was shown to be upregulated in mouse lung in response to LPS. Using CYP1A1‐deficient (CYP1A1−/−) mice, we found that CYP1A1 knockout enhanced LPS‐induced ALI, as evidenced by increased TNF‐α, IL‐1β, IL‐6, and nitric oxide in lung; these effects were mediated by overactivation of NF‐κB and iNOS. Furthermore, we found that aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatinine levels were elevated in serum of LPS‐induced CYP1A1−/− mice. Altogether, these data provide novel insights into the involvement of CYP1A1 in LPS‐induced lung injury.