Hyperoxia-mediated transcriptional activation of cytochrome P4501A1 (CYP1A1) and decreased susceptibility to oxygen-mediated lung injury in newborn mice

Abstract

Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this study, we tested the hypothesis that newborn transgenic mice carrying the human CYP1A1-Luc promoter will display transcriptional activation of the human CYP1A1 promoter in vivo upon exposure to hyperoxia, and that these mice will be less susceptible to hyperoxic lung injury and alveolar simplification than similarly exposed wild type (WT) mice. Newborn WT (CD-1) or transgenic mice carrying a 13.2 kb human CYP1A1 promoter and the luciferase (Luc) reporter gene (CYP1A1-luc) were maintained in room air or exposed to hyperoxia (85% O) for 7-14 days. Hyperoxia exposure of CYP1A1-Luc mice for 7 and 14 days resulted in 4- and 30-fold increases, respectively, in hepatic Luc (CYP1A1) expression, compared to room air controls. In lung, hyperoxia caused a 2-fold induction of reporter Luc at 7 days, but the induction declined after 14 days. The newborn CYP1A1-Luc mice were less susceptible to lung injury and alveolar simplification than similarly exposed wild type (WT) CD-1 mice. Also, the CYP1A1-Luc mice showed increased levels of hepatic and pulmonary CYP1A1 expression and hepatic CYP1A2 activity after hyperoxia exposure. Hyperoxia also increased NADP(H) quinone reductase (NQO1) pulmonary gene expression in both CD-1 and CYP1A1-Luc mice at both time points, but this was more pronounced in the latter at 14 days. Our results support the hypothesis that hyperoxia activates the human CYP1A1 promoter in newborn mice, and that increased endogenous expression of CYP1A1 and NADP(H) quinone reductase (NQO1) contributes to the decreased susceptibilities to hyperoxic lung injury in the transgenic animals. This is the first report providing evidence of hyperoxia-mediated transcriptional activation of the human CYP1A1 promoter in newborn mice, and this in conjunction with decreased lung injury, suggests that these phenomena have important implications for BPD.

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

“…Unsurprisingly, the induction of CYP1A1 function by β-naphthoflavone reduced the classical features of hyperoxic lung injury in mice, as did the transgenic overexpression of the CYP1A1 promoter in newborn mice subjected to hyperoxia. The studies on the CYP1A1 promoter overexpression found that the hyperoxic exposure per se induces the activation of the promoter and the CYP1A1 activity that is responsible for the attenuation of hyperoxic lung injury [29,30]. Further studies extending these initial findings have provided evidence that β-naphthoflavone action is not restricted to CYP1A1, as postnatal administration in CYP1A1-knockout mice induced the expression of CYP1A2 and NAD(P)H quinone oxidoreductase, which led to comparable reduction in lung injury to that in wild-type mice [31].…”

Is There a Genetic Predisposition to Postoperative Adhesion Development?

“…The induced hypoxemic conditions in intraperitoneal adhesion development [ 28 , 44 – 46 ] are theorized to disrupt the balance of persistence of the fibrin gel matrix with fibroblast infiltration laying down collagen (a prerequisite to adhesion development) [ 47 ], lower apoptosis through S-nitrosylation of caspase-3 [ 33 ] and lower fibrinolysis [ 48 ], leading to the formation of disarrayed dense tissue. Similarly, hyperoxemia as with oxygen treatment can also cause oxidative stress via an increase in the NADH oxidase and P450 reductase pathway [ 49 ] as shown in Fig. 1 .…”

Nrf2‑Keap1‑ARE‑NQO1 signaling attenuates hyperoxia‑induced lung cell injury by inhibiting apoptosis

“…A previous study demonstrated the significant upregulation of NQO1 expression in transgenic mice carrying the human CYP1A1-Luc promoter upon exposure to hyperoxia, and suggested that these mice are less susceptible than wild-type mice to hyperoxia-induced ALI and alveolar simplification (36). In another study, miR-494 was shown to negatively regulate NQO1 and block the Nrf2 signaling pathway, resulting in the acceleration of ALI in rats with sepsis-associated acute respiratory distress syndrome (37).…”