Speaker
Description
Supplemental oxygen administration is frequently encountered in infants and adults with pulmonary insufficiency. Hyperoxia contributes to acute respiratory distress syndrome (ARDS) in humans. In this investigation, we tested the hypotheses that (i) hyperoxia induces CYP1A1 via the formation of 6-Formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for the Ah receptor (AHR; and (ii) FICZ would attenuate hyperoxic lung injury in vivo. Adult (10 week old) wild type (WT) mice were maintained in room air or exposed to hyperoxia (> 95% O2) for 6-48 h, and lungs were analyzed for the formation of FICZ. FICZ was detected in vivo in mouse lungs exposed to hyperoxia at 6 h, as revealed by LC-MS/MS. Secondly, WT mice were treated with FICZ (2 mg/kg), i.p., once daily for 3 days, and the animals were exposed to room air or hyperoxia (> 95% O2) for 72 h. FICZ significantly upregulated CYP1A1 and CYP1B1 in lung and liver and CYP1A2 in liver at the mRNA, protein, and enzyme levels, and attenuated lung injury mediated by hyperoxia. Thirdly, WT, Cyp1a1-null, Cyp1a2-null, Cyp1b1-null, Cyp1a1/1a2-double null, Cyp1a1/1a2/1b1 triple null, and AHR-null mice were treated with FICZ (2 mg/kg), i.p, and FICZ levels were found to be highest in AHR-null mice. In conclusion, our results demonstrate the role of FICZ in novel role of FICZ in the induction of CYP1A1 by hyperoxia via the AHR and in protection against hyperoxic lung injury by FICZ. Further studies could lead to the development of novel AHR agonists in the prevention/treatment of ARDS in humans.
