Omeprazole attenuates hyperoxic injury in H441 cells via the aryl hydrocarbon receptor

Abstract

Hyperoxia contributes to the development of bronchopulmonary dysplasia in premature infants. Earlier we observed that aryl hydrocarbon receptor (AhR)-deficient mice are more susceptible to hyperoxic lung injury than AhR-sufficient mice, and this phenomenon was associated with a lack of expression of cytochrome P450 1A enzymes. Omeprazole, a proton pump inhibitor, used in humans with gastric acid related disorders, activates AhR in hepatocytes in vitro. However, the effects of omeprazole on AhR activation in the lungs and its impact on hyperoxia-induced ROS generation and inflammation are unknown. In this study, we tested the hypothesis that omeprazole attenuates hyperoxia-induced cytotoxicity, ROS generation, and expression of monocyte chemoattractant protein-1 (MCP-1) in the human lung derived H441 cells via AhR activation. Experimental groups included cells transfected with AhR small interfering RNA (siRNA). Hyperoxia resulted in significant increases in cytotoxicity, ROS generation, and MCP-1 production, which were significantly attenuated with the functional activation of AhR by omeprazole. The protective effects of omeprazole on cytotoxicity, ROS production, and MCP-1 production were lost in H441 cells whose AhR gene was silenced by AhR siRNA. These findings support the hypothesis that omeprazole protects against hyperoxic injury in vitro via AhR activation that is associated with decreased ROS generation and expression of MCP-1.

338: Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury

“…Furthermore, recent studies have demonstrated an attenuating effect of CYP1A1 inducers on hyperoxic lung injury both in vitro [10,24] as well as in vivo [11][12][13].…”

“…Transplacental transfer is present but low, and dependent on the maternal plasma levels [23]. To our knowledge the use of omeprazole in preventing hyperoxia induced lung injury has only been demonstrated so far in vitro [24] and in in vivo mice models [12,25]. Herein, we test the hypothesis that in a hyperoxic induced lung injury preterm rabbit model, prenatal or neonatal administration of omeprazole (1) induces transcription of CYP1A1 in a dose-dependent way and (2) improves pulmonary outcome both on histological as well as functional level.…”

Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone

“…In tumors in human, overexpression of COX-2 leads to an increase in prostaglandin (PG) levels which affects many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, and stimulation of cell growth, as well as invasiveness and the metastatic potential of tumor cells (Cervello and Montalto, 2006). Several reports suggest that OPZ might have an anti-inflammation effect (Kedika et al, 2009;Shivanna et al, 2011). Indeed, OPZ inhibited ROS production and protected against oxidative stress by inducing heme-oxygenase-1 (Kedika et al, 2009;Shivanna et al, 2011).…”

“…Several reports suggest that OPZ might have an anti-inflammation effect (Kedika et al, 2009;Shivanna et al, 2011). Indeed, OPZ inhibited ROS production and protected against oxidative stress by inducing heme-oxygenase-1 (Kedika et al, 2009;Shivanna et al, 2011). However, the ligands of AhR, including TCDD and B[a]P, induced Cox-2 expression (Degner et al, 2007 and.…”

Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor

“…Total mRNA was isolated and reverse transcribed to cDNA as mentioned before (Shivanna et al, 2011a). Real-time quantitative reverse-transcription polymerase chain reaction analysis was performed with the 7900HT Real-Time PCR System using iTaq Universal SYBR Green Supermix (1725121; Bio-Rad).…”