Nox2-derived ROS in PPARγ signaling and cell-cycle progression of lung alveolar epithelial cells

Reactive oxygen species (ROS) play important roles in peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling and cell-cycle regulation. However, the PPAR gamma redox-signaling pathways in lung alveolar epithelial cells remain unclear. In this study, we investigated the in vivo and in vitro effects of PPAR gamma activation on the levels of lung ROS production and cell-cycle progression using C57BL/6J wild-type and Nox2 knockout mice (n = 10) after intraperitoneal injection of a selective PPAR gamma agonist (GW1929, 5 mg/kg body wt, daily) for 14 days. Compared to vehicle-treated mice, GW1929 increased significantly the levels of ROS production in wild-type lungs, and this was accompanied by significant up-regulation of PPAR gamma, Nox2. PCNA, and cyclin D1 and phosphorylation of ERK1/2 and p38MAPK. These effects were absent in Nox2 knockout mice. In cultured alveolar epithelial cells, GW1929 (5 mu M for 24 h) increased ROS production and promoted cell-cycle progression from G0/G1 into S and G2/M phases, and these effects were abolished by (1) adding a PPAR gamma antagonist (BADGE, 1 mu M), (2) knockdown of PPAR gamma using siRNA, or (3) knockout of Nox2. In conclusion, PPAR gamma activation through Nox2-derived ROS promotes cell-cycle progression in normal mouse lungs and in cultured normal alveolar epithelial cells. (C) 2011 Elsevier Inc. All rights reserved.