Thioredoxin-1 suppresses lung injury and apoptosis induced by diesel exhaust particles (DEP) by scavenging reactive oxygen species and by inhibiting DEP-induced downregulation of Akt

Diesel exhaust particles (DEP) are reactive oxygen species (ROS)-inducing toxic agents that damage lungs. Thioredoxin-l (Trx-l) is a thiol protein with antioxidant and redox-regulating effects. In this study, we demonstrate that Trx- I scavenges ROS generated by DEP and attenuates the lung injury. Intratracheal instillation of DEP resulted in the generation of more hydroxyl radicals in control mice than in human Trx-1 (hTrx-l)-transgenic mice as measured by noninvasive L-band in vivo electron spin resonance. DEP caused acute lung damage with massive infiltration of inflammatory cells in control mice, but much less damage in hTrx-l-transgenic mice. The hTrx-l transgene protected the mice against DEP toxicity. To investigate further the molecular mechanism of the protective role of Trx-I against DEP-induced lung injury, we used hTrx-l-transfected L-929 cells and recombinant hTrx-l (rhTrx-l)-pretreated A-549 cells. DEP-induced ROS generation was suppressed by hTrx-l transfection or pretreatment with r1Trx-l. Endogenous Trx-I expression was induced by DEP in control cells. The downregulation of Akt phosphorylation by DEP resulted in apoptosis, which was prevented by Trx-I, Moreover, an Akt inhibitor canceled this protective effect of Trx-l. Collectively, the results suggest that Trx-I exerts antioxidant effects in vivo and in vitro and that this plays a role in protection against DEP-induced lung damage by regulating Akt-mediated antiapoptotic signaling. (c) 2005 Elsevier Inc. All rights reserved.