Hepatocyte growth factor (HGF) is involved in many cellular responses, such as mitogenesis and apoptosis protection; however, its effect against oxidative injury induced by ethanol metabolism is not well understood. The aim of this work was to address the mechanism of HGF-induced protection against ethanol-generated oxidative stress damage in the human cell line VL-17A (cytochrome P450 2E1/alcohol dehydrogenase-transfected HepG2 cells). Cells were pretreated with 50 ng/ml HGF for 12 h and then treated with 100 mM ethanol for 0-48 h. Some parameters of oxidative damage were evaluated. We found that ethanol induced peroxide formation (3.3-fold) and oxidative damage as judged by lipid peroxidation (5.4-fold). Damage was prevented by HGF. To address the mechanisms of HGF-induced protection we investigated the cellular antioxidant system. We found that HGF increased the GSH/GSSG ratio, as well as SOD1, catalase, and gamma-glutamylcysteine synthetase expression. To explore the signaling pathways involved in this process, VL-17A cells were pretreated with inhibitors against PI3K, Akt, and NF-kappaB. We found that all treatments decreased the expression of the antioxidant enzymes, thus abrogating the HGF-induced protection against oxidative stress. Our results demonstrate that HGF protects cells from the oxidative damage induced by ethanol metabolism by a mechanism driven by NF-kappaB and PI3K/Akt signaling.

Exposure to particulate matter (PM) has been implicated in oxidative stress (OxS) and inflammation as underlying mechanisms of lung damage and cardiovascular alterations. PM is a chemical mixture that can be subdivided according to their aerodynamic size into coarse (CP), fine (FP), and ultrafine (UFP) particulates. We investigated, in a rat model, the induction of OxS (protein oxidation and antioxidant response), carcinogen-DNA adduct formation, and inflammatory mediators in lung in response to different airborne particulate fractions, CP, FP, and UFP, after an acute and subchronic exposure. In addition, OxS was evaluated in the aorta to assess the effects beyond the lungs. Exposure to CP, FP, and UFP induced time-and size-dependent lung protein oxidation and DNA adduct formation. After acute and subchronic exposure, nuclear factor erythroid-2 (Nrf2) activation was observed in the lung, by electrophoretic mobility shift assay, and the induction of mRNA antioxidant enzymes in the FP and UFP groups, but not in the CP. Cytokine concentration of interleukin 1, interleukin 6, and macrophage inflammatory protein-2 was significantly increased in bronchoalveolar lavage fluid after acute exposure to FP and UFP. Activation of Nrf2 and expression of mRNA antioxidant enzymes were observed only after the subchronic exposure to FP and UFP in the aorta. Our results indicate that FP and UFP were mainly accountable for the oxidant toxic effects in the lung; OxS is spread from the lung to the cardiovascular system. We conclude that the biological mechanisms associated with transient OxS and inflammation are particle size and timedependent exposure resulting in acute lung injury, which later reaches the vascular system.

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