Adenovirus-delivered angiopoietin-1 suppresses NF-κB and p38 MAPK and attenuates inflammatory responses in phosgene-induced acute lung injury.

Animals exposed to phosgene (Psg) result in acute lung injury (ALI). We have recently reported that angiopoietin-1 (Ang1) reduces inflammation and vascular hyperpermeability in ALI animals. In this study, we examined whether the beneficial effects of adenovirus-delivered Ang1 (Ad/Ang1) on inflammatory responses in Psg-induced ALI rats are due to the suppression of the nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) pathways, which play crucial roles in inflammatory responses in ALI. We demonstrated that Psg increased Ang2 and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-4 (IL-4), IL-6, IL-8, and IL-10, in the serum and bronchoalveolar lavage fluid of ALI rats, determined by ELISA. Ang1 inhibits pro-inflammatory mediators (TNF-α, IL-6 and IL-8) and has no effect on anti-inflammatory mediators (IL-4 and IL-10). Furthermore, the inhibitory action of Ang1 was mediated by the suppression of the NF-κB and p38 MAPK pathways, leading to the attenuation of inflammatory responses of ALI. Thus, Ad/Ang1 may provide a useful tool for the effective treatment in Psg-induced ALI.

[Protective effect of melatonin in rats with phosgene-induced lung injury].

OBJECTIVE: To investigate the antioxidant effect of melatonin (MT) in the rats with phosgene-induced lung injury and its possible mechanism. METHODS: Fifty male SD rats were equally randomized into phosgene exposure group, air control group, MT treatment group, dexamethasone (DX) treatment group, and negative control group. All groups except the air control group were exposed to 8.33 mg/L phosgene for 5 min, and the MT treatment group, DX treatment group, and negative control group were injected with MT (10 mg/kg), DX (2.5 mg/kg), and 1% ethanol saline (1 ml/kg), respectively, via the caudal vein 1 hour after exposure. The rats were sacrificed 6h later. Then, the wet/dry ratio of the lung, the total protein content and neutrophil count in bronchoalveolar lavage fluid (BALF), and the malonaldehyde (MDA) content and superoxide dismutase (SOD) and myeloperoxidase (MPO) activities in lung homogenate were measured; pathological observation was made on the lung tissue under an optical microscope; the protein expression of inducible nitric oxide synthase (iNOS) and NF-κB in the lung tissue was measured by Western blot. RESULTS: Compared with the air control group, the phosgene exposure group showed significantly increased wet/dry ratio of the lung and total protein content and neutrophil count in BALF (P < 0.01) as well as significantly increased MDA content and MPO activity in the lung tissue (P < 0.05). Compared with the phosgene exposure group, the MT treatment group showed significantly decreased MDA content and MPO activity and significantly increased SOD activity (P < 0.01), and the MT treatment group and DX treatment group showed significantly decreased protein expression of iNOS and NF-κB (P < 0.01). CONCLUSION: MT has protective effect in phosgene-induced lung injury, and its protective mechanism may be associated with scavenging free radicals and inhibiting expression of iNOS and NF-κB.