Gene expression of cytokines and growth factors in the lungs after paraquat administration in mice.
ABSTRACT It is well known that the intake of paraquat (PQ), an herbicide, causes severe lung injury at chronic phases. We examined the intrapulmonary gene expression of cytokines and growth factors after PQ administration. To induce lung injury, C57BL/6 mice were intraperitoneally injected twice a week with 20 mg/kg of PQ. Histopathologically, at the early phase, lots of alveolar spaces contained edematous fluid. At 3 weeks after PQ challenge, a marked thickening of the alveolar walls with the accumulation of macrophages and T cells was found. Azan staining revealed the patchy distribution of collagen accumulation, indicating pulmonary fibrosis. Consistently, intrapulmonary hydroxyproline contents were significantly elevated, compared with the controls. Semi-quantitative RT-PCR analysis demonstrated that the gene expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 were significantly increased at 3 weeks after PQ challenge compared with the controls. The mRNA expression of macrophage inflammatory protein (MIP)-1alpha and MIP-2 was significantly enhanced at 1 and 2 weeks after PQ treatment, respectively. Moreover, PQ-treated mice showed enhanced gene expression of fibrogenic growth factors such as transforming growth factor-beta, platelet-derived growth factor-A, acidic fibroblast growth factor, and hepatoctyte growth factor at 2 and/or 3 weeks after PQ challenge. The synergistic effects of these molecules are presumed to cause pulmonary fibrosis due to PQ challenge.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Paraquat, a widely used herbicide, is well known to exhibit oxidative stress and lung injury. In the present study, we investigated the possible underlying mechanisms of cannabinoid receptor-2 (CB2) activation to ameliorate the proinflammatory activity induced by PQ in rats. JWH133, a CB2 agonist, was administered by intraperitoneal injection 1 h prior to PQ exposure. After PQ exposure for 4, 8, 24, and 72 h, the bronchoalveolar lavage fluid was collected to determine levels of TNF- α and IL-1 β , and the arterial blood samples were collected for detection of PaO2 level. At 72 h after PQ exposure, lung tissues were collected to determine the lung wet-to-dry weight ratios, myeloperoxidase activity, lung histopathology, the protein expression level of CB2, MAPKs (ERK1/2, p38MAPK, and JNK1/2), and NF- κ Bp65. After rats were pretreated with JWH133, PQ-induced lung edema and lung histopathological changes were significantly attenuated. PQ-induced TNF- α and IL-1 β secretion in BALF, increases of PaO2 in arterial blood, and MPO levels in the lung tissue were significantly reduced. JWH133 could efficiently activate CB2, while inhibiting MAPKs and NF- κ B activation. The results suggested that activating CB2 receptor exerted protective activity against PQ-induced ALI, and it potentially contributed to the suppression of the activation of MAPKs and NF- κ B pathways.BioMed Research International 01/2014; 2014:971750. · 2.71 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: To evaluate the possible therapeutic effect of ambroxol on pulmonary fibrosis induced by paraquat. Adult male Sprague-Dawley rats (n=144, 200-250 g) were divided into four groups (Control, Ambroxol, Paraquat, and Paraquat+Ambroxol group) and sacrificed on day 1, 3, 5, 7, 14 and 28. Several significant oxidant stress markers (MDA, SOD and GSH-PX), MPO activity, cytokines (TNF-α, MCP-1, TGF-β1, MMP-2 and TIMP-1), total inflammatory cell count, hydroxyproline content, collagen I and III mRNA were analyzed. In Paraquat group, the MDA, MPO activity, hydroxyproline contents, the mRNA expression of TNF-α, MCP-1, TGF-β1, MMP-2, TIMP-1, collagen I, collagen III and the number of total inflammatory cells were up-regulated in lung tissue, but SOD and GSH-PX activity were down-regulated in lung tissue compared with Control group (p<0.05). In paraquat+ambroxol group, the MDA, MPO activity, hydroxyproline content, the mRNA expression of TNF-α, MCP-1, TGF-β1, MMP-2, TIMP-1 collagen I, collagen III and the number of total inflammatory cells were significantly decreased, while the SOD and GSH-PX activities in lung tissue were increased compared with Paraquat group (p<0.05). Histological examination of paraquat-treated rats showed lung injury with interstitial edema and widespread inflammatory cell infiltration in the alveolar space and septum, as well as pulmonary fibrosis. Ambroxol could markedly reduce such damage in lung tissue and prevent pulmonary fibrosis. The results of this study indicated that ambroxol could reduce lung damage and prevent pulmonary fibrosis induced by paraquat.Internal Medicine 01/2011; 50(18):1879-87. · 0.97 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Although 4,4'-diaminodiphenylsulfone (DDS, dapsone) has been used to treat several dermatologic conditions, including Hansen disease, for the past several decades, its mode of action has remained a topic of debate. We recently reported that DDS treatment significantly extends the lifespan of the nematode C. elegans by decreasing the generation of reactive oxygen species. Additionally, in in vitro experiments using non-phagocytic human fibroblasts, we found that DDS effectively counteracted the toxicity of paraquat (PQ). In the present study, we extended our work to test the protective effect of DDS against PQ in vivo using a mouse lung injury model. Oral administration of DDS to mice significantly attenuated the lung tissue damage caused by subsequent administration of PQ. Moreover, DDS reduced the local expression of mRNA transcripts encoding inflammation-related molecules, including endothelin-1 (ET-1), macrophage inflammatory protein-1α (MIP-1α), and transforming growth factor-β (TGF-β). In addition, DDS decreased the PQ-induced expression of NADPH oxidase mRNA and activation of protein kinase Cμ (PKCμ). DDS treatment also decreased the PQ-induced generation of superoxide anions in mouse lung fibroblasts. Taken together, these data suggest the novel efficacy of DDS as an effective protective agent against oxidative stress-induced tissue damages.Experimental and Molecular Medicine 07/2011; 43(9):525-37. · 2.57 Impact Factor