Gene expression of cytokines and growth factors in the lungs after paraquat administration in mice

Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
Legal Medicine (Impact Factor: 1.24). 04/2006; 8(2):102-9. DOI: 10.1016/j.legalmed.2005.08.010
Source: PubMed


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.

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    • "Therefore, SOD and tempol, the O 2 U − scavengers, were employed in the study to find out the specific role of O 2 U − . TGF-β1 is the major growth factor produced by fibroblasts and has been implicated as the key mediator in fibrogenesis (Border and Noble, 1994; Sanderson et al., 1995; Ihn, 2002; Ishida et al., 2006; Cutroneo et al., 2007). Growing evidence suggests that some regulation mechanism occurs between ROS and TGF-β1 in fibrogenesis (Cucoranu et al., 2005; Higashiyama et al., 2007). "
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    European journal of pharmacology 12/2013; 724(1). DOI:10.1016/j.ejphar.2013.12.033 · 2.53 Impact Factor
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    • "The toxic drug-induced high expression of mRNA for monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) is responsible for the pulmonary fibrosis in the lung tissues (Ishida et al., 2006). Transforming growth factor-β (TGF-β), a potent fibrogenic growth factor, also promotes pulmonary fibrosis, by enhancing the transcription of collagen genes (Ishida et al., 2006). In addition, endothelin-1 (ET-1) has been reported to participate in the pathogenesis of bleomycin-induced and idiopathic pulmonary fibrosis (Kähler et al., 2000; Kaehler et al., 2002). "
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    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. DOI:10.3858/emm.2011.43.9.060 · 3.45 Impact Factor
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    • "One group served as normal and received either saline or 1% tween 80 (p.o.), daily for 3 weeks. The second group received PQ (i.p.) at a dose of 20 mg/kg twice (Monday and Thursday) a week during 3 weeks (Ishida et al., 2006). The remaining four groups received deprenyl [(10 mg/kg/day; i.p.) (Fuller et al., 1988), quercetin (50 mg/kg/day; p.o.) (Piantelli et al., 2006)], green tea extract (1 mg/kg/day; p.o.) (Levites et al., 2001) or malt extract (625 mg/kg/day; p.o.) (Hong and Maeng, 2004), respectively daily for 3 successive weeks. "
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    ABSTRACT: The possible protective potentials of quercetin (50 mg/kg, p.o.), green tea extract (1 mg/kg, p.o.) malt extract (625 mg/kg, p.o.) and deprenyl (10 mg/kg, i.p.) against paraquat (PQ)-induced lung injury in rats were examined. PQ was administered twice a week (20 mg/kg, i.p.) with or without daily pretreatment with any of the chosen agents for 3 successive weeks. Changes in the enzymatic activities of myeloperoxidase (MPO), superoxide dismutase (SOD) and lactate dehydrogenase (LDH) as well as reduced glutathione (GSH), protein thiols (Pr-SHs) and nitric oxide (NO) contents of the lungs were determined. In addition, estimation of lung content of thiobarbituric acid reactive substances (TBARS) measured as malondialdehyde. Moreover, histopathological examination of the lung tissue was performed. On the biochemical level, PQ provoked remarkable lung damage noted by elevation of neutrophils MPO activity accompanied by decreased activities of cytosolic SOD and LDH, depletion of GSH and Pr-SHs contents as well as increased production of NO and TBARS. Furthermore, histopathological examination revealed marked edema, subpleural hemorrhage, acute inflammation and lymphocytic infiltration. Treatment significantly protected against most of PQ-induced lung biochemical and histopathological changes. It could be concluded that quercetin, green tea, malt extract and deprenyl offered remarkable protection against PQ-induced lung injury.
    African journal of pharmacy and pharmacology 05/2009; 3(5). · 0.84 Impact Factor
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