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: Nesrine El Sayed[Show abstract] [Hide abstract]
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.
[Show abstract] [Hide abstract]
ABSTRACT: Paraquat (PQ) poisoning, with the lung as a primary target organ, is a devastating disease which irreversibly progresses to diffuse alveolitis followed by extensive lung fibrosis. In the present study, we aimed to investigate the effect of FTY720, an immune modulator, on PQ-induced lung injury in mice. C57BL/6 mice were randomized into four groups: 1) PQ group (n=12): mice was instilled with PQ (30mg/kg, ip); 2) PQ+FTY720 group (n=12): animals received FTY720 (0.1mg/kg, ip) solution 2h after PQ exposure and twice a week for 4 consecutive weeks; 3) FTY720 group (n=5): FTY720 (0.1mg/kg, ip) was administrated twice a week for 4 consecutive weeks; and 4) Control group (n=10): same volumes of saline were injected. Mice were sacrificed on either day 3 or day 28 for histopathological, biochemical and immunohistochemical analyses of lung damage indicators. We found that FTY720 treatment attenuated PQ-induced acute lung injury and lung fibrosis as evaluated by histopathological changes and Ashcroft score. On day 3, FTY720 administration reduced PQ-induced increases in lung wet weight/body weight (LW/BW), total protein and cytokine levels including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalceolar lavage fluid (BALF). On day 28, the expressions of alpha-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β) and vascular endothelial growth factor (VEGF) detected by immunohistochemistry, as well as the mRNA levels of α-SMA, Type-I Collagen and Type-III Collagen examined by Real-time PCR were down-regulated after FTY720 treatment. These results indicate that FTY720 could attenuate PQ-induced lung injury, but further investigation is necessary.International Immunopharmacology 05/2014; DOI:10.1016/j.intimp.2014.05.025 · 2.71 Impact Factor
[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. DOI:10.1155/2014/971750 · 2.71 Impact Factor