| Objective: To observe the effect of angiotensin II type 1 receptor(AT1R) blocker(ARB) Losartan on the expression of angiotensin converting enzyme 2(ACE2)/angiotensin(1-7)[Ang-(l-7)]/Mas receptor axis, transforming growth factor beta 1(TGF-β1) in lung of rats with paraquat poisoning, to investigate the protective effect and mechanism of losartan on paraquat poisoning-induced lung injury and pulmonary fibrosis, and provide a theoretical basis for the clinical application of losartan in the treatment of paraquat induced-acute lung injury and pulmonary fibrosis.. Methods: Fifty-four clean Sprague-Dawley(SD) rats were randomly divided into three groups: normal control group(Group N),PQ administration model group(Group PQ) and Losartan treatment group(Group L). Each group was randomly divided into three subgroups of six rats according to 3, 7 or 21 days. The rats in Group PQ and Group L were treated with PQ(18mg/kg) by intraperitoneal injection, while the rats in Group N were treated with the same dose of saline. 0.5 hour after PQ intraperitoneal injection, the rats in Group L were treated with losartan(10mg/kg) by intragastric administration daily while the rats in Group PQ and Group N received the same dose of saline.daily. The rats in each subgroup were sacrificed at either 3, 7 or 21 days after PQ administration. The micro-computed tomography(micro-CT) was used to observe the pulmonary morphology of rates in each group on the day 3rd, 21 th. The body weight and lung wet weight of rats were measured, and the lung coefficient of rats in each group were measured and compared to observe pulmonary edema. The lung in each group rats was excised for HE staining and Masson Staining to observe pulmonary alveolitis and pulmonary fibrosis. TGF-β1, AngII and Ang-(l-7) levels in homogenate of lung tissue were tested by enzyme-linked immunosorbent assay(ELISA). The levels of protein expression of ACE2 and MAS recepter in lung tissue were detected by immunohistochemistry staining. Results:(1) Lung imaging changes: Group N imaging showed: no abnormal density in the lung fields, lung markings clear and uniform distribution, the bronchial bundle and vascular bundle traveled rules from the inside to the outside of the lung and their branch tapered. Group PQ: on the day 3rd, part of lung markings was fuzzy, part of the region density increased, partial integration into patchy shadows. On the day 21 st, parenchymal density was significantly increased, showed a honeycomb-like changes in lung tissue, lung interstitial abnormalitied, septal thickening, bronchial and vascular bundle thickening, interstitial nodules scattered in the lung field. Group L showed an alleviation of the above changes.(2) Pathological changes: Group PQ: on the day 3rd,appeared severe alveolitis in the alveolar spaces, on the day 7th alveolitis relieved gradually, appeared mild pulmonary fibrosis, on the day 21 st a serious pulmonary fibrosis formed. The pathobiology of Group L were similar to those of Group PQ, but their intensity were attenuated. Group N showed no pathological changes of alveolitis and pulmonary fibrosis. On the day 3rd and 7th, alveolitis classification score of Group PQ and Group L were higher than Group N, alveolitis classification score of Group L was much lower than Group PQ, the difference were all statistically significant(all P<0.05). On the 7th and 21 th day, pulmonary fibrotic scores of Group PQ and Group L were higher than that of Group N, while pulmonary fibrotic scores of Group L was much lower than that of Group PQ, the difference being all statistically significant(all P<0.05).(3) On the day 3, 7 and 21, the lung coefficient of rats in Group PQ and Group L were all higher than that in Group N, while Group L was much lower than that in Group PQ, the difference being all statistically significant(all P<0.05).(4) On the day 3, 7 and 21, TGF-β1, Ang II level in homogenate of lung tissue of rats in Group PQ and Group L were all higher than that in Group N, while Group L was much lower than Group PQ, the difference being all statistically significant(all P<0.05).(5) On the day 3rd, Ang-(1-7) level in homogenate of lung tissue of rats in Group PQ and Group L were all lower than that in Group N. On the day 7th, 21 st, Ang-(1-7) level in homogenate of lung tissue of rats in Group PQ and Group L were all higher than that in Group N. On day 3, 7 and 21, Ang-(1-7) level in homogenate of lung tissue of rats in Group L were all higher than that in Group PQ, the difference being all statistically significant(all P<0.05).(6) Compared with Group N, the expression of ACE2 protein and MAS receptor protein were lower in the lung tissues in Group PQ and Group L on the day 3rd, 7th. On the day 21 st, the expression of ACE2 protein and MAS receptor protein in the lung tissues in Group PQ and Group L were higher than that in Group N. The expression of ACE2 protein and MAS receptor protein in Group L were all higher than these in Group PQ, the difference being statistically significant(all P<0.05). Conclusions:(1) Paraquat poisoning may lead to acute lung injury at the early stage and, ultimately, pulmonary fibrosis in rats.(2) Losartan can alleviate lung injury and pulmonary fibrosis in rats with PQ poisoning.(3) Losartan exerts against PQ-induced pulmonary fibrosis effect, probably through inhibiting RAS aix and upregulating ACE2/Ang-(l-7)/Mas recepter aix to reduce expression of fibrogenic factor TGF-β1. |
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