RESUMO
BACKGROUND/AIMS: Acute pancreatitis-associated lung injury (APALI) is one of the most common and most dangerous form of extra-pancreatic organ damage in severe acute pancreatitis (SAP). The treatment options for SAP were limited thus far; as a result, approximately 60%-80% of patients with SAP would die within a week. Hypaconitine (HC), one of the most important active ingredients in a Mongolian traditional medicine Radix Aconiti Kusnezoffii has an excellent anti-inflammatory effect. MATERIALS AND METHODS: To ascertain whether HC has a protective effect against APALI, we investigated the therapeutic effects and the underlying mechanisms in vivo and in vitro and attempted to elucidate the mechanism in detail. In this study, APALI rats and human pulmonary microvascular endothelial cells were treated with therapeutic doses of HC after establishing a model with sodium taurocholate and lipopolysaccharide, respectively. RESULTS: Serum amylase and lipase activity, lung wet/dry weight ratio, lung myeloperoxidase activity, and pancreatic and lung histopathological changes showed that HC alleviated APALI in a dose-dependent way, which can be abolished by an aquaporin-1 (AQP-1) knockdown. The results of the reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemical staining confirmed the expression of AQP-1, a kind of transmembrane protein that mainly distributed in the membranes of pulmonary cells and contributed to maintain water balance in the body by interacting with tumor necrosis factor-alpha (TNF-α), is negatively associated with APALI. On the contrary, HC treatment up-regulated AQP-1 expression and down-regulated the TNF-α expression as a consequence in APALI. CONCLUSION: These results suggest that HC has a good anti-inflammatory therapeutic effect on APALI with a possible underlying mechanism that affects the AQP-1/TNF-α pathway.
Assuntos
Aconitina/análogos & derivados , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Aquaporina 1/metabolismo , Pancreatite/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Aconitina/farmacologia , Doença Aguda , Lesão Pulmonar Aguda/etiologia , Animais , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Microvasos/citologia , Pâncreas/patologia , Pancreatite/complicações , Ratos , Ratos Sprague-Dawley , Mucosa Respiratória/irrigação sanguínea , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Hypoxia-induced oxidative stress and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) play important roles in the pathological process of hypoxic pulmonary hypertension (HPH). Grape seed procyanidin extract (GSPE) possesses antioxidant properties and has beneficial effects on the cardiovascular system. However, the effect of GSPE on HPH remains unclear. In this study, adult Sprague-Dawley rats were exposed to intermittent chronic hypoxia for 4 weeks to mimic a severe HPH condition. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio and median width of pulmonary arteries. GSPE attenuated the elevation of RVSP, RV/LV+S, and reduced the pulmonary vascular structure remodeling. GSPE also increased the levels of SOD and reduced the levels of MDA in hypoxia-induced HPH model. In addition, GSPE suppressed Nox4 mRNA levels, ROS production and PASMCs proliferation. Meanwhile, increased expression of phospho-STAT3, cyclin D1, cyclin D3 and Ki67 in PASMCs caused by hypoxia was down-regulated by GSPE. These results suggested that GSPE might potentially prevent HPH via antioxidant and antiproliferative mechanisms.
Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Extrato de Sementes de Uva/uso terapêutico , Hipertensão Pulmonar/prevenção & controle , Músculo Liso Vascular/metabolismo , Estresse Oxidativo , Proantocianidinas/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/efeitos adversos , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Proliferação de Células , Células Cultivadas , Suplementos Nutricionais/efeitos adversos , Regulação Enzimológica da Expressão Gênica , Extrato de Sementes de Uva/efeitos adversos , Extrato de Sementes de Uva/metabolismo , Hipertensão Pulmonar/dietoterapia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Peroxidação de Lipídeos , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/patologia , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , NADPH Oxidase 4 , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Proantocianidinas/efeitos adversos , Proantocianidinas/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/dietoterapia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Mucosa Respiratória/irrigação sanguínea , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Remodelação VascularRESUMO
This research work was planned to investigate the antioxidant potential of methanolic crude extract of Oxalis corniculata (OCME) against lung injuries initiated by carbon tetrachloride (CCl4) in rats at histological and biochemical level. A total of 42 female Sprague Dawley rats were randomly distributed in to seven groups and each group comprised of six rats. Experiment was completed in 22 days (10 doses at alternate days). Group I was not treated (control rats), while group II was administered with vehicles (olive oil and dimethyl sulfoxide), groups III, IV, and V were treated with 1 ml kg(-1) body weight (b.w.) of CCl4 (20% in olive oil). Group III received only CCl4, whereas groups IV and V were administered with 100 and 200 mg kg(-1) b.w. of OCME, respectively. Group VI was administered with OCME (200 mg kg(-1) b.w.) alone. Group VII was treated with sylimarin (50 mg kg(-1) b.w.). CCl4 enhanced the lipid peroxidation while reduced the glutathione in lung samples. Activities of antioxidant enzymes, catalase, peroxidase, superoxide dismutase, and glutathione-S-transferase decreased in lung homogenates with CCl4. Treatment of CCl4 induced deleterious changes in the microanatomy of lungs by rupturing the alveolar septa, thickening of alveolar walls, and damaging the cells with subsequent collapse of blood vessels due to the accumulation of degenerated blood cells. OCME, dose dependently, prevented the alterations in these parameters. These results suggest that OCME protected the lungs due to its intrinsic properties by scavenging of free radicals generated by CCl4.