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首页> 外文期刊>Journal of biochemical and molecular toxicology >Pinitol attenuates LPS-induced pneumonia in experimental animals: Possible role via inhibition of the TLR-4 and NF-κB/IκBα signaling cascade pathway
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Pinitol attenuates LPS-induced pneumonia in experimental animals: Possible role via inhibition of the TLR-4 and NF-κB/IκBα signaling cascade pathway

机译：拼胶醇在实验动物中衰减LPS诱导的肺炎：通过抑制TLR-4和NF-κB/IκBα信号传导级联路径的可能作用

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摘要

Pneumonia is a chronic disorder of the respiratory system associated with worsening quality of life and a significant economic burden. Pinitol, a plant cyclic polyol, has been documented for immune-inflammatory potential. The aim of present investigation was to evaluate the potential and possible mechanism of action of pinitol against lipopolysaccharide (LPS)-induced pneumonia in the experimental animal model. Pneumonia was induced in Sprague-Dawley rats by intratracheal administration of LPS (2 mg/kg). Animals were treated with either vehicle or dex-amethasone or pinitol (5 or 10 or 20 mg/kg). Potential of pinitol against LPS-induced pulmonary insult was assessed based on behavioral, biochemical, molecular, and ultrastructural studies. Intratracheal instillation of LPS induced significant (P<.05) inflammatory infiltration in bronchoalveolar lavage fluid (BALF) and lung tissue reflected by elevated pleural effusion volume, lung edema, BALF polymorphonuclear leukocytes count and lung myeloperoxidase levels, which was attenuated by pinitol (10 and 20mg/kg) administration. Pinitol also markedly (P<.05) inhibited LPS-induced alterations in electrocardiographic, hemodynamic changes, right ventricular, and lung function tests. The LPS-induced downregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), whereas upregulated transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and inducible nitric oxide synthase (iNOs) lung messenger RNA expressions were significantly (P<.05) inhibited by pinitol. Western blot analysis suggested pinitol markedly (P<.05) decreased nuclear factor-κB (NF-κB), inhibitor of nuclear factor κB (IκBα), toll-like receptor 4 (TLR-4), and cyclooxygenase-ll (COX-II) protein expressions in the lung. These findings were further supported by histological and ultrastructural analyses of lung tissue that show pinitol significantly (P<.05) ameliorates LPS-induced aberrations in lung tissue. In conclusion, pinitol attenuated LPS-induced pneumonia via inhibition of TLR-4 to downregulate the NF-κB/lκBα signaling cascade and thus ameliorated the production of proinflammatory cytokines (TNF-α, ILs, NLRP3, and TGF-β), inflammatory mediators (COX-II and iNOs) and elevated oxidative stress (Nrf-2 and HO-1).
机译：肺炎是一种慢性呼吸系统疾病，伴随着生活质量的恶化和巨大的经济负担。松果醇是一种植物环状多元醇，已被证明具有免疫炎症潜能。本研究的目的是在实验动物模型中评估松果醇对脂多糖（LPS）诱导的肺炎的潜在作用和可能机制。通过气管内注射LPS（2 mg/kg）在Sprague-Dawley大鼠中诱导肺炎。用溶媒或地塞米松或松果醇（5或10或20 mg/kg）治疗动物。根据行为、生化、分子和超微结构研究，评估了松果醇对LPS诱导的肺损伤的潜在作用。气管内滴注LPS可在支气管肺泡灌洗液（BALF）和肺组织中诱导显著（P<0.05）炎性浸润，其表现为胸腔积液量增加、肺水肿、BALF多形核白细胞计数和肺髓过氧化物酶水平升高，而松糖醇（10和20mg/kg）给药可使其减弱。松果醇还显著（P<0.05）抑制LPS诱导的心电图、血流动力学变化、右心室和肺功能测试的改变。LPS诱导核因子-红系2相关因子2（Nrf-2）和血红素加氧酶-1（HO-1）下调，而转化生长因子-β（TGF-β）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6、NOD-、LRR-和吡啉结构域含蛋白3（NLRP3）上调，松果醇显著抑制诱导型一氧化氮合酶（iNOs）肺信使RNA的表达（P<0.05）。Western-blot分析表明，松糖醇显著（P<0.05）降低了肺组织中的核因子-κB（NF-κB）、核因子κB抑制剂（IκBα）、toll样受体4（TLR-4）和环氧合酶ll（COX-II）蛋白表达。这些发现进一步得到了肺组织的组织学和超微结构分析的支持，这些分析表明，松糖醇显著（P<0.05）改善了LPS诱导的肺组织畸变。总之，松果醇通过抑制TLR-4下调NF-κB/lκBα信号级联，从而改善促炎细胞因子（TNF-α、ILs、NLRP3和TGF-β）、炎症介质（COX-II和iNOs）和氧化应激升高（Nrf-2和HO-1）的产生，从而减轻LPS诱导的肺炎。

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