Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
Pulm Pharmacol Ther. 2018 Aug;51:32-40. doi: 10.1016/j.pupt.2018.06.003. Epub 2018 Jun 28.
Pulmonary fibrosis (PF) is a lethal end stage of interstitial lung disease with increasing prevalence. The disease burden of PF has seen a sharp surge in the past two decades owing to entry of heavy amount of particulate matter due to industrialization and urbanization. In this work, we developed an oropharyngeal aspiration model of silica (1.5 mg/mice) induced pulmonary fibrosis as a homogeneous, reproducible, simple and alternative strategy in Swiss albino mice. Various BALF (protein, albumin, cell count), biochemical parameters (MDA, GSH, hydroxyproline), cytokines (IL-1β, IL-6, TNF-α and TGF-β1), histological (H&E and PSR staining) and protein expression (N-cadherin, vimentin, α-SMA, CTGF, collagen-1) studies were conducted to validate the model. Oropharyngeal administration of silica in Swiss mice produced significantly changes in lung morphology with statistically higher lung weights compared to normal control animals. The silica treated mice showed profoundly elevated BALF soluble and cytological parameters and enhanced oxidative and nitrosative stress in lungs. The levels of hydroxyproline were increased by 2.6 fold in the silica treated mice. The expression of pro-inflammatory cytokines were profoundly increased in silica treated mice. The histology and PSR staining indicated increased inflammatory infiltration and staggering fibrosis in silica treated group. In addition, the expression of EMT markers (N-cadherin, vimentin, α-SMA and CTGF) were significantly increased indicating their role in silica induced pulmonary fibrosis. Our work clearly demonstrates the superiority of stress free oropharyngeal instillation of silica with dose reduction over the conventional invasive and non-homogeneous intratracheal route.
肺纤维化（PF）是一种致命的间质性肺疾病终末期，其发病率呈上升趋势。由于工业化和城市化导致大量颗粒物的进入，PF 的疾病负担在过去二十年中急剧增加。在这项工作中，我们开发了一种口腔抽吸模型，用于研究二氧化硅（1.5mg/mice）诱导的肺纤维化，这是一种在瑞士白化小鼠中均匀、可重复、简单和替代的策略。我们进行了各种支气管肺泡灌洗液（BALF）（蛋白、白蛋白、细胞计数）、生化参数（MDA、GSH、羟脯氨酸）、细胞因子（IL-1β、IL-6、TNF-α和 TGF-β1）、组织学（H&E 和 PSR 染色）和蛋白质表达（N-钙黏蛋白、波形蛋白、α-SMA、CTGF、胶原-1）研究，以验证该模型。与正常对照组动物相比，口腔给予二氧化硅后，瑞士小鼠的肺部形态发生了显著变化，肺重明显增加。用二氧化硅处理的小鼠显示出明显升高的 BALF 可溶性和细胞学参数，并增强了肺部的氧化和硝化应激。用二氧化硅处理的小鼠羟脯氨酸水平增加了 2.6 倍。用二氧化硅处理的小鼠促炎细胞因子的表达显著增加。组织学和 PSR 染色表明，二氧化硅处理组的炎症浸润和纤维性增加。此外，上皮间质转化（EMT）标志物（N-钙黏蛋白、波形蛋白、α-SMA 和 CTGF）的表达显著增加，表明它们在二氧化硅诱导的肺纤维化中发挥作用。我们的工作清楚地表明，与传统的侵入性和非均匀性气管内途径相比，无应激口腔吸入二氧化硅并减少剂量具有优越性。
