Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, 13083-863 CP 6109, Campinas, Sao Paulo, Brazil.
Life Sci. 2020 Oct 15;259:118191. doi: 10.1016/j.lfs.2020.118191. Epub 2020 Aug 7.
Numerous population studies conducted worldwide indicate that the prevalence of asthma is higher in obese versus lean individuals. It has been reported that sensitized lean mice has a better recovery of lung inflammation in asthma. Extracellular matrix (ECM) plays an essential role in the structural support of the lungs regulating the airways diameter, thus preventing its collapse during expiration. ECM renewal by metalloproteinase (MMPs) enzymes is critical for pulmonary biology. There seems to be an imbalance of MMPs activity in asthma and obesity, which can impair the lung remodeling process. In this study, we characterized the pulmonary ECM of obese and lean mice, non-sensitized and sensitized with ovalbumin (OVA). Pharmacological intervention was performed by using anti-TNF-α, and MMP-8 and MMP-9 inhibitors in obese and lean sensitized mice. Activity of MMPs was assessed by gelatinase electrophorese, western blotting and zymogram in situ. Unbalance of MMP-2, MMP-8, MMP-9 and MMP-12 was detected in lung tissue of OVA-sensitized obese mice, which was accompanied by high degradation, corroborating an excessive deposition of types I and III collagen in pulmonary matrix of obese animals. Inhibitions of TNF-α and MMP-9 reduced this MMP imbalance, clearly suggesting a positive effect on pulmonary ECM. Obese and lean mice presented diverse phenotype of asthma regarding the ECM compounds and the inhibition of MMPs pathway could be a good alternative to regulate the activity in ECM lungs of asthmatic obese individuals.
许多全球范围内的人群研究表明，肥胖人群中哮喘的患病率高于消瘦人群。据报道，致敏的瘦小鼠在哮喘中肺部炎症的恢复更好。细胞外基质 (ECM) 在调节气道直径的肺部结构支撑中起着至关重要的作用，从而防止在呼气时塌陷。细胞外基质由金属蛋白酶 (MMPs) 酶的更新对于肺生物学至关重要。哮喘和肥胖中似乎存在 MMPs 活性的失衡，这会损害肺重塑过程。在这项研究中，我们对肥胖和瘦小鼠、未致敏和卵清蛋白 (OVA) 致敏的肺部 ECM 进行了表征。在肥胖和瘦致敏小鼠中，通过使用抗 TNF-α 和 MMP-8 和 MMP-9 抑制剂进行了药物干预。通过明胶酶电泳、western blot 和原位酶谱评估 MMPs 的活性。在 OVA 致敏肥胖小鼠的肺组织中检测到 MMP-2、MMP-8、MMP-9 和 MMP-12 的失衡，这伴随着 I 型和 III 型胶原蛋白在肥胖动物肺部基质中的过度沉积，这表明 MMP 失衡。TNF-α 和 MMP-9 的抑制减少了这种 MMP 失衡，这显然表明对肺 ECM 有积极影响。肥胖和瘦小鼠的哮喘 ECM 化合物呈现出不同的表型，抑制 MMPs 途径可能是调节肥胖哮喘患者肺部 ECM 活性的良好选择。
