Ang-(1-7)/Mas受体敲除小鼠慢性过敏性肺部炎症显著加重
2018/01/05
摘要
血管紧张素-（1-7）/Mas受体通路被认做一种与RAS系统在多种病理生理条件下相互平衡的作用轴。之前的研究已经证实Ang-(1-7)可以减轻实验模型气道炎症和重塑。本项研究探索Mas受体缺失是否可以改变OVA诱导慢性气道炎症模型炎症应答。Mas野生型小鼠（MasWT）和敲除小鼠（MasKO）接受4剂OVA(20μg/小鼠），间隔期为14天。第21天开始1%OVA雾化，每周3次直至第46天。对照组接受0.9%生理盐水以及雾化。MasWT-OVA小鼠发展为轻度炎症反应和轻度气道重塑。MasKO-OVA小鼠表现出炎症细胞浸润增加、细胞外基质的沉积增加，肺泡实质增厚以及肺部细支气管平滑肌层增厚，促炎细胞因子和趋化因子增加，以上均为慢性哮喘的特征表现。此外，与MasWT-OVA小鼠相比较，MasKO-OVA小鼠ERK1/2磷酸化显著增加。进一步研究发现MasKO-OVA小鼠相较于MasWT-OVA小鼠最大活动耐受能力更差。本项研究提示Mas受体触发的效应对于减轻小鼠肺内慢性过敏性炎症和重塑过程具有重要作用。我们的数据提示Ang-(1-7)/Mas受体通路的损害可以导致哮喘病理生理状态的恶化。
Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.
Am J Physiol Lung Cell Mol Physiol. 2016 Dec 1;311(6):L1141-L1148. doi: 10.1152/ajplung.00029.2016.
Magalhães GS, Rodrigues-Machado MG, Motta-Santos D, Alenina N, Bader M, Santos RA, Barcelos LS, Campagnole-Santos MJ.
Abstract
The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma.
Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma.
血管紧张素-（1-7）/Mas受体通路被认做一种与RAS系统在多种病理生理条件下相互平衡的作用轴。之前的研究已经证实Ang-(1-7)可以减轻实验模型气道炎症和重塑。本项研究探索Mas受体缺失是否可以改变OVA诱导慢性气道炎症模型炎症应答。Mas野生型小鼠（MasWT）和敲除小鼠（MasKO）接受4剂OVA(20μg/小鼠），间隔期为14天。第21天开始1%OVA雾化，每周3次直至第46天。对照组接受0.9%生理盐水以及雾化。MasWT-OVA小鼠发展为轻度炎症反应和轻度气道重塑。MasKO-OVA小鼠表现出炎症细胞浸润增加、细胞外基质的沉积增加，肺泡实质增厚以及肺部细支气管平滑肌层增厚，促炎细胞因子和趋化因子增加，以上均为慢性哮喘的特征表现。此外，与MasWT-OVA小鼠相比较，MasKO-OVA小鼠ERK1/2磷酸化显著增加。进一步研究发现MasKO-OVA小鼠相较于MasWT-OVA小鼠最大活动耐受能力更差。本项研究提示Mas受体触发的效应对于减轻小鼠肺内慢性过敏性炎症和重塑过程具有重要作用。我们的数据提示Ang-(1-7)/Mas受体通路的损害可以导致哮喘病理生理状态的恶化。
（上海交通大学医学院附属瑞金医院呼吸与危重症医学科 周剑平 万欢英 摘译）
（Am J Physiol Lung Cell Mol Physiol. 2016 Dec 1;311(6):L1141-L1148. doi: 10.1152/ajplung.00029.2016.）
（Am J Physiol Lung Cell Mol Physiol. 2016 Dec 1;311(6):L1141-L1148. doi: 10.1152/ajplung.00029.2016.）
Chronic allergic pulmonary inflammation is aggravated in angiotensin-(1-7) Mas receptor knockout mice.
Am J Physiol Lung Cell Mol Physiol. 2016 Dec 1;311(6):L1141-L1148. doi: 10.1152/ajplung.00029.2016.
Magalhães GS, Rodrigues-Machado MG, Motta-Santos D, Alenina N, Bader M, Santos RA, Barcelos LS, Campagnole-Santos MJ.
Abstract
The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma.
Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma.
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ACE2/Ang-(1-7)/Mas受体轴抗炎作用：基础和临床研究的证据
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