Division of Clinical Sciences, Department of Medicine, University of Toronto, Ontario, Canada.
Am J Respir Cell Mol Biol. 2012 Apr;46(4):532-40. doi: 10.1165/rcmb.2011-0293OC. Epub 2011 Nov 22.
The increase of airway smooth muscle (ASM) mass in asthma results from hypertrophic and hyperplastic stimuli, and leads to an increase in cellular contractile proteins. However, little evidence correlates the relative contributions of hypertrophic and hyperplastic muscle with functional effects on airway resistance. We performed a ventilator-based assessment of respiratory mechanics and responsiveness to methacholine in a murine model of acute (3-week) ovalbumin (OVA)-induced airway inflammation, compared with a chronic (12-week) model. We correlated functional changes in airways Newtonian resistance (RN), peripheral tissue damping (G), and elastance (H) with the relative contributions of proliferation, hypertrophy, and apoptosis to increased ASM mass. Immunohistochemical analyses of treated (OVA-sensitized and OVA-challenged; OVA/OVA) and control (OVA-sensitized and saline-challenged; OVA/PBS) murine lungs showed an increase in ASM area in chronic, but not acute, OVA/OVA-treated mice that correlated positively with increased airway resistance to methacholine. Acute OVA/OVA-treated ASM exhibited an increase in proliferation with diminished apoptosis, which resolved in the chronic OVA/OVA model. Chronic OVA/OVA-treated ASM exhibited hypertrophy. Distinct temporal differences exist in the response of murine airways to antigenic challenge. We report that ASM proliferation and diminished apoptosis occur during the acute phase, followed by the development of smooth muscle hypertrophy and an increased muscle mass with chronic challenge, that correlate strongly with increased airway Newtonian resistance. The identification of a functionally relevant hypertrophic bronchial muscle mass highlights the possibility of regulating airway muscle hypertrophy as a novel therapeutic target in asthma.
气道平滑肌（ASM）质量在哮喘中的增加是由肥大和增生刺激引起的，导致细胞收缩蛋白增加。然而，几乎没有证据表明肥大和增生的肌肉相对贡献与气道阻力的功能影响相关。我们在急性（3 周）卵清蛋白（OVA）诱导的气道炎症的小鼠模型中进行了基于呼吸机的呼吸力学和对乙酰甲胆碱反应的评估，与慢性（12 周）模型进行了比较。我们将气道牛顿阻力（RN）、外周组织阻尼（G）和弹性（H）的功能变化与增殖、肥大和细胞凋亡对增加的 ASM 质量的相对贡献相关联。对治疗（OVA 致敏和 OVA 挑战；OVA/OVA）和对照（OVA 致敏和盐水挑战；OVA/PBS）小鼠肺的免疫组织化学分析显示，慢性而非急性 OVA/OVA 治疗的小鼠 ASM 面积增加，与对乙酰甲胆碱的气道阻力增加呈正相关。急性 OVA/OVA 治疗的 ASM 表现出增殖增加而凋亡减少，这种情况在慢性 OVA/OVA 模型中得到解决。慢性 OVA/OVA 治疗的 ASM 表现出肥大。在抗原挑战下，小鼠气道的反应存在明显的时间差异。我们报告说，ASM 增殖和凋亡减少发生在急性期，随后是平滑肌肥大和慢性挑战时的肌肉质量增加，这与气道牛顿阻力的增加密切相关。功能性相关的肥大支气管肌肉质量的鉴定突出了作为哮喘的一种新型治疗靶点调节气道肌肉肥大的可能性。
