SMOOTH MUSCLE MECHANISMS IN DYNAMIC AIRWAY PROPERTIES

本项目的总体目标是进一步了解 调节气道平滑肌张力的机制 在呼吸期间存在的动态条件。 气道反应 平滑肌对收缩刺激的反应不仅取决于 细胞内信号传导途径启动这些刺激，但也通过 肌肉的机械环境。 肌肉的动态变化 例如在呼吸期间发生长度和负荷深刻地影响 呼吸音 气道平滑肌是平滑肌组织中的一种特殊组织 因为它经常受到大的机械扰动 调节其对收缩刺激的反应。 如此简单 等长力的测量不足以充分评估 药物对气道张力的潜在影响。 气道平滑肌对机械强度变化的反应 环境主要由动力学性质决定， 天桥 平滑肌组织中的过桥行为被调节 通过多种第二信使影响收缩蛋白的活性。 激活不同第二信使途径的激动剂可能具有 对收缩蛋白有明显的调节作用，因此具有 对横桥动力学行为的不同影响。 拟议 研究是基于这样的假设，即不同的影响， 各种激动剂和激素对交叉桥动力学的影响将改变 气道平滑肌对机械扰动的反应。 拟议研究的初步目标将是确定如何 激活犬气道平滑的多种药理学机制 肌肉影响力的产生和缩短速度，并确定 这些机械性能如何与细胞内Ca+，收缩 蛋白质磷酸化和第二信使的产生。 一 第二个目标是确定肌肉的行为 在诸如长度或负载的阶跃变化的机械扰动期间， 或连续的延长或缩短，受到不同的影响， 药理刺激 研究将调查这些机械 扰动影响附加的横桥对 产生的主动力量，以及肌肉长度和长度的历史 影响细胞内Ca2+和收缩蛋白磷酸化， 对各种刺激的反应。 这些研究的最终目标是 确定不同机制的药理学刺激如何 激活对离体支气管力学性能的影响 在动态条件下。 患有哮喘或支气管炎等病理状况的患者 气道对肺部变化的反应出现异常 音量. 因此，更全面地了解细胞内机制 其控制动态下气道平滑肌的行为 这些条件可能有助于我们理解阻塞性气道 疾病

The overall goal of this project is to further our understanding of the mechanisms which govern the regulation of airway smooth muscle tone under the dynamic conditions present during breathing. The responses of airway smooth muscle to contractile stimuli are determined not only by the intracellular signalling pathways initiated by those stimuli, but also by the mechanical environment of the muscle. Dynamic changes in muscle length and load such as occur during breathing profoundly influence airway tone. Airway smooth muscle is unique among smooth muscle tissues in that it is constantly subjected to large mechanical perturbations which modulate its responses to contractile stimuli. Thus simple measurements of isometric force are not adequate to fully,evaluate the potential effects of pharmacologic agents on airway tone. The response of airway smooth muscle to changes in its mechanical environment are determined primarily by the kinetic properties of crossbridges. Crossbridge behavior in smooth muscle tissues is modulated by multiple second messengers which affect contractile protein activity. Agonists which activate different second messenger pathways may have distinct modulatory effects on contractile proteins, and therefore have different effects on the kinetic behavior of crossbridges. The proposed studies are based on the hypothesis that differences in the effects of various agonists and hormones on crossbridge kinetics will modify the response of airway smooth muscle to mechanical perturbations. The initial objective of the proposed studies will be to determine how diverse pharmacologic mechanisms for activating canine airway smooth muscles affect force generation and shortening velocity, and to determine how these mechanical properties relate to intracellular Ca+, contractile protein phosphorylation, and the production of second messengers. A second objective will be to determine how the behavior of the muscle during mechanical perturbations such as step changes in length or load, or continuous lengthening or shortening, is affected by diverse pharmacologic stimuli. Studies will investigate how these mechanical perturbations affect the contribution of attached crossbridges to the generation of active force, and how muscle length and length history affect intracellular Ca2+ and contractile protein phosphorylation in response to various stimuli. A final goal of these studies will be to determine how pharmacologic stimuli with different mechanisms of activation affect the mechanical properties of isolated bronchial segments under dynamic conditions. Patients with pathological conditions such as asthma or bronchitis exhibit abnormalities in the response of the airways to changes in lung volume. Thus a fuller understanding of the intracellular mechanisms which control the behavior of airway smooth muscle under dynamic conditions may contribute to our understanding of obstructive airway disease.