ONTOGENY AND SENSITIZATION MEDIATE AIRWAY CONTRACTILITY

个体发育和敏化介导气道收缩

• 批准号: 6184558
• 负责人: THOMAS Miles MURPHY
• 金额: $ 23.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184558
• 关键词: age difference; asthma; bronchomotion; early experience; guinea pigs; muscle contraction; myosin light chain kinase; respiratory hypersensitivity; respiratory muscles; smooth muscle

The prevalence and expression of asthma is greater during childhood than in adult life. Studies indicate that airway reactivity in several species increases from minimal levels during fetal life and birth to a substantial level in a few days to weeks. While reasons for this difference are unclear, prior investigations have focused on the mechanical instability of juvenile airways and the greater frequency and impact of inflammatory stimuli such as viral pathogens and allergic sensitization. More recent studies emphasized the role of airway smooth muscle (ASM). Allergic sensitization has been shown greatly to increase shortening velocity (VS) and maximal shortening in ASM. Early allergic sensitization may contribute to the increased reactivity in immature airways and confer permanent hyperresponsiveness by altering normal maturational changes in the contractile phenotype of ASM. The application proposes to investigate the mechanism of maturational changes in ASM contractility at baseline and after allergic sensitization. The hypotheses are: 1) Juvenile ASM has increased VS compared to infant or adult ASM due to differences in opposing contractile properties: increases in myosin light chain kinase (MLCK) concentration in juveniles without a synchronous increase in internal resistance of shortening (IRS) until adult life. 2) Allergic sensitization with ovalbumin (OA) in juveniles further increases contractility by increasing levels of MLCK and preventing the normal increase in IRS. 3) The consequence of early sensitization is a further increase in VS that persists into adult life. The specific aims are: 1) Determine the effect of ontogeny on airway smooth muscle shortening; and 2) Determine the effect of allergic sensitization on the ontogeny of shortening.

哮喘的患病率和表现在儿童期高于 在成人生活中。 研究表明，多种气道反应性 物种在胎儿生命和出生期间从最低水平增加到 在几天到几周内达到实质性水平。 虽然这样做的原因 差异尚不清楚，之前的调查集中在 幼年气道的机械不稳定性以及更大的频率和 病毒病原体和过敏等炎症刺激的影响 敏化。 最近的研究强调了气道畅通的作用 肌肉（ASM）。 过敏致敏已被证明大大增加 ASM 中的缩短速度 (VS) 和最大缩短。 早期过敏 致敏作用可能会导致未成熟细胞的反应性增加 气道并通过改变正常值来赋予永久性高反应性 ASM 收缩表型的成熟变化。 这 申请提出研究成熟机制 基线时和过敏后 ASM 收缩力的变化 敏化。假设是： 1) 青少年 ASM 的 VS 增加 与婴儿或成人 ASM 相比，由于反对的差异 收缩特性：肌球蛋白轻链激酶 (MLCK) 增加 青少年的浓度没有同步增加 直到成年为止的缩短抵抗力（IRS）。 2）过敏 青少年卵清蛋白（OA）致敏进一步增加 通过增加 MLCK 水平并防止正常的收缩 国税局增加。 3）早期致敏的后果是进一步 VS 的增加持续到成年。 具体目标是： 1）确定个体发育对气道的影响 平滑肌缩短； 2) 确定过敏的影响 对缩短的个体发育的敏感性。