ONTOGENY AND SENSITIZATION MEDIATE AIRWAY CONTRACTILITY

点击翻译按钮获取中文摘要

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.