Asthma prevalence is greater during childhood and early airway insults may affect the expression of asthma in adults. Airway reactivity in several species increases from minimal during fetal life and birth to a substantial level in a few days to weeks. We have discovered key and parallel roles for the phosphorylation of myosin light chain (MLC20) by myosin light chain kinase (MLCK) and the reduced mechanical opposition to shortening in the normally augmented shortening of airway smooth muscle (ASM) in 3 week old juvenile guinea pigs and immune-augmented shortening in adults following neonatal sensitization. Maximal force generation is unchanged with maturation and following sensitization. Based on our results: ASM shortening declines from juveniles to adulthood while the internal resistance to shortening Rsi and the passive stiffness of the muscle increase. MLCK levels and the phosphorylation of MLC20 decline in parallel. In preliminary experiments neonatal sensitization increases ASM shortening and MLCK content and decreases the Rsi of adult ASM only. In this application, these findings are integrated into a novel hypothetical mechanism that reflects a new paradigm for augmented smooth muscle shortening in normal non-neonatal juveniles and in adults previously sensitized as neonates. This paradigm suggests that changes in the cytoskeleton matrix to facilitate shortening are of similar importance to those factors that facilitate the phosphorylation of myosin light chain. It also suggests that airway hyperresponsiveness may have its origins (and thus the need for intervention) early in life.
The specific aims are: 1. To determine whether or not increased MLCK content plays a key regulatory role in the increased ASM shortening in normal juvenile trachealis and adults sensitized as newborns. To determine whether or not the increased content of the fast isoforms SM1B and SM2B of myosin heavy chain increases ASM shortening. 2. To determine the genetic and protein regulation of MLCK expression with development and following neonatal sensitization. 3. To determine whether the increased shortening in normal juvenile trachealis and in adults sensitized as newborns is associated with passive mechanical properties that reduce the internal resistance to shortening. To determine whether the content/phosphorylation of the intermediate filaments desmin and vimentin plays a role in the internal resistance to shortening of airway smooth muscle. ? ? ? ? ? ?
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