Chitano Pasquale, Wang Lu, Murphy Thomas M
Division of Pediatric Pulmonary and Sleep Medicine and the Neonatal Perinatal Research Institute, Room 302, Bell Building, Duke University, Durham, NC 27710, USA.
Can J Physiol Pharmacol. 2007 Jul;85(7):715-26. doi: 10.1139/Y07-063.
Evidence for contributions of airway smooth muscle (ASM) to the hyperresponsiveness of newborn and juvenile airways continues to accumulate. In our laboratory, 3 novel paradigms of hyperresponsiveness of newborn and young ASM have recently emerged using a guinea pig model of maturation in 3 age groups: 1 week (newborn), 3 weeks (juvenile), and 2-3 months (adult). The first paradigm includes evidence for a natural decline after newborn and juvenile life of the velocity of ASM shortening associated with a decrease in regulatory myosin light chain phosphorylation and a parallel decline in the content of myosin light chain kinase. Associated with the decrease in ASM shortening with age is an increase in the internal resistance to shortening. Dynamic stiffness is shown to relate inversely to the expression of myosin light chain kinase. This suggests that developmental changes in shortening relate inversely to the stiffness of the ASM early in shortening, suggesting a dynamic role for the cytoskeleton in facilitating and opposing ASM shortening. This relationship can be approximated as (dP/dt)max approximately (dP/dL)passive x (dL/dt)max (the maximal rate of increase of active stress generation approximately to the passive stiffness x the maximal shortening velocity). The second paradigm demonstrates that newborn ASM, unlike that in adults, does not relax during prolonged electric field stimulation. The impaired relaxation is related to changes in prostanoid synthesis and acetylcholinesterase function. The third paradigm demonstrates that, whereas oscillatory strain serves to transiently relax adult ASM, in newborns it induces (after the initial relaxation) a sustained potentiation of active stress. This is related to developmental changes in the prostanoid release. Together, these paradigms demonstrate that ASM contributes by multiple mechanisms to the natural hyperresponsiveness of newborn and juvenile airways. Future studies will elaborate the mechanisms and extend these paradigms to ASM hyperresponsiveness following sensitization in early life.
气道平滑肌（ASM）对新生儿和幼年气道高反应性的作用证据不断积累。在我们实验室，最近利用豚鼠模型在3个年龄组（1周龄，新生儿；3周龄，幼年；2 - 3月龄，成年）建立了3种新生儿和幼年ASM高反应性的新范例。第一个范例包括证据表明，在新生儿期和幼年期之后，ASM缩短速度自然下降，这与调节性肌球蛋白轻链磷酸化减少以及肌球蛋白轻链激酶含量平行下降有关。随着年龄增长，ASM缩短减少的同时，缩短的内部阻力增加。动态刚度与肌球蛋白轻链激酶的表达呈负相关。这表明缩短过程中的发育变化与ASM缩短早期的刚度呈负相关，提示细胞骨架在促进和对抗ASM缩短中具有动态作用。这种关系可以近似表示为（dP/dt）max≈（dP/dL）被动×（dL/dt）max（主动应力产生的最大增加速率≈被动刚度×最大缩短速度）。第二个范例表明，与成年ASM不同，新生儿ASM在长时间电场刺激期间不会松弛。松弛受损与前列腺素合成和乙酰胆碱酯酶功能的变化有关。第三个范例表明，振荡应变可使成年ASM短暂松弛，而在新生儿中，它会诱导（初始松弛后）主动应力持续增强。这与前列腺素释放的发育变化有关。总之，这些范例表明ASM通过多种机制导致新生儿和幼年气道的自然高反应性。未来的研究将详细阐述这些机制，并将这些范例扩展到生命早期致敏后ASM的高反应性。
