Neural regulation of immature airways serves to balance airway smooth muscle [ASM] contractile and relaxant pathways. This balance is readily disrupted in early postnatal life and may predispose to later airway hyperreactivity. In the two previous cycles of this proposal we have studied hyperoxia-exposed rat pups and demonstrated that increased expression of the neuropeptide, substance P [SP] and downregulation of nitric oxide [NO] signaling may contribute to increased airway reactivity in this model. Our most recent preliminary data have documented a key role for the neurotrophin, brain derived growth factor [BDNF], in upregulating cholinergic output to ASM. We have shown that ASM from hyperoxia-exposed rat pups exhibits increased expression of BDNF together with its high affinity TrkB receptor at both message and protein levels. We have also demonstrated a clear physiologic role for BDNF-TrkB signaling in enhancing airway contractile responses after neonatal hyperoxic exposure. Our additional preliminary data reveal that SP upregulates BDNF expression in ASM;blockade of BDNF-TrkB receptor signaling decreases acetylcholine [Ach] levels in lungs of hyperoxia-exposed rat pups. Our collaborators at the Mayo Clinic have shown that BDNF/TrkB signaling alters regulation of intracellular calcium toward increased contractility in cultured ASM cells. These preliminary data support our hypothesis that BDNF acting on its TrkB receptor upregulates cholinergic traits, resulting in enhanced contractile responses of immature airways exposed to hyperoxic stress.
In Aim 1 we will characterize the role of SP in increasing BDNF expression;
in Aim 2 we will identify the cholinergic traits upregulated by BDNF;and in Aim 3 we will characterize the downstream effects of BDNF in regulation of intracellular Ca2+ and resultant ASM contraction. In each Aim we will integrate physiologic, biochemical and molecular studies in order to provide new understanding of the mechanistic role of the neurotrophin BDNF on airway reactivity elicited by hyperoxic exposure in early life. This novel line of investigation holds promise for identifying how neonatal lung injury, manifest as bronchopulmonary dysplasia, causes changes in airway function. Project Narrative: Respiratory morbidity in former preterm infants is a major public health problem. This typically takes the form of asthma or wheezing disorders in childhood. Our approach is focused on neurotrophins and how they regulate airway contractility during early development. We will perform novel experiments in a newborn animal model to elucidate neural mechanisms that are a consequence of neonatal lung injury and potentially lead to later airway dysfunction. In this way, we hope to gain insight into the causes of later wheezing disorders in former preterm infants.
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