Role of brain-derived neurotrophic factor in hyperoxia-induced enhancement of contractility and impairment of relaxation in lung parenchyma

Departments of 1 Pediatrics and 2 Medicine, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio Submitted 14 February 2008 ; accepted in final form 23 May 2008 Prolonged hyperoxic exposure contributes to neonatal lung injury, and airway hyperreactivity is characterized by enhanced contraction and impaired relaxation of airway smooth muscle. Our previous data demonstrate that hyperoxia in rat pups upregulates expression of brain-derived neurotrophic factor (BDNF) mRNA and protein, disrupts NO-cGMP signaling, and impairs cAMP production in airway smooth muscle. We hypothesized that BDNF-tyrosine kinase B (TrkB) signaling plays a functional role in airway hyperreactivity via upregulation of cholinergic mechanisms in hyperoxia-exposed lungs. Five-day-old rat pups were exposed to 95% oxygen or room air for 7 days and administered daily tyrosine kinase inhibitor K-252a (50 µg·kg –1 ·day –1 ip) to block BDNF-TrkB signaling or vehicle. Lungs were removed for HPLC measurement of ACh or for in vitro force measurement of lung parenchymal strips. ACh content doubled in hyperoxic compared with room air-exposed lungs. K-252a treatment of hyperoxic pups restored ACh content to room air levels. Hyperoxia increased contraction and impaired relaxation of lung strips in response to incremental electrical field stimulation. K-252a administration to hyperoxic pups reversed this increase in contraction and decrease in relaxation. K-252a or TrkB-Fc was used to block the effect of exogenous BDNF in vitro. Both K-252a and TrkB-Fc blocked the effects of exogenous BDNF. Hyperoxia decreased cAMP and cGMP levels in lung strips, and blockade of BDNF-TrkB signaling restored cAMP but not cGMP to control levels. Therefore, hyperoxia-induced increase in activity of BDNF-TrkB receptor signaling appears to play a critical role in enhancing cholinergically mediated contractile responses of lung parenchyma. adenosine 3',5'-cyclic monophosphate; guanosine 3',5'-cyclic monophosphate; contraction; K-252a; tyrosine kinase B receptors Address for reprint requests and other correspondence: S. I. A. Zaidi, Dept. of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve Univ., 11100 Euclid Ave., Cleveland, OH 44106-6009 (e-mail: syed.zaidi{at}case.edu )