Role of brain-derived neurotrophic factor in hyperoxia-induced enhancement of contractility and impairment of relaxation in lung parenchyma.
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 >or=95% oxygen or room air for 7 days and administered daily tyrosine kinase inhibitor K-252a (50 microg x kg(-1) x day(-1) i.p.) 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.
Deptartment of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH 44106-6009, USA.
Ramadan B
RB
Sopi
Richard J
RJ
Martin
Musa A
MA
Haxhiu
Ismail A
IA
Dreshaj
Qin
Q
Yao
Anjum
A
Jafri
Syed I A
SI
Zaidi
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D026121:Indole Alkaloids / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D055370:Lung Injury; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C049985:staurosporine aglycone; D000242:Cyclic AMP; D020813:Receptor, trkB; D006152:Cyclic GMP; D000109:Acetylcholine