title: cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle.
abstract: Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA.
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Britt
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA.
authors.forename: Ine
authors.initials: I
authors.lastname: Kuipers
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA.
authors.forename: Alecia
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA.
authors.forename: James
authors.initials: J
authors.lastname: Thu
authors.affiliation: Department Pediatrics, University of Leicester, Leicester, UK.
authors.forename: Hitesh C
authors.initials: HC
authors.lastname: Pandya
authors.affiliation: Department of Pediatrics, Division of Neonatology, Rainbow Babies Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: MacFarlane
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.affiliation: Department of Pediatrics, Division of Neonatology, Rainbow Babies Children's Hospital, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: Department of Anesthesiology Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. Electronic address: Prakash.ys@mayo.edu.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB; D014132:Trachea / Q000378:metabolism* / Q000473:pathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020662:Guanine Nucleotide Exchange Factors; D008562:Membrane Glycoproteins; C442864:RAPGEF4 protein, human; C486707:Rapgef4 protein, mouse; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: Cyclic nucleotide; Development; Epac; Hyperoxia; Lung; Neurotrophin