PMID- 26112987 OWN - NLM STAT- MEDLINE DCOM- 20151130 LR - 20240323 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1853 IP - 10 Pt A DP - 2015 Oct TI - cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle. PG - 2506-14 LID - S0167-4889(15)00198-6 [pii] LID - 10.1016/j.bbamcr.2015.06.008 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Thompson, Michael A AU - Thompson MA AD - Department of Anesthesiology Mayo Clinic, Rochester, MN, USA. FAU - Britt, Rodney D Jr AU - Britt RD Jr AD - Department of Anesthesiology Mayo Clinic, Rochester, MN, USA. FAU - Kuipers, Ine AU - Kuipers I AD - Department of Anesthesiology Mayo Clinic, Rochester, MN, USA. FAU - Stewart, Alecia AU - Stewart A AD - Department of Anesthesiology Mayo Clinic, Rochester, MN, USA. FAU - Thu, James AU - Thu J AD - Department of Anesthesiology Mayo Clinic, Rochester, MN, USA. FAU - Pandya, Hitesh C AU - Pandya HC AD - Department Pediatrics, University of Leicester, Leicester, UK. FAU - MacFarlane, Peter AU - MacFarlane P AD - Department of Pediatrics, Division of Neonatology, Rainbow Babies Children's Hospital, Case Western Reserve University, Cleveland, OH, USA. FAU - Pabelick, Christina M AU - Pabelick CM AD - Department of Anesthesiology Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. FAU - Martin, Richard J AU - Martin RJ AD - Department of Pediatrics, Division of Neonatology, Rainbow Babies Children's Hospital, Case Western Reserve University, Cleveland, OH, USA. FAU - Prakash, Y S AU - Prakash YS AD - 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. LA - eng GR - F32 HL123075/HL/NHLBI NIH HHS/United States GR - R01 HL056470/HL/NHLBI NIH HHS/United States GR - R01 HL088029/HL/NHLBI NIH HHS/United States GR - T32 HL105355/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150622 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (Membrane Glycoproteins) RN - 0 (RAPGEF4 protein, human) RN - 0 (Rapgef4 protein, mouse) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Bronchi/*metabolism/pathology MH - Calcium Signaling/genetics MH - Cells, Cultured MH - Cyclic AMP/genetics/*metabolism MH - Guanine Nucleotide Exchange Factors/genetics/metabolism MH - Humans MH - Hyperoxia/genetics/metabolism/pathology MH - Membrane Glycoproteins/genetics/metabolism MH - Mice MH - Muscle, Smooth/*metabolism/pathology MH - Myocytes, Smooth Muscle/*metabolism/pathology MH - Protein-Tyrosine Kinases/genetics/metabolism MH - Receptor, trkB MH - Trachea/*metabolism/pathology PMC - PMC4558218 MID - NIHMS705122 OTO - NOTNLM OT - Cyclic nucleotide OT - Development OT - Epac OT - Hyperoxia OT - Lung OT - Neurotrophin EDAT- 2015/06/27 06:00 MHDA- 2015/12/15 06:00 PMCR- 2016/10/01 CRDT- 2015/06/27 06:00 PHST- 2015/01/15 00:00 [received] PHST- 2015/05/28 00:00 [revised] PHST- 2015/06/20 00:00 [accepted] PHST- 2015/06/27 06:00 [entrez] PHST- 2015/06/27 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2016/10/01 00:00 [pmc-release] AID - S0167-4889(15)00198-6 [pii] AID - 10.1016/j.bbamcr.2015.06.008 [doi] PST - ppublish SO - Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2506-14. doi: 10.1016/j.bbamcr.2015.06.008. Epub 2015 Jun 22.