PMID- 27317689 OWN - NLM STAT- MEDLINE DCOM- 20170526 LR - 20200930 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 311 IP - 2 DP - 2016 Aug 1 TI - Mechanisms of BDNF regulation in asthmatic airway smooth muscle. PG - L270-9 LID - 10.1152/ajplung.00414.2015 [doi] AB - Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous, as well as inflammation (TNF-alpha)-induced BDNF secretion in ASM of nonasthmatic vs. asthmatic humans. We focused on specific Ca(2+) regulation- and inflammation-related signaling cascades and quantified BDNF secretion. We find that TNF-alpha enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC, and PKC cascades, Rho kinase, and transcription factors cAMP response element binding protein and nuclear factor of activated T cells. Basal BDNF expression and secretion are elevated in asthmatic ASM and increase further with TNF-alpha exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling. CI - Copyright (c) 2016 the American Physiological Society. FAU - Aravamudan, Bharathi AU - Aravamudan B AD - Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and. FAU - Thompson, Michael A AU - Thompson MA AD - Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and. FAU - Pabelick, Christina M AU - Pabelick CM AD - Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota. FAU - Prakash, Y S AU - Prakash YS AD - Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota prakash.ys@mayo.edu. LA - eng GR - R01 HL088029/HL/NHLBI NIH HHS/United States GR - R01 HL056470/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20160617 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (TRPC Cation Channels) RN - 7171WSG8A2 (BDNF protein, human) SB - IM MH - Airway Remodeling MH - Asthma/*metabolism/physiopathology MH - Brain-Derived Neurotrophic Factor/*physiology MH - Bronchi/pathology MH - Cell Proliferation MH - Cell Survival MH - Cells, Cultured MH - Gene Expression MH - Humans MH - Muscle Contraction MH - Muscle, Smooth/pathology MH - Myocytes, Smooth Muscle/*physiology MH - Promoter Regions, Genetic MH - Secretory Pathway MH - Signal Transduction MH - TRPC Cation Channels/metabolism PMC - PMC5142459 OTO - NOTNLM OT - airway OT - asthma OT - brain-derived neurotrophic factor OT - inflammation OT - neurotrophin OT - secretion EDAT- 2016/06/19 06:00 MHDA- 2017/05/27 06:00 PMCR- 2017/08/01 CRDT- 2016/06/19 06:00 PHST- 2015/12/04 00:00 [received] PHST- 2016/06/09 00:00 [accepted] PHST- 2016/06/19 06:00 [entrez] PHST- 2016/06/19 06:00 [pubmed] PHST- 2017/05/27 06:00 [medline] PHST- 2017/08/01 00:00 [pmc-release] AID - ajplung.00414.2015 [pii] AID - L-00414-2015 [pii] AID - 10.1152/ajplung.00414.2015 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2016 Aug 1;311(2):L270-9. doi: 10.1152/ajplung.00414.2015. Epub 2016 Jun 17.