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Glial-derived neurotrophic factor in human airway smooth muscle.
Bhallamudi, Sangeeta; Roos, Benjamin B; Teske, Jacob J; Wicher, Sarah A; McConico, Andrea; M Pabelick, Christina; Sathish, Venkatachalem; Prakash, Y S.
Afiliação
  • Bhallamudi S; Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
  • Roos BB; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
  • Teske JJ; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
  • Wicher SA; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
  • McConico A; Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
  • M Pabelick C; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
  • Sathish V; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
  • Prakash YS; Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA.
J Cell Physiol ; 236(12): 8184-8196, 2021 12.
Article em En | MEDLINE | ID: mdl-34170009
ABSTRACT
Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as brain-derived neurotrophic factor (BDNF). The glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs) are nonclassical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor (GFR) α1 and α2 respectively that pair with Ret receptor to accomplish signaling. In this study, we found GDNF is expressed in human lung and increased in adult asthma, while human ASM expresses GDNF and its receptors. Accordingly, we used human ASM cells to test the hypothesis that ASM expression and autocrine signaling by GFLs regulate [Ca2+ ]i . Serum-deprived ASM cells from non-asthmatics were exposed to 10 ng/ml GDNF or NRTN for 15 min (acute) or 24 h (chronic). In fura-2 loaded cells, acute GDNF or NRTN alone induced [Ca2+ ]i responses, and further enhanced responses to 1 µM ACh or 10 µM histamine. Ret inhibitor (SPP86; 10 µM) or specific GDNF chelator GFRα1-Fc (1 µg/ml) showed roles of these receptors in GDNF effects. In contrast, NRTN did not enhance [Ca2+ ]i response to histamine. Furthermore, conditioned media of nonasthmatic and asthmatic ASM cells showed GDNF secretion. SPP86, Ret inhibitor and GFRα1-Fc chelator markedly decreased [Ca2+ ]i response compared with vehicle, highlighting autocrine effects of secreted GDNF. Chronic GDNF treatment increased histamine-induced myosin light chain phosphorylation. These novel data demonstrate GFLs particularly GDNF/GFRα1 influence ASM [Ca2+ ]i and raise the possibility that GFLs are potential targets of airway hyperresponsiveness.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sistema Respiratório / Fator Neurotrófico Derivado de Linhagem de Célula Glial / Músculo Liso Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sistema Respiratório / Fator Neurotrófico Derivado de Linhagem de Célula Glial / Músculo Liso Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article