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Hyperoxia enhances intracellular calcium in human fetal airway smooth muscle via cyclic nucleotide regulation of brain‐derived neurotrophic factor release
Author(s) -
Thompson Michael A,
Martin Richard J,
Zaidi Syed I,
Pandya Hitesh,
Pabelick Christina M,
Prakash Y S
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.864.3
Subject(s) - hyperoxia , endocrinology , medicine , neurotrophic factors , brain derived neurotrophic factor , neurotrophin , cyclic nucleotide , bronchopulmonary dysplasia , chemistry , biology , nucleotide , lung , biochemistry , receptor , gene , pregnancy , genetics , gestational age
Supplemental oxygen places the immature airway at risk for bronchopulmonary dysplasia and asthma. Hyperoxia enhances intracellular Ca2+ ([Ca2+]i) and contractility of airway smooth muscle (ASM), and impairs relaxation (potentially by altering cyclic nucleotide levels). The neurotrophin brain‐derived neurotrophic factor (BDNF) enhances [Ca2+]i in adult ASM. We tested the hypothesis that hyperoxia‐induced airway hyperreactivity involves cyclic nucleotide‐mediated enhancement of BDNF release in human fetal (18–22 weeks) ASM cells exposed to 21% (normoxia) or 80% oxygen in the presence/absence of 1mM dibutyryl cAMP (DBcAMP) or 8‐Br‐cGMP. BDNF release (ELISA) was increased by hyperoxia (143% of normoxia). DBcAMP enhanced BDNF release with normoxia (242% of baseline) and even more with hyperoxia (280%), while 8‐Br‐cGMP blunted BDNF release in normoxia (57% of baseline) but to a lesser extent with hyperoxia (68% of baseline). Measurements of [Ca2+]i in fetal ASM cells showed DBcAMP increasing [Ca2+]i responses to histamine or ACh (effects enhanced with hyperoxia). Further, chelation of released BDNF using chimeric TrkB‐Fc (1?g/ml) reversed DBcAMP effects and blunted [Ca2+]i responses to below controls. We conclude that an imbalance between cAMP vs. cGMP enhances BDNF release in the developing airway, resulting in greater airway reactivity with hyperoxia. Supported by NIH grants HL056470 and HL088029