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Brain-Derived Neurotrophic Factor in TNF- Modulation of Ca²⁺ in Human Airway Smooth Muscle

¹ Departments of Anesthesiology and ² Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota

Correspondence and requests for reprints should be addressed to Y. S. Prakash, M.D., Ph.D., 4-184 W. Jos SMH, Mayo Clinic College of Medicine, Rochester, MN 55905. E-mail: prakash.ys{at}mayo.edu

There is increasing recognition that neurotrophin (NT) signaling occurs in non-neuronal tissues, including airway smooth muscle (ASM). We recently demonstrated that NTs, such as brain-derived neurotrophic factor (BDNF), enhance intracellular Ca²⁺ ([Ca²⁺]_i) and force regulation in human ASM. Increased NT expression has been observed in airway diseases, such as asthma and allergy. In the present study, we tested the hypothesis that NTs contribute to inflammation-induced enhancement of ASM contractility. Using human ASM cells and real-time fluorescence [Ca²⁺]_i imaging, we examined the contribution of the high-affinity tropomyosin-related kinase and low-affinity, pan-NT p75NTR receptors to [Ca²⁺]_i regulation under control conditions and after exposure to the proinflammatory cytokine TNF- (20 ng/ml). Exposure to TNF- enhanced [Ca²⁺]_i responses to agonist (acetylcholine, histamine). Exposure to 10 nM BDNF for even 30 minutes substantially and synergistically enhanced TNF- effects on [Ca²⁺]_i responses to agonist. Small interfering RNA suppression of tropomyosin-related kinase substantially blunted the effect of BDNF on [Ca²⁺]_i responses to agonist (with greater effect on Ca²⁺ influx via store-operated Ca²⁺ entry compared with sarcoplasmic reticulum Ca²⁺ release) in both control and TNF-–exposed cells. However, p75NTR suppression by small interfering RNA had no significant effect on [Ca²⁺]_i responses in either cell group. These novel data demonstrate that NTs influence ASM contractility, and suggest a potential role for NTs in airway diseases.

Key Words: neurotrophin/tropomyosin–related kinase • lung inflammation • cytokine • sarcoplasmic reticulum • capacitative calcium entry