Neurotrophin effects on human airway smooth muscle cells: a potential contributor to airway hyperreactivity.

Neurotrophins such as brain derived neurotrophic factor (BDNF), neurotrophin-4 (NT4) and neurotrophin-3 (NT3) are expressed in non-neuronal tissues including airway smooth muscle (ASM). We previously demonstrated that BDNF and NT4 increase, while NT3 decreases, ASM intracellular Ca2+ ([Ca2+]i) and contractility. Accordingly, in this study, we hypothesized that neurotrophins contribute to airway hyperreactivity. We examined the interactions between neurotrophins and the pro-inflammatory cytokines TNFα and IL-13 vis-à-vis [Ca2+]i regulation in isolated human ASM cells. In cells exposed for 48h to 20 nM TNFα, gene array analysis found increased expression of BDNF, NT4, NT3 and the BDNF/NT4 receptor TrkB, but not the NT3 receptor TrkC, compared to control cells. Similar results were suggested by semi-quantitative immunofluorescence. In ASM cells exposed for 30 min to 10 nM BDNF or NT4, [Ca2+]i responses to ACh and histamine were significantly greater than control, while 10 nM NT3 significantly decreased [Ca2+]i responses. Following 48 h exposure to 20 nM TNFα, [Ca2+]i responses to ACh and histamine were significantly greater compared to control. Addition of 30 min exposure to 10 nM BDNF resulted in even greater [Ca2+]i responses to agonist. In contrast, 10 nM NT3 slightly blunted TNFα induced increases in [Ca2+]i responses to both agonists. These novel data suggest that neurotrophins, regardless of their source, influence [Ca2+]i regulation in ASM, and enhance inflammatory effects on ASM function. [ABSTRACT FROM AUTHOR]