Brain-Derived Neurotrophic Factor in Cigarette Smoke–Induced Airway Hyperreactivity

Abstract

Enhanced airway smooth muscle (ASM) contractility contributes to increased resistance to airflow in diseases such as bronchitis and asthma that occur in passive smokers exposed to secondhand smoke. Little information exists on the cellular mechanisms underlying such airway hyperreactivity. Sputum samples of patients with chronic sinusitis, bronchitis, and asthma show increased concentrations of growth factors called neurotrophins, including brain-derived growth factor (BDNF), but their physiological significance remains unknown. In human ASM, we tested the hypothesis that BDNF contributes to increased contractility with cigarette smoke exposure. The exposure of ASM to 1% or 2% cigarette smoke extract (CSE) for 24 hours increased intracellular calcium ([Ca 21 ] i ) responses to histamine, and further potentiated the enhancing effects of a range of BDNF concentrations on such histamine responses. CSE exposure increased the expression of the both high-affinity and lowaffinity neurotrophin receptors tropomyosin-related kinase (Trk)-B and p75 pan-neurotrophin receptor, respectively. Quantitative ELISA showed that CSE increased BDNF secretion by human ASM cells. BDNF small interfering (si)RNA and/or the chelation of extracellular BDNF, using TrkB-fragment crystallizable, blunted the effects of CSE on [Ca 21 ] i responses as well as the CSE enhancement of cell proliferation, whereas TrkB siRNA blunted the effects of CSE on ASM contractility. These data suggest that cigarette smoke is a potent inducer of BDNF and TrkB expression and signaling in ASM, which then contribute to cigarette smoke-induced airway hyperresponsiveness.Keywords: neurotrophin; asthma; TrkB; environmental tobacco exposure; secondhand smoke Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) can be triggered or exacerbated by cigarette smoke and secondhand smoke exposure (1-4). Furthermore, in people with preexisting airway diseases such as asthma, acute exposure to cigarette smoke can produce a bronchospastic response. Considerable evidence already exists that airway inflammation occurs with cigarette smoke exposure, and contributes to airway disease even in passive smokers. Regardless of the underlying causes for airway inflammation (of which there are many), increased airway smooth muscle (ASM) contractility is certainly a key factor contributing to the pathological airway narrowing and increased airflow resistance observed in asthma and bronchitis. Although smoke exposure is recognized to increase airway contractility, the mechanisms by which cigarette smoke enhances ASM contractility remain under investigation.In the nervous system, growth factors called neurotrophins (NTs) are well recognized for their role in the generation, growth, and maintenance of different neuronal populations (5-9). Both short-term (seconds or minutes) and long-term (hours or days) effects of NTs on nuclear and cytosolic signals have been recognized as favoring increased synaptic transmission and plasticity, cell proliferation, and surviva...

Active and Passive Smoking and the Incidence of Asthma in the Black Women’s Health Study

“…In an animal model, chronic tobacco smoke exposure has been reported to increase airway responsiveness, an effect that may be mediated in part by IL-13, a cytokine important in the pathophysiology of asthma (30). In addition to immune system-mediated effects of airway responsiveness, in vitro data suggest that cigarette smoke induces neurotrophin and neurotrophin receptor in human airway smooth muscle, thereby increasing neurotrophin signaling, which may contribute to cigarette smoke-induced airway hyperresponsiveness (32). Although the precise mechanisms that link smoking to the development of adult-onset asthma are uncertain, it appears that adverse effects on the airway epithelium, immune cells in the airways, and airway smooth muscle may play roles.…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…However, a number of recent studies have found that the Trk family of receptors (RTK class VII; Fig. 4) that are responsive to the neurotrophin family of growth factors (238) has novel, diverse roles in ASM, including enhancing [Ca 2ϩ ] i and contractility, particularly in the setting of inflammation (120,200,223,236,239,248,268,344). Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well recognized in the nervous system for both long-term genomic effects on neuronal growth, differentiation, and survival (181), as well as nongenomic, rapid effects of enhancing [Ca 2ϩ ] i and neurotransmitter release (24,159).…”

“…The presumed target of the released NGF is ASM, given expression of the cognate TrkA receptors in ASM (75,213,222,238). However, there are now considerable data that ASM also expresses the TrkB and TrkC receptors for BDNF/neurotrophin 4 and neurotrophin 3, respectively (200,213,236,239,268,291,345). Here, it appears that ASM itself can release BDNF (200,324) both at baseline and in response to inflammatory stimuli.…”

Secreted Brain-Derived Neurotrophic Factor and Asthma Severity

“…However, in prior murine studies, BDNF was more strongly expressed in bronchial epithelial cells, while moderately expressed in ASM, being further enhanced in the epithelium after allergen challenge (3)(4)(5). According to these reports, we immunostained for BDNF (Santa Cruz Biotechnology, Santa Cruz, CA) on human tissue from one healthy subject and one patient with severe asthma.…”

“…Altered BDNF levels have been reported in asthma, allergy, and even lung cancer (3,4). A possible mechanistic role for BDNF has been suggested in airway inflammation, remodeling, and hyperreactivity (3,5,6). All these reports obviously raise questions regarding cell sources versus targets of BDNF.…”