Nerve growth factor: the central hub in the development of allergic asthma?
ABSTRACT Neurotrophins like nerve growth factor (NGF), originally described as nerve growth factors in neuronal development, have been implicated in many physiological processes in the last years. They are now regarded as important factors involved in the resolution of pathological conditions. NGF has profound effects on inflammation, repair and remodeling of tissues. However, in the lung these beneficial effects can transact into disease promoting actions, e.g., in allergic inflammation or respiratory syncytial virus (RSV) infection. Overproduction of NGF then enhances inflammation, and promotes (neuronal) airway hyperreactivity and neurogenic inflammation. We hypothesize that NGF overexpression in certain vulnerable time windows during infancy could be a major risk factor for the development of asthma symptoms.
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ABSTRACT: Nerve growth factor (NGF) is overexpressed in patients with inflammatory lung diseases, including virus infections. Airway surface liquid (ASL), which is regulated by epithelial cell ion transport, is essential for normal lung function. No information is available regarding the effect of NGF on ion transport of airway epithelium. To investigate whether NGF can affect ion transport, human primary air-interface cultured epithelial cells were placed in Ussing chambers to obtain transepithelial voltage (−7.1 ± 3.4 mV), short-circuit current (Isc, 5.9 ± 1.0 μA), and transepithelial resistance (750 Ω·cm2), and to measure responses to ion transport inhibitors. Amiloride (apical, 3.5 × 10−5 mol/L) decreased Isc by 55.3%. Apically applied NGF (1 ng/mL) reduced Isc by 5.3% in 5 min; basolaterally applied NGF had no effect. The response to amiloride was reduced (41.6%) in the presence of NGF. K-252a (10 nmol/L, apical) did not itself affect Na+ transport, but it attenuated the NGF-induced reduction in Na+ transport, indicating the participation of the trkA receptor in the NGF-induced reduction in Na+ transport. PD-98059 (30 μmol/L, apical and basolateral) did not itself affect Na+ transport, but attenuated the NGF-induced reduction in Na+ transport, indicating that trkA activated the Erk 1/2 signaling cascade. NGF stimulated phosphorylation of Erk 1/2 and the β-subunit of ENaC. K-252a and PD-98059 inhibited these responses. NGF had no effect on Isc in the presence of apical nystatin (50 μmol/L). These results indicate that NGF inhibits Na+ transport through a trkA-Erk 1/2-activated signaling pathway linked to ENaC phosphorylation.07/2014; 2(7). DOI:10.14814/phy2.12073
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ABSTRACT: Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension <100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m(3); 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma.Journal of Toxicology and Environmental Health Part A 08/2010; 73(20):1353-69. DOI:10.1080/15287394.2010.497436 · 1.83 Impact Factor
Article: Neurogenic inflammation and allergy