Allergic asthma is an increasingly common disease that is characterized by inflammation of the bronchioles and hypersensitivity of airway smooth muscle and sensory nerves. Allergen inhalation triggers the activation of inflammatory immune cells including eosinophils, mast cells, neutrophils, and T cells, which infiltrate the airway.1 Local sensory nerve C-fibers release neuropeptides that induce smooth muscle contraction and increase airway sensitivity to a wide range of irritants including cold air and cigarette smoke.1
Nerve growth factor (NGF) has been implicated in both the immune and neuronal components of allergic asthma pathogenesis. It is constitutively produced by bronchiolar epithelial and smooth muscle cells, and is upregulated by these cells and infiltrating immune cells during asthma attacks.1 NGF enhances the allergen-dependent activation, infiltration, and viability of eosinophils, an effect which is reduced by neurotrophin blockade.4, 5 In the normal lung, the receptors for NGF [NGF R/p75 Neurotrophin Receptor (NTR) and TrkA] are restricted to sensory nerve bundles and terminals. Following sensitization and allergen challenge, they are additionally present on infiltrating hematopoietic cells.5, 6, 7, 8 Experimental blockade of the Trk receptors limits sensory nerve hyperreactivity and airway inflammation.6
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|The Role of Nerve Growth Factor (NGF) in Asthma. During an allergic asthma attack, increased amounts of NGF are produced by bronchiolar smooth muscle cells, endothelial cells, and infiltrating immune cells. The interaction of NGF with NGF Receptors (NGF R/p75 NTR; TrkA) on sensory neurons amplifies neuronal sensitivity, while the interaction of NGF with its receptors on hematopoietic cells promotes cellular activation and infiltration of the bronchiole.|
Kerzel et al. examined the involvement of NGF R/p75NTR in allergic asthma with the use of knockout mice lacking this receptor.7 These animals were capable of mounting a systemic allergen-specific IgE response, but they exhibited significantly lower eosinophil counts in the bronchoalveolar lavage fluid (BALF). This reduced eosinophil infiltration was partially mimicked in wild-type mice by intranasal administration of anti-NGF R antibodies. Knockout of NGF R/p75NTR had no effect on hyperresponsiveness to methacholine, an agonist of muscarinic M3 receptors expressed on smooth muscle cells. However, knockout of NGF R/p75NTR caused a reduction in typical hyperresponsiveness to capsaicin, an agonist of TRPV1 vanilloid receptors on C-fiber sensory nerves. As with cellular infiltration, anti-NGF R antibodies partially prevented capsaicin-induced hyper-responsiveness in wild-type mice. The authors concluded that both neuronal hyperreactivity and inflammation require NGF R/p75NTR expression.
To evaluate the relative contribution of NGF R/p75NTR on sensory nerves and hematopoietic cells, Nassenstein et al. designed NGF R/p75NTR knockouts in which the receptor is absent on one or both of these cell types.8 Sensitization and allergen challenge of the mice triggered neuronal hyperreactivity only if NGF R/p75NTR was expressed on sensory nerves, while its presence on immune cells was not involved. In contrast, allergen-provoked eosinophil, lymphocyte, and neutrophil infiltration was dependent on NGF R/p75NTR expression on immune cells, but not on sensory nerves. Therefore the effects of NGF binding to NGF R/p75NTR are determined by which cell type expresses the receptor. The reduced neuronal and immune responses in NGF R/p75NTR knockout mice are due to the absence of the receptor rather than a loss of neurotrophin production, as demonstrated by the unchanged levels of NGF and BDNF in the BALF of mice lacking NGF R/p75NTR in either tissue compartment.
NGF plays an important role in the early stages of allergic asthma by exerting tissue-specific effects on the local nervous and immune systems. Following the onset of an allergic asthma reaction, sensitized nerves reinforce existing airway inflammation by releasing neuropeptides, while activated immune cell-derived mediators aggravate neuronal sensitivity. Modulation of NGF interactions with its receptors shows potential for the control of both of these aspects of allergic asthma.
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