Nerve growth factor derived from bronchial epithelium after chronic mite antigen exposure contributes to airway hyperresponsiveness by inducing hyperinnervation, and is inhibited by in vivosiRNA

Authors

  • H. Ogawa,

    Corresponding author
    • Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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  • M. Azuma,

    1. Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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  • H. Uehara,

    1. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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  • T. Takahashi,

    1. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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  • Y. Nishioka,

    1. Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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  • S. Sone,

    1. Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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  • K. Izumi

    1. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
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Correspondence: Hirohisa Ogawa, Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan.

E-mail address: hy-ogawa@tv-naruto.ne.jp

Abstract

Background

Bronchial asthma is a chronic allergic airway inflammatory disease. Neurotrophins, including nerve growth factor (NGF), play an important role in the pathogenesis of asthma. However, the effects of NGF derived from epithelium on airway hyperresponsiveness (AHR) after antigen sensitization/exposure remain uncertain.

Objective

In this study, we examined the role of NGF on AHR after chronic antigen exposure and the effect of inhibiting NGF by in vivo siRNA on AHR exacerbation.

Methods

We generated chronic mouse models of bronchial asthma using house-dust mite antigen (Dermatophagoides pteronyssinus; Dp). NGF concentrations in bronchoalveolar lavage fluid (BALF), lung histopathology, hyperresponsiveness, and related neuronal peptides and cytokines in supernatants of lung homogenates were determined.

Results

NGF in BALF was increased in a dose- and time-dependent manner, and was expressed primarily in bronchial epithelium. Nerve fibres and substance P-positive fibres were detected in subepithelium of Dp-sensitized and challenged mice over 4 weeks of mite antigen exposure. AHR was positively correlated with NGF concentration and nerve fibre innervation. AHR, modulation of innervation, and increased substance P were inhibited by in vivo administration of siRNA that targeted NGF, although the inhibition of NGF did not affect allergic inflammation and subepithelial fibrosis.

Conclusion and clinical relevance

These findings suggest that NGF derived from bronchial and alveolar epithelium plays an important role in AHR after chronic exposure to mite antigen. NGF inhibition could potentially manage bronchial asthma, including AHR.

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