Small Interfering RNA Targeting Nerve Growth Factor Alleviates Allergic Airway Hyperresponsiveness

Abstract

Airway hyperresponsiveness is the hallmark of allergic asthma and caused by multiple factors. Nerve growth factor (NGF), a neurotrophin, is originally known for regulation of neural circuit development and function. Recent studies indicated that NGF contributes to airway hyperresponsiveness and pathogenesis of asthma. The objective of this study is to develop a small interfering RNA against NGF to attenuate airway hyperresponsiveness and further elucidate the underlying mechanism. In a murine model of allergic asthma, the ovalbumin-sensitized mice were intratracheally delivered small interfering RNA against NGF or administered an inhibitor targeting NGF receptor, tropomyosin-related kinase A, as a positive treatment control. In this study, knockdown NGF derived from pulmonary epithelium significantly reduced airway resistance in vivo. The levels of NGF, proinflammatory cytokines and infiltrated eosinophils in airway were decreased in small interfering RNA against NGF group but not in tropomyosin-related kinase A inhibitor and mock siRNA group. Furthermore, induction of neuropeptide (substance P) and airway innervation were mediated by NGF/tropomyosin-related kinase A pathway. These findings suggested that NGF targeting treatment holds the potential therapy for antigen-induced airway hyperresponsiveness via attenuation of airway innervation and inflammation in asthma.

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

“…The neuro-protective/ trophic properties of NGF are well established [24, 30, 31], albeit therapeutic applications are currently limited due to pathogenic side effects including neuropathic [4, 5] and deep tissue pain [10, 11] atopic dermatitis [7 – 9], arthritis, asthma [10, 12, 13], intervertebral disc degeneration [14] and cancer. [15 – 17] Therefore, there is a need for identification of small MW neurotrophic compounds that may have therapeutic value in treatment of peripheral/CNS injury or neurodegenerative disorders, without the limitations of endogenous neurotrophins.…”

“…While most drug regimens have capacity to improve quality of life, they do not address the underlying etiology of the disease and thereby do not arrest progression degenerative processes. Although endogenous synthesis of trophic molecules such as nerve growth factor (NGF) [1], brain-derived neurotrophic factor (BDNF) and neurotrophin-3/neurotrophin-4 can effectively stimulate neuronal growth/repair [2, 3], therapeutic applications are limited by a wide range of negative side effects such as neuropathic pain [4, 5], bladder/urinary pain [6], itchy skin (pruritus) atopic dermatitis [7 – 9], deep tissue tenderness [10, 11], exacerbated inflammatory conditions such as arthritis, asthma [10, 12, 13], inter-vertebral disc degeneration [14] and cancer [15 – 17]. Furthermore, elevated levels of NGF in various neuronal tissue can lead to behavioral/cognitive disorders such as autism [18], bipolar [19] and attention deficit/hyperactivity disorder.…”

Neurotrophins in Asthma

“…In contrast, mice treated with a neutralizing NGF antibody during allergen exposure showed a reduction in the number of eosinophils, levels of type 2 cytokines, and airway bronchoconstriction [29]. Consistently, in vivo inhibition of NGF via siRNA administration diminished bronchoconstriction, airway innervation density, and immune cell infiltration following allergen exposure [31••]. The effect of NGF in these rodent models of asthma was at least in part mediated by neurotransmitters, such as serotonin and substance P [29, 30, 32–34].…”

Review of Methods to Study Gene Expression Regulation Applied to Asthma

“…Levels of NGF, proinfl ammatory cytokines, and infi ltrated eosinophils in airway were decreased in the siRNA group. The fi ndings suggested that NGF is a target for a potential therapy of antigeninduced airway hyperresponsiveness via attenuation of the airway innervations and infl ammation in asthma [ 105 ].…”