Role of endogenous nerve growth factor in laryngeal airway hyperreactivity and laryngeal inflammation induced by intermittent hypoxia in rats

Obstructive sleep apnea, characterized by airway exposure to intermittent hypoxia (IH), is associated with laryngeal airway hyperreactivity (LAH) and laryngeal inflammation. The sensitization of capsaicin-sensitive superior laryngeal afferents (CSSLAs) by inflammatory mediators has been implicated in the pathogenesis of LAH. Nerve growth factor (NGF) is an inflammatory mediator that acts on tropomyosin receptor kinase A (TrkA) and the p75 neurotrophin receptor (p75^NTR) to induce lower airway hyperresponsiveness. In this study, we investigated the role of NGF in the development of LAH and laryngeal inflammation induced by IH in anesthetized rats. Compared with rats subjected to room air exposure for 14 days, rats with 14-day IH exposure exhibited augmented reflex apneic responses to the laryngeal provocation of three different chemical stimulants of CSSLAs, resulting in LAH. The apneic responses to laryngeal stimulants were abolished by either perineural capsaicin treatment (a procedure that selectively blocks the conduction of CSSLAs) or denervation of the superior laryngeal nerves, suggesting that the reflex was mediated through CSSLAs. The IH-induced LAH was significantly attenuated by daily treatment with anti-NGF antibody, but was unaffected by daily treatment with immunoglobulin G. IH exposure also induced laryngeal inflammation as evidenced by increases in laryngeal levels of NGF, lipid peroxidation, tumor necrosis factor-α, interleukin-1β, TrkA, and p75^NTR. Similarly, IH-induced laryngeal inflammation was significantly reduced by daily treatment with anti-NGF antibody. We concluded that NGF contributes to the development of LAH and laryngeal inflammation induced by IH in rats. The LAH may result from the sensitizing effect of NGF on CSSLAs.