Dawn D. Hunter

Allergen–Induced Sensory Neuroplasticity in Airways

This study investigates the influence of allergic inflammation in airway sensory innervation. We conclude that allergic inflammation in the guinea pig leads to both an increase in excitability, as manifested by an increase in the mechanical sensitivity of the airway nerve endings, and an induction of substance P production in airway sensory neurons. The data are consistent with the hypothesis that the induction of substance P occurs in fast conducting nodose sensory neurons that were previously devoid of this neuropeptide. Thus, allergen challenge is associated with a phenotypic change in the airway tachykinergic innervation. We also provide evidence that nerve growth factor is a potentially important mediator for these effects, and that it is elevated in the bronchoalveolar lavage of asthmatic subjects.

Neurobiology of the upper and lower airways

The airways, from the nose to the terminal bronchioles, are abundantly innervated by sensory and autonomic nerves. This innervation plays a critical role in host defense and in the maintenance of physiological homeostasis. To carry out these functions appropriately, airway nerves must be able to adjust rapidly to alterations in their environment. Indeed, changes in the airway environment, especially those associated with inflammation, can lead to substantive changes in both the anatomy and electrical excitability of the neurons (1). Although this neuroplasticity plays an essential role in providing defense and physiological balance, it may become dysregulated to the extent that it contributes to, or causes, airway inflammatory diseases. The fact that sensory nerves from both the upper and lower airway can lead to profound reflex changes in the lower airway function heightens the interest in the potential interactions between upper and lower airways in dseases such as asthma. Regrettably, there are relatively few studies aimed at critically evaluating this interaction in human disease. We have therefore chosen not to focus specifically on the interactions between the upper and lower airways, but rather to provide a brief overview of the anatomy and physiology of upper and lower airway innervation. In addition, we will review some of the pertinent literature pertaining to neural plasticity in airway inflammation. It is hoped that the information reviewed here may provide a useful framework for future studies aimed at evaluating potential neuronal communication networks between upper and lower airways that may have bearing on airway pathophysiology. The literature reviewed focuses on the nerves involved in regulating the physiology of the airway wall. This means that two major areas of airway innervation

Prenatal and Early, but Not Late, Postnatal Exposure of Mice to Sidestream Tobacco Smoke Increases Airway Hyperresponsiveness Later in Life

Background Cigarette smoke exposure in utero and during early postnatal development increases the incidence of asthma and airway hyperresponsiveness (AHR) later in life, suggesting that a possible critical period of developmental sensitivity exists in the prenatal and early postnatal periods. Objective We investigated mechanisms of susceptibility during critical developmental periods to sidestream smoke (SS) exposure and evaluated the possible effects of SS on neural responses. Methods We exposed three different age groups of mice to either SS or filtered air (FA) for 10 consecutive days beginning on gestation day (GD) 7 by maternal exposure or beginning on postnatal day (PND) 2 or PND21 by direct inhalation. Lung function, airway substance P (SP) innervation, and nerve growth factor (NGF) levels in broncho alveolar lavage fluid were measured after a single SS exposure on PND59. Results Methacholine (MCh) dose response for lung resistance (RL) was significantly elevated, and dynamic pulmonary compliance (Cdyn) was significantly decreased, in the GD7 and PND2 SS exposure groups compared with the FA groups after SS exposure on PND59. At the same time points, the percent area of SP nerve fibers in tracheal smooth muscle and the levels of NGF were significantly elevated. MCh dose–response curves for RL and Cdyn, SP nerve fiber density, and the level of NGF were not significantly changed in the PND21 exposure group after SS exposure on PND59. Conclusions These results suggest that a critical period of susceptibility to SS exposure exists in the prenatal and early postnatal period of development in mice that results in increased SP innervation, increased NGF levels in the airway, and enhanced MCh AHR later in life.

Neurotrophins and asthma.

The neurotrophins are a family of peptides that promote survival, growth, and differentiation of neurons. Neurotrophins may also influence the function of nonneuronal cell types, including immune cells. The development and maintenance of asthma is thought to involve the nervous system and the immune system, but the role that neurotrophins play in asthma is unknown. The cellular sources of the neurotrophins include mast cells, lymphocytes, macrophages, epithelial cells, smooth muscle cells, and eosinophils. The activation of neurotrophin receptors in immune cells and neurons involves ligand-induced homodimerization, which leads to activation of intrinsic Trk receptor kinase. The exact consequences of activating these receptors on immune cells is unknown, but rather than having unique actions on immune cells, the neurotrophins appear to act in concert with known immune regulating factors to modulate the maturation, accumulation, proliferation, and activation of immune cells. Neurotrophins can modulate afferent nerve function by stimulating the production of neuropeptides within airway afferent neurons. These neuropeptides may be released from the central terminals of airway afferent neurons, which leads to heightened autonomic reflex activity, and increased reactivity in the airways.