Sensory Nerves in Lung and Airways

Abstract

Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases.

Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats

“…or endogenous chemical mediators (e.g., hydrogen ion, adenosine 5=-triphosphate, bradykinin, eosinophil granule-derived cationic proteins, etc.) can elicit powerful protective reflex responses, such as cough, mucus secretion, bronchoconstriction, dyspneic sensation, and J reflex (5,21). Furthermore, these sensory nerves have been recognized to play an important role in the neural-immune interaction in response to various airway assaults (e.g., allergens, irritant chemicals) (21,28); for example, neuropeptides (e.g., substance P) released from pulmonary C-fiber endings upon activation can interact with a number of immune cells (e.g., macrophage, mast cell) and modulate their activity and cytokine release (21,28).…”

“…can elicit powerful protective reflex responses, such as cough, mucus secretion, bronchoconstriction, dyspneic sensation, and J reflex (5,21). Furthermore, these sensory nerves have been recognized to play an important role in the neural-immune interaction in response to various airway assaults (e.g., allergens, irritant chemicals) (21,28); for example, neuropeptides (e.g., substance P) released from pulmonary C-fiber endings upon activation can interact with a number of immune cells (e.g., macrophage, mast cell) and modulate their activity and cytokine release (21,28). Hence, their sensitivity is not only important in protecting the lung and body against potential health hazardous actions caused by air-borne chemical irritants, but also in regulating airway function under various pathophysiological conditions (5,21).…”

“…These unmyelinated afferents innervate the entire respiratory tract and play an important role in regulating the respiratory functions under various physiological and pathophysiological conditions (5,21). Activation of these afferents elicits centrally mediated protective reflex responses via the cholinergic pathway, which include laryngeal closure, bronchoconstriction and airway hypersecretion, accompanied by cough, airway irritation, dyspneic sensation, and J reflex (5,21).…”

“…These unmyelinated afferents innervate the entire respiratory tract and play an important role in regulating the respiratory functions under various physiological and pathophysiological conditions (5,21). Activation of these afferents elicits centrally mediated protective reflex responses via the cholinergic pathway, which include laryngeal closure, bronchoconstriction and airway hypersecretion, accompanied by cough, airway irritation, dyspneic sensation, and J reflex (5,21). Activation of these sensory nerves can also trigger release of tachykinins and calcitonin gene-related peptide from the sensory terminals, which can act on a number of effector cells in the respiratory tract (e.g., smooth muscles, cholinergic ganglia, mucous glands, immune cells), and elicit the local "axon reflexes" such as bronchoconstriction, protein extravasation, and inflammatory cell chemotaxis (5,18,21).…”

“…Severe hemorrhage, a medical condition frequently encountered in patients who suffer from traumatic injury, can lead to tissue ischemia, hypoxia, and acidosis (8), accompanied by elevated levels of adenosine (32), lactate (23), pro-inflammatory cytokines (7), and reactive oxygen species (ROS) (27) in the circulating blood. Many of these chemical substances and mediators are known to exert potent stimulatory and sensitizing effects on pulmonary C-fiber afferents (21). In particular, acidosis can both activate (15) and sensitize vagal pulmonary C-fibers (10) to chemical stimuli.…”