Neural Mechanisms Underlying the Coughing Reflex

Abstract

Breathing is an intrinsic natural behavior and physiological process that maintains life. The rhythmic exchange of gases regulates the delicate balance of chemical constituents within an organism throughout its lifespan. However, chronic airway diseases, including asthma and chronic obstructive pulmonary disease, affect millions of people worldwide. Pathological airway conditions can disrupt respiration, causing asphyxia, cardiac arrest, and potential death. The innervation of the respiratory tract and the action of the immune system confer robust airway surveillance and protection against environmental irritants and pathogens. However, aberrant activation of the immune system or sensitization of the nervous system can contribute to the development of autoimmune airway disorders. Transient receptor potential ion channels and voltage-gated Na⁺ channels play critical roles in sensing noxious stimuli within the respiratory tract and interacting with the immune system to generate neurogenic inflammation and airway hypersensitivity. Although recent studies have revealed the involvement of nociceptor neurons in airway diseases, the further neural circuitry underlying airway protection remains elusive. Unraveling the mechanism underpinning neural circuit regulation in the airway may provide precise therapeutic strategies and valuable insights into the management of airway diseases.

Keywords: Airway disease; Cough; Na+ channel; Neural circuit; Transient receptor potential; Treatment.

Fig. 1

Diagram of cough factors. The external environmental stimuli including cold air, pathogens, allergens, and chemical substances enter the trachea during inspiration and trigger cough through stimulating nociceptors and mediating the immune response. The image was created with BioRender.com.

Fig. 2

Model of the interaction of immune responses and nociceptor neurons in the airway. The initiation of type 2 inflammation requires the cooperation of dendritic cells and nociceptor neurons. Nociceptor neurons transmit activating signals to various immune cells, causing bronchoconstriction and inflammation. The immune response can be triggered by specific neuropeptides such as SP or inhibited by somatostatin (SST). The inflammatory factors can in turn stimulate and sensitize nociceptor neurons. The image was created with BioRender.com.

Fig. 3

Diagram of correlation between stimuli and fibers. Different kinds of stimuli act on Aδ- or C-fibers within the jugular and nodose ganglia. Aδ- and C-fibers innervate the trachea and bronchi and provide noxious sensing in the airway. The image was created with BioRender.com.

Fig. 4

Neural circuit of the cough reflex. Nerves innervating the airway originate from the nodose ganglion or the jugular ganglion. The nodose and jugular ganglia project ascending fibers to the NTS and paratrigeminal nucleus, respectively. A subpopulation of neurons in the medial and lateral thalamus receiving an ascending projection from the nodose nerve further projects to the insular cortex. Another subpopulation of neurons in the medial and lateral thalamus receives a jugular nerve projection and further projects to the somatosensory cortex. The lower airway receives innervation from dorsal root ganglia, originating from thoracic vertebrae T1-T4, which further project to the brain. The image was created with BioRender.com.

Fig. 5

Diagram of the descending pathway of cough. The cough center is within the respiratory group in the medulla, which contains the pre-Bötzinger complex, Bötzinger complex, cVRG, VRG, and DRG. The cough center receives inputs from the motor cortex, cognitive area, and thalamus. After integrating information from higher regions, the cough center controls the larynx, trachea, bronchi, intercostal muscles, and diaphragm to exert cough through the spinal motor, phrenic, and vagal nerves. The image was created with BioRender.com.

Fig. 6

Diagram of receptors and voltage-gated sodium channels on the postsynaptic membrane. Nociceptors sense stimuli such as capsaicin, reactive oxygen species, citric acid, IL-5, PGD2, and cold air, and transmit the initial potential to voltage-gated sodium channels, which further produce action potentials. The image was created with BioRender.com.