Pulmonary Stress Induced by Hyperthermia: Role of Airway Sensory Nerves

Effect of Hyperthermia on Airway Function: Soldiers in battle field are often subjected to severe and prolonged stress of hyperthermia. ilyperthermia can occur under both normal and pathophysiological conditions. The most common cause of hyperthermia is an increase in metabolic rate such as during vigorous exercise. Body core temperature (temp) exceeding 41 °C has been reported during exertional exercise in healthy man (62,82). Hyperthermia also occurs frequently under pathophysiological conditions caused by endogenous pyrogens or infection, such as in patients suffering from severe fever (15). Moreover, tissue inflammation is known to lead to local hyperemia and an increase in temp in the inflamed area (32,80). In fact, a recent study has reported a significantly higher tissue temp in the airways of asthmatic patients (74,77). More interestingly, when asthmatic subjects hyperventilated with air of varying temp and relative humidity, the most intense bronchoconstriction that occurred immediately after the termination of hyperventilation was generated by breathing hot humid air (almost two-fold of the bronchoconstriction caused by cold dry air at the same time point in the same patients) (2). It is well documented that cold air-induced asthma attack is caused by mucosal damage and subsequent release of inflammatory mediators, which leads to bronchoconstriction, reaching a peak after 5-10 mm (3,63). The rapid response of the hot air-induced bronchoconstriction (within one minute) suggests a possible involvement of neural reflexes, but the underlying mechanism is yet not fully understood (2). A recent study in our laboratory has reported the first evidence that hyperthermia (threshold -~3 9.2 °C) elevated the baseline activity of vagal pulmonary C-fiber endings and induced a distinct increase in their sensitivities to chemical stimulants and to lung inflation in anesthetized rats (84). A similar stimulatoiy effect of hyperthermia has also been demonstrated in isolated pulmonary sensory neurons (67- 69; Fig. 1,2, 4). In addition, we have recently demonstrated that increasing airway temperature induced a transient bronchoconstriction in anesthetized guinea pigs, and two thirds of the response was generated by hyperthermia activation of sensory nerves (Section 1-3-4; Fig. 6, 7). More importantly, our pilot study has further shown that the hyperthermia-induced acute airway constriction in asthmatic patients was indeed mediated through the cholinergic reflex (Fig. 10). Transient Receptor Potential Vanilloid Receptor Type 1 (TRPV 1): [More in-depth information is presented in two recent reviews written by P1 (references 43 & 53)] TRPVs are a subfamily of the TRP super-family of ion channel proteins containing six trans-membrane domains that form non-selective, non-voltage-gated cationic channels (9,13,14). The subtypes of TRPV channels, TRPV1 -4, are generally considered as the primary thermal sensors in mammalian species, and each type of TRPVs is activated in a different temp range (4,28,75,88). TRPVI is expressed mainly in small-size, neurofilament-negative neurons (4,36). TRPV1 can be also activated by a variety of physiological and pharmacological stimuli (11,13,35,36,75,76). In addition to its role as a thermal sensor, the function of TRPV1 as a polymodal transducer for various nociceptive stimuli in primary sensory neurons has been well documented (9,46). More importantly, a number of endogenous inflammatory mediators (e.g., POE2, bradykinin, acid, etc.) can sensitize TRPV1 during tissue inflammation, which leads to nociceptor hypersensitivity and hyperalgesia (7,10). The mechanisms underlying the sensitization of TRPVI are not yet fully understood, but several signal transduction mechanisms are known to be involved; TRPV1 has several consensus phosphorylation sites that can be phosphorylated by protein kinases A, C, and G (PKA, C and G), tyrosine kinase, etc. (34,50,81,90). For example, we have recently shown that PGE2-induced TRPV1 sensitization involves an activation of Os protein-coupled pmstanoid EP receptors located on the neuronal membrane, which in turn activates the intracellular cAMP-PKA pathway and increases the phosphorylation of TRPVI, and enhances its excitability (34,55).