Substance P (SP), an undecapeptide distributed widely but unevently in neurons of the central and peripheral nervous systems, is thought to act as a transmitter in nociceptive systems, is released from sensory terminals in several tissues in which it participates in inflammatory responses, and is present in intrinsic nerves in gut and probably in lung. In smooth muscle of intestine and airways SP is a potent contractile agonist. We have demonstrated that a major portion of the contractile response in guinea pig ileum smooth muscle to leukotriene D4(LTD4) is accounted for by release of SP(58). Histamine, long thought to mediate spread to neurogenic inflammation from locally stimulated sensory neurons to adjacent neurons, did not release SP. This suggests that (LTs) rather than histamine may be the intermediate agents that, after irritation and activation of local SP containing afferent nerve terminals via the axon reflex, stimulate surrounding SP neurons to release SP, thus spreading the inflammatory cascade. The present proposal is designed to test this hypothesis in guinea pig trachea and bronchi. Several criteria will be analyzed to determine whether Lts function to spread inflammation in the airways as follows: (1) Release of SP by LT (2) Release of LT(s) by SP (3) Release of both SP and LT(s) by irritants. (4) Inhibition by LT antagonists of SP release in response to iritants (5) Inhibition by SP antagonists of LT release in response to irritants. To determine whether SP release in response to LT is from only sensory neurons or whether intrinsic SP enurons (59,60) also respond to LT we will test the effects of capsaicin pretreatment on the SP contribution to the LT contractile response. We also will determine whether LT evoked SP release is through activation of NA+ dependent action potentials by use of tetrodotoxin (TTx). Whether or not our hypothesis regarding the role of LTs is spread of neurogenic inflammation holds up, these studies will provide important basic information on interactions between SP and LTs in inflammatory airway constriction, information crucial to development of more rational therapies for obstructive airway disease such as chornic bronchitis, asthma, and cystic fibrosis.
| Bloomquist, E I; Kream, R M (1990) Release of substance P from guinea pig trachea leukotriene D4. Exp Lung Res 16:645-59 |
| Bloomquist, E I; Kream, R M (1987) Leukotriene D4 acts in part to contract guinea pig ileum smooth muscle by releasing substance P. J Pharmacol Exp Ther 240:523-8 |
