Our limited knowledge of the neuronal control of human airway smooth muscle is derived mostly from studies of large central airways. Based on these studies it can be concluded that the innervation of human airway smooth muscle is dominated by a cholinergic contractile system and a relaxant system that is non-adrenergic in nature. In addition, recent evidence supports the hypothesis that the human airway smooth muscle also receives noncholinergic contractile innervation. Recent studies with animal models have yielded exciting new information on the non-adrenergic, non-cholinergic innervation of the airways, and its potential regulation by inflammation. With this information and the new investigative tools available, the time is ripe to re-evaluate the nature of the innervation of human airways. The objective of the present proposal is to critically investigate the nature of the innervation of human central (2nd - 7th generation bronchi) and peripheral (bronchioles) airway smooth muscle. Using a multidisciplinary approach, experiments will be designed to determine the nature of the neurotransmitters involved in the non-adrenergic and noncholinergic responses in the airways, the regional distribution of contractile and relaxant innervation along the airway tree, and the regulation of the relaxant and contractile innervation by specific mediators known to be present in the airways during inflammatory reactions. The hypothesis that vasoactive intestinal peptide (or related peptides) and/or nitric oxide mediate the non-adrenergic relaxation and that tachykinins released from capsaicin-sensitive nerves mediate the non-cholinergic contractions will be examined using new pharmacological tools including specific antibodies to the putative transmitters, novel nitric oxide synthase inhibitors and selective tachykinin receptor agonists and antagonists. In parallel with these studies, experiments will be carried out on the innervation of the guinea pig airways so that the validity of this animal as a model for the innervation of human airways can be objectively evaluated. The proposal provides for a systematic characterization of the innervation of human central and peripheral airways. The information gained from these studies will begin to address the long range goal of understanding the contribution of the peripheral nervous system to pulmonary physiology and pathophysiology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL048680-02
Application #
3473917
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1992-07-08
Project End
1996-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ellis, J L (1997) Role of soluble guanylyl cyclase in the relaxations to a nitric oxide donor and to nonadrenergic nerve stimulation in guinea pig trachea and human bronchus. J Pharmacol Exp Ther 280:1215-8
Ellis, J L; Sham, J S; Undem, B J (1997) Tachykinin-independent effects of capsaicin on smooth muscle in human isolated bronchi. Am J Respir Crit Care Med 155:751-5
Ellis, J L; Conanan, N D (1996) Prejunctional inhibition of cholinergic responses by prostaglandin E2 in human bronchi. Am J Respir Crit Care Med 154:244-6
Ellis, J L (1995) Neurokinin receptors subserving bronchoconstriction. Can J Physiol Pharmacol 73:923-6
Ellis, J L; Conanan, N D (1995) Modulation of relaxant responses evoked by a nitric oxide donor and by nonadrenergic, noncholinergic stimulation by isozyme-selective phosphodiesterase inhibitors in guinea pig trachea. J Pharmacol Exp Ther 272:997-1004
Ellis, J L; Undem, B J (1994) Role of cysteinyl-leukotrienes and histamine in mediating intrinsic tone in isolated human bronchi. Am J Respir Crit Care Med 149:118-22
Ellis, J L; Undem, B J (1994) Pharmacology of non-adrenergic, non-cholinergic nerves in airway smooth muscle. Pulm Pharmacol 7:205-23
Ellis, J L; Conanan, N D (1994) Effect of potassium channel blockers on relaxations to a nitric oxide donor and to nonadrenergic nerve stimulation in guinea pig trachea. J Pharmacol Exp Ther 271:782-6
Fernandes, L B; Ellis, J L; Undem, B J (1994) Potentiation of nonadrenergic noncholinergic relaxation of human isolated bronchus by selective inhibitors of phosphodiesterase isozymes. Am J Respir Crit Care Med 150:1384-90
Ellis, J L; Conanan, N (1994) L-citrulline reverses the inhibition of nonadrenergic, noncholinergic relaxations produced by nitric oxide synthase inhibitors in guinea pig trachea and human bronchus. J Pharmacol Exp Ther 269:1073-8

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