Idiopathic persistent nonproductive cough (PNPC) is characterized by enhanced cough sensitivity to inhaled capsaicin, suggesting that capsaicin-sensitive afferent airway nerves are either present in increased numbers or functionally upregulated. In 16 patients with idiopathic PNPC and eight healthy control subjects, we measured cough sensitivity to inhaled capsaicin and the anatomic density in bronchial epithelium of nerves immunoreactive for the general nerve-marker protein gene product (PGP)-9.5 and the sensory neuropeptides calcitonin-gene-related-peptide (CGRP) and substance-P (SP). The log concentrations of capsaicin required to elicit at least two (C2) and five (C5) coughs were significantly lower in patients (P) than in control subjects (C) (median [range] log C2, P = 0.3 [-0.3 to 1.2] microM; C = 1.5 [0.9 to 2.1], p < 0.0005; log C5, P = 0.8 [-0.3 to 2.1]; C = 2.6 [1.8 to 3.0], p < 0.0005). In bronchial epithelium taken from the carina of the right upper lobe (RUL) and a subsegmental carina of the right lower lobe (RLL), total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant. CGRP-immunoreactive nerve density was significantly higher in P than in C in the RUL (median [range] P = 1.05% [0.13 to 5.08]; C = 0.02% [0 to 0.24], p = 0.001) and RLL (P = 0.59% [0.04 to 3.14]; C = 0% [0 to 0.50], p < 0.02). SP-immunoreactive nerves were not significantly different in the two groups. Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary vascular tone is regulated by many vasoactive mediators produced either locally in endothelium, airway epithelium, vascular smooth muscle or nerves, or systemically via the blood. The main effect of alveolar hypoxia is pulmonary hypertension, which is modulated by many counteracting mediators. Amongst the possible candidates is calcitonin gene-related peptide (CGRP) [1], a potent vasodilator that is also present in the sensory innervation and endocrine cells of the rat respiratory tract [1][2][3], which is known to be involved in regulating pulmonary vascular tone [2,4].In previous studies, hypoxia has been shown to cause an increase in whole lung CGRP concentrations [5], particularly in the pulmonary endocrine cells [6,7], and decreased plasma levels of the peptide in rats [5]. Release We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.Eur Respir J., 1995Respir J., , 8, 2029Respir J., -2037 of endogenous CGRP may be of importance in maintaing pulmonary equilibrium, and impaired release may, thus, be relevant to the pulmonary hypertension that is a consequence of hypoxia.Peptides elicit their effect by interacting with specific receptors on the target cell, which in turn will activate various intracellular pathways that lead to a biological response. These receptors can be identified partly by ligand binding studies and localized quantitatively by using tissue sections for the binding. CGRP binding sites are of two types, termed CGRP1 and CGRP2 [8,9].We hypothesized that changes in the amount of CGRP released will be reflected by an adaptive response shown by changes in its binding sites and, thus, its physiological effects, and have directed our study to investigate the

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Morphologic changes are reported to occur in rat lung vasculature after 3 days of hypoxia. We have previously shown that immunoreactivity for the vasodilator calcitonin gene-related peptide (CGRP) is increased in pulmonary endocrine cells by 7 days of hypoxia. Because these cells may be among the earliest mediators of the hypoxic response, we examined endocrine cell CGRP content in rat lung after 0, 2, 4, and 8 h and 1, 5, 10, 15, 20, 28, and 35 days of normobaric hypoxia, using optimal and supraoptimal dilutions of CGRP antibodies to demonstrate changes in CGRP immunoreactivity. This was compared with temporal changes in pulmonary vascular smooth muscle after 1, 5, and 20 days of hypoxia exposure by evaluating vascular immunoreactivity for alpha-smooth muscle actin (alpha-SM actin), platelet-derived growth factor (PDGF) beta-receptor, and proliferating cell nuclear antigen (PCNA). Significant increases in endocrine cell CGRP immunoreactivity were found after 4 h of hypoxia, and levels increased up to 1 day, followed by a decrease (at 5 days) and then a progressive increase up to 35 days. After 1 day of hypoxia, the number of vessels displaying immunoreactivity for alpha-SM actin, PDGF beta-receptor, and PCNA were also significantly increased. Whereas PDGF beta-receptor and PCNA returned to control values by day 20, alpha-SM actin reached a plateau that persisted until 20 days. The results indicate that modulation of endocrine cell CGRP content in response to hypoxia is rapid and characterized by a significant and persistent increase, paralleled by a proliferation of vascular cells leading to vascular muscularization.(ABSTRACT TRUNCATED AT 250 WORDS)

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