Pulmonary Endocrine Cells Research Articles

Procalcitonin versus C-reactive protein as indicator of acute rejection during orthotropic liver transplanation

Abstract Background Procalcitonin is the precursor for the hormone calcitonin (CT), which is found in the thyroid C cells and the pulmonary endocrine cells, it has a metabolic role in calcium homeostasis. In normal subjects, PCT is found in the blood at a very low concentration but during bacterial infection, there is more than 1,000 fold increase in its blood concentration as it is released by many other tissues as Liver, Spleen and Lungs. Aim of the Work to compare between procalcitonin and CRP as a markers of infection versus rejection in orthotropic liver transplantation; this comparison with their plasma level and the clinical difference during postoperative period. Patients and Methods This study was conducted on 25 patients aged 2-60 years old of both sexes scheduled for elective liver transplantation from living donors; after ethical committee approval and informed consent from patients and/or their first degree relatives, Ain Shams Specialized Hospitals. Results The study revealed that the normal course after liver transplantation for postoperative 28 days was (48%), rejection (16%), sepsis (24%) and rejection and sepsis (12%). Conclusion Procalcitonin is a good early diagnostic marker and is superior to CRP and WBCs in early detection of postoperative sepsis after orthotropic liver transplantation.

A histopathological analysis of spontaneous neoplastic and non-neoplastic lesions in aged male RccHan:WIST rats.

Histopathological information about spontaneous lesions in aged Hannover Wistar rats is limited. In this study, we describe spontaneous lesions found in 39 male RccHan:WIST rats used as a control in a carcinogenicity study. Neoplastic lesions were frequently seen in the endocrine system, such as pituitary adenomas in the pars distalis. This strain exhibited a high incidence of thymoma (10.3%), compared to other strains. We encountered an oligodendroglioma, a pituitary adenoma of the pars intermedia, and a prostate adenocarcinoma, which are comparatively rare in rats. While the variety and incidence of non-neoplastic lesions were similar to those in other strains, several interesting lesions occurred with relatively high incidence, including “harderianization” of the extraorbital lacrimal gland, common bile duct ectasia, and hyperplasia of pulmonary endocrine cells in the lung. Furthermore, comparative analyses demonstrated that the severity of chronic progressive nephropathy and murine progressive cardiomyopathy in RccHan:WIST rats was less than that in F344 rats.

Vagal Sensory Neuron Subtypes that Differentially Control Breathing

Breathing is essential for survival and under precise neural control. The vagus nerve is a major conduit between lung and brain required for normal respiration. Here, we identify two populations of mouse vagus nerve afferents (P2ry1, Npy2r), each a few hundred neurons, that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping revealed that these neurons densely innervate the lung and send long-range projections to different brainstem targets. Npy2r neurons are largely slow-conducting C fibers, while P2ry1 neurons are largely fast-conducting A fibers that contact pulmonary endocrine cells (neuroepithelial bodies). Optogenetic stimulation of P2ry1 neurons acutely silences respiration, trapping animals in exhalation, while stimulating Npy2r neurons causes rapid, shallow breathing. Activating P2ry1 neurons did not impact heart rate or gastric pressure, other autonomic functions under vagal control. Thus, the vagus nerve contains intermingled sensory neurons constituting genetically definable labeled lines with different anatomical connections and physiological roles.

Fluoxetine may worsen hyperoxia-induced lung damage in neonatal rats.

Fluoxetine shows controversial lung effects as it prevents pulmonary hypertension in adult rats but exposure during gestation causes pulmonary hypertension in neonatal rats. In the present study, we tested the null hypothesis that the antidepressant drug fluoxetine does not modify the development of bronchopulmonary dysplasia (BPD) in neonatal rats. Experimental categories included I: room air (controls) with daily injection of saline; II: room air with daily injection of 10 mg/kg fluoxetine, i.p., during two weeks; III: 60% oxygen with daily injection of saline; and IV: 60% oxygen with daily injection of 10 mg/kg fluoxetine, i.p., during two weeks. Hyperoxia resulted in significant reduction in alveolar density and an increase in pulmonary endocrine cells, as well as increases in muscle layer areas of bronchi and arteries. Fluoxetine treatment generated a further increase in muscularisation and did not significantly modify the hyperoxia-induced reductions in alveolar density and increases in the endocrine cells. In hyperoxia, Real-Time PCR showed a lower pulmonary expression of vascular endothelial growth factor (VEGF) with no significant changes in the expression of matrix metalloproteinases (MMP) 2 and 12. Fluoxetine did not affect VEGF or MMP-2 expression but it significantly increased MMP-12 mRNA in both normoxic and hyperoxic groups. Zymographic analysis of MMP-2 activity in bronchoalveolar fluid showed a significantly reduced MMP-2 activity in hyperoxia, while fluoxetine treatment restored MMP-2 activity to levels comparable with the normoxic group. In conclusion, our data show that fluoxetine may worsen bronchial and arterial muscularisation during development of BPD and may up-regulate MMP expression or activity.

Overexpression of the NOTCH1 Intracellular Domain Inhibits Cell Proliferation and Alters the Neuroendocrine Phenotype of Medullary Thyroid Cancer Cells

The role of NOTCH1 as an oncogene or tumor suppressor appears to be cell type-specific. Medullary thyroid cancer (MTC) cells characteristically express the transcription factor ASCL1 (achaete-scute complex-like 1) as well as high levels of the neuroendocrine (NE) markers calcitonin and chromogranin A (CgA). In this study, we show that the active NOTCH1 intracellular domain is absent in human MTC tumor tissue samples and MTC-TT cells. To determine the effects of NOTCH1 expression, we created a doxycycline-inducible NOTCH1 intracellular domain in MTC cells (TT-NOTCH cells). Treatment of TT-NOTCH cells with doxycycline led to dose-dependent induction of NOTCH1 protein with corresponding decreases in ASCL1 protein and NE hormones. ASCL1 promoter-reporter assay and Northern analysis revealed that ASCL1 reduction by NOTCH1 activation is predominantly via silencing of ASCL1 gene transcription. Overexpression of ASCL1 in MTC cells indicated that CgA expression is highly dependent on the levels of ASCL1. This was further confirmed by experiments using small interfering RNA against ASCL1, in which reduction in ASCL1 led to reduction in both CgA and calcitonin. Furthermore, we demonstrate that NOTCH1 signaling activation leads to ERK1/2 phosphorylation, but that reduction in NE markers is independent of ERK1/2 activation. Activation of NOTCH1 resulted in significant MTC cell growth inhibition. Notably, reduction in MTC cell growth was dependent on the level of NOTCH1 protein present. Moreover, no increase in growth upon expression of ASCL1 in NOTCH1-activated cells was observed, indicating that the growth suppression observed upon NOTCH1 activation is independent of ASCL1 reduction. Mechanistically, we show that MTC cell growth inhibition by NOTCH1 is mediated by cell cycle arrest associated with up-regulation of p21.

Pulmonary Endocrine Cells in Hypoplastic Lungs Due to Foetal Urinary Tract Obstruction: A Microscopic Immunohistochemical Study

We performed a urinary tract obstruction (UTO) surgical procedure at 93-107 days' gestation in lambs to investigate the relationship between pulmonary hypoplasia and the appearance of pulmonary endocrine cells by quantitative analysis of respiratory tract cells using light microscopic immunohistochemistry. UTO produced a significant reduction in lung weight, lung/body weight ratio, air capacity, air capacity/body weight ratio (p < 0.01) and radial alveolar count (p < 0.05), which indicated the presence of lung hypoplasia. These foetuses also showed a significant increase in the number of neuron-specific enolase (NSE)-positive pulmonary endocrine cells, expressed as the number of NSE-positive cells per bronchus (p < 0.01) or bronchiole (p < 0.05), the number of NSE-positive cells per unit perimeter of bronchus or bronchiole (p < 0.01), and the number of NSE-positive cells per unit bronchial or bronchiolar surface area (p < 0.01). These results suggest that UTO significantly retards and modifies the structural growth and functional development of pulmonary endocrine cells in NSE expression. We speculate that pulmonary endocrine cells and their mediators may play a role in the problems associated with UTO during intrauterine life.

Treatment of bronchial asthma with tianeptine

Although circulating catecholamines and free serotonin in the plasma (f-5-HT) were found to be increased during asthma attacks, only f-5-HT levels correlated positively with bronchoconstriction and clinical severity. Tianeptine, a drug that enhances serotonin uptake by platelets and serotonergic axons at the central nervous system (CNS), provoked an abrupt disappearance of asthma attacks. This fact explains why tianeptine has proven to be a powerful therapeutic tool in controlling asthma. Its success has been demonstrated not only in two double-blind placebo, cross-over trials, but through an open study lasting more than seven years that included over 25,000 asthmatic patients. In the present article, we discuss the peripheral and central nervous system mechanisms that may explain the therapeutic success of tianeptine. These are summarized below. F-5-HT is taken up by pulmonary endocrine cells (PNEC) located at the parasympathetic terminals. A presynaptic element, these cells release serotonin and potentiate acetylcholine (ACh)-induced contraction of bronchial muscle. This effect is mediated by 5-HT(3) and 5-HT(4) postsynaptic receptors located at the bronchial muscle. According to the above, the increased f-5-HT plasma level, triggered by both platelet aggregation and nocturnal and/or diurnal hyperparasympathetic activity, potentiates ACh-induced bronchoconstriction. The fact that serotonin released by medullary serotonergic axons stimulates the medullary vagal cardiorespiratory neurons obliges us to think that serotonin-induced CNS mechanisms are also involved. Furthermore, the finding that drugs that interfere with serotonin uptake, by both platelets and 5-HT-terminals, worsen asthma symptoms and are able to provoke asthma attacks gives additional support to the above peripheral and CNS mechanisms.

Quantitative Study of Pulmonary Endocrine Cells in Fetal, Postnatal and Adult Sheep

Using light microscopic immunohistochemistry, neuron-specific enolase (NSE)-positive endocrine cells were quantitatively analyzed in the sheep lung during different stages of development from the canalicular stages to adulthood. In all stages, NSE-positive endocrine cells were usually located in the bronchi and bronchioles as solitary cells, although a few NSE-positive cell clusters, the so-called neuroepithelial bodies, were found in some places. The number of NSE-positive endocrine cells decreased with advanced stages of gestation. In the late alveolar stage, the number of NSE-positive endocrine cells reached its bottom during the fetal period. There was a gradual upturn after birth. The overall pattern of growth and differentiation of the endocrine cells is most likely species-related and depends on the state of airway development; the number of the endocrine cells of almost all animals, excluding the sheep, in relation to the size of the lung reaches a peak in the late fetal and early neonatal periods and decreases shortly thereafter. NSE-positive endocrine cells were also predominantly located in the large airways during the early stage of development (canalicular stage), and were found more frequently in the small peripheral airways towards the term. These results show the number of NSE-positive endocrine cells in the sheep to be different from that seen in other species.

Hamster pulmonary endocrine cells with positive immunostaining for calbindin-D28K.

We have examined the distribution of calcium-binding proteins (CaBPs) in adult and fetal lungs of Syrian golden hamsters (Mesocricetus auratus) using immunostaining with confocal laser microscopy and electron microscopy. Single and grouped (neuroepithelial body; NEB) endocrine cells were distributed from bronchi to alveolar ducts in the adult lung. Serial frozen sections immunostained for CaBPs in combination with immunostaining for endocrine markers such as calcitonin gene-related peptide, serotonin, PGP9.5, and synaptophysin revealed that positive immunostaining for calbindin-D28K (CB-D28K) was seen in single endocrine cells and NEBs. However, other so-called EF-hand family CaBPs, parvalbumin and calretinin, were not detected. Electron microscopically, positive immunoreaction for CB-D28K was mainly in the organelle-free cytoplasmic matrix of endocrine cells, and partly in nuclei and associated with secretory granules and endoplasmic reticulum. In fetal developing lungs, endocrine cells appeared first on gestational day 13, and they were positive for all the endocrine markers used. However, pulmonary endocrine cells were positively immunostained for CB-D28K from gestational days 15 and 16 onward. In summary, our observations suggest that CB-D28K is a useful marker for endocrine cells of the lung, and CB-D28K could function as a mediator of endocrine stimulation or calcium homeostasis in pulmonary endocrine cells.

Pulmonary endocrine cell hyperplasia and papilloma in rats induced by intratracheal injections of extract from particulate air pollutants

We investigated the effect of intratracheal injections of an extract of suspended particulate matter (SPM) obtained from the urban ambient air of Tokyo, upon the development of proliferative lesions of pulmonary endocrine cells (PECs) in the rat. We also examined the modification effects of nitrogen dioxide, sulfur dioxide, or both of them on the PEC lesions. Male F344 rats were divided into six experimental groups of 5 animals each. Twenty animals were treated with intratracheal instillations of SPM admixed with carbon once a week for 4 weeks with or without additional gaseous exposure (6 ppm nitrogen dioxide or 4 ppm sulfur dioxide) 16 hrs a day for 11 months. Five animals were given intratracheal injections of carbon suspended in saline and the other five were untreated. The subcardiac lobes of the right lung were fixed with 4% paraformaldehyde, and embedded in paraffin. PEC hyperplasias and papillomas were counted in 200 serial sections, 4 microns thick. The average incidences of PEC hyperplasia in the untreated animals and in those treated with carbon were 194 and 200/cm3, respectively. The average incidences of PEC hyperplasia in the animals exposed to SPM tar only, SPM tar plus nitrogen dioxide and sulfur dioxide, SPM tar with nitrogen dioxide and SPM tar with sulfur dioxide were 376, 378, 372 and 349/cm3, respectively. These were significantly higher than the levels of the control animals, and additional gaseous stimuli had no effect on the incidence of PEC hyperplasia. Besides PEC hyperplasia, a few PEC papillomas were found in the animals treated with SPM tar, regardless of gaseous exposure, but in the control animals no papilloma was evident. Thus, compounds in airborne particulates are considered to be responsible for the development of PEC hyperplasias and papillomas.

Effects of hydrogen and bicarbonate ions on endocrine cells in fetal rat lung organ cultures.

Concentrations of H+ and HCO3- rise in fluid lining hypercapnic airways. Effects of these ions on pulmonary endocrine cells were studied in 119 fetal rat lung organ cultures by semiquantitative staining for calcitonin gene-related peptide (CGRP)-like immunoreactive material. Intracellular CGRP was determined in cultures under "no-release" baseline conditions and after incubation in control or test media. After exposure to HCO3(-)-free medium at pH 7.4 (incubation control), CGRP fell moderately from no-release levels. Bombesin (1 ng/ml) promoted further significant loss of peptide, which was dependent on extracellular Ca2+ and inhibited by somatostatin and [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]substance P, a bombesin receptor antagonist. CGRP staining of explants incubated with 24 mM HCO3- maintained no-release levels at and above pH 7.1 but decreased significantly at pH 6.8. The drop was blocked by somatostatin or exclusion of HCO3- and was not augmented by bombesin or 48 mM HCO3-. Results suggest that pulmonary endocrine cells may respond to hypercapnia by releasing bioactive peptides like CGRP, thus stimulating afferent nerves and altering patterns of ventilation and perfusion.

Pulmonary endocrine cells in anthracosilicotic lungs.

It has been suggested by some studies of human and animal lungs that the products of pulmonary endocrine cells, particularly gastrin-releasing peptide, might play a role in fibrogenesis, but more recent detailed studies of fibrotic human lungs have failed to confirm this. We have made a detailed quantitative examination of a series of fibrotic human lungs to see if we could determine whether there was any relationship between endocrine cells and fibrosis. Using immunocytochemistry, we investigated the morphology, content, distribution and number of pulmonary endocrine cells in 15 pairs of fibrotic lungs from coal miners, and compared their features with those of equivalent cells in age-matched controls. Proliferation of endocrine cells was seen in the lungs of just two miners, in which it was focal and associated with acute bronchitis and bronchopneumonia. There was no difference between the miners and controls in the appearance (mostly solitary cells), content (predominantly gastrin-releasing peptide and calcitonin), distribution (mainly in small bronchi and bronchioles), or number (4.5 vs 4.1 cells per 10,000 epithelial cells, respectively) of endocrine cells. It seems unlikely that the substances secreted by these cells play any role in stimulating fibrosis in human lungs, but rather that they have a function in the inflammatory response to pulmonary injury.

Increased intracellular levels of calcitonin gene-related peptide-like immunoreactivity in pulmonary endocrine cells in an experimental model of congenital diaphragmatic hernia

A congenital diaphragmatic hernia (CDH) model was induced in pregnant rats following administration of 100 mg nitrofen. The fetuses were stored and fixed in Bouin's solution for 24 h after caesarean section at term. After fixation, the lungs were dissected out. Immunostaining of the CDH lungs and controls with rabbit anti-rat calcitonin gene-related peptide (CGRP) antibody at "optimal" and "supraoptimal" dilution levels was obtained by examining the intensity of staining with a series of dilutions of the antisera from 1: 1,000 to 1: 20,000. Supraoptimal dilution detects variations in antigen concentration that may be masked if the routine optimal dilution is used. Immunostaining of the lung by antisera to platelet-derived growth factor (PDGF) and alpha-smooth-muscle actin (ASMA) was performed to examine vascular remodelling. The number of CGRP-immunoreactive cells was significantly (P <0.001) greater in the lungs of CDH rats (n = 26) (0.74 +-0.19 NEB [neuroepithelial bodies]/mm(2); mean +- SEM) compared with controls (n = 21) (0.30+-0.16 NEB/mm(2)) seen at supraoptimal dilution (1:20,000). Since CGRP is a vasodilator, this could have important implications in the development of pulmonary hypertension. The pattern of ASMA and PDGF immunostaining was similar in CDH lungs and controls, and therefore, vascular remodelling is not a feature of CDH lungs in fetuses delivered by caesarean section and not exposed to hypoxia.

Endocrine cells in tumour-bearing lungs.

When hormones are detected in the serum of patients with bronchial carcinoma they are generally considered to originate from the tumour, but this may be not the only explanation. Pulmonary endocrine cells proliferate in lungs affected by non-neoplastic disease and their products are often demonstrable in the serum. The aim of this study was to examine the pulmonary endocrine systems of a series of tumour-bearing lungs to see whether any changes in them could possibly account for raised levels of pulmonary peptides in the blood. The morphology, number, distribution, and content of pulmonary endocrine cells in 30 pairs of tumour-bearing lungs from patients coming to necropsy with bronchial carcinoma were examined. These features were related to the pathology of the tumour and to other pathological changes present in the lungs, and compared with pulmonary endocrine cells in 10 pairs of control lungs from patients without pulmonary disease. Increased numbers of endocrine cells, often in the form of large abnormal aggregates, were present in 17 pairs of tumour-bearing lungs where they were associated not with the tumour but with non-tumoral pathology, especially inflammation and changes associated with cardiac failure. Appropriate and inappropriate peptides were identified within them. The possibility is raised that, in some subjects with bronchial carcinoma who have raised serum hormone levels, the source of these substances might be the endocrine cells in the diseased lung around the tumour.

Hamster pulmonary endocrine cells with neural cell adhesion molecule (NCAM) immunostaining

Pulmonary endocrine cells of Syrian golden hamster were stained for neural cell adhesion molecule (NCAM) with indirect fluorescent immunostaining and observed with a confocal laser scanning microscope equipped with an argon laser. Sections 100 microns thick of hamster lung fixed with phosphate-buffered 4% paraformaldehyde were prepared. The sections were incubated with rat monoclonal antibody against NCAM, followed by fluorescence-labeled antibody against rat immunoglobulin. Some were doubly immunostained for NCAM and one of the following endocrine markers: neuron-specific enolase, calcitonin gene-related peptide and serotonin. Expression of NCAM in the hamster airway epithelium was seen in cell nests resembling neuroepithelial bodies (NEBs). NCAM immunostaining was positive at the lateral cell borders between the cells composing the nest, but negative at the border with the adjacent, presumably non-endocrine cells. Double immunostaining confirmed that the grouped cells with NCAM immunoreactivity were of an endocrine nature, but that single endocrine cells did not show NCAM immunoreactivity. An electron microscopic study with NCAM immunostaining confirmed the light microscopic study. These suggest that NCAM expression could be important for the morphogenesis of NEBs. A confocal laser microscope was used to make three-dimensional images of NEBs after NCAM immunostaining and the spatial interaction between NEBs and the surrounding microenvironment was studied.

Pulmonary endocrine cells in plexogenic pulmonary arteriopathy associated with cirrhosis.

A clear association has been described between numbers of pulmonary endocrine cells and the migration and/or proliferation of myofibroblasts which is thought to underlie the vascular changes seen in plexogenic pulmonary arteriopathy due to cardiac shunts and primary pulmonary hypertension. In contrast, the pulmonary endocrine system in a subject with florid pulmonary plexogenic arteriopathy associated with cirrhosis was entirely normal, suggesting possible differences in its pathogenesis.

An Immunocytochemical Study of the Respiratory System of Podarcis hispanica ( Reptilia)

The endocrine cells and nerves of the respiratory tract of the reptile Podarcis hispanica were investigated by immunocytochemistry under light microscopy. Immunoreactivities were more numerous in the lung than in the trachea. In the tracheal epithelium, endocrine cells immunoreactive to PHI, PYY, and Leu-enkephalin were detected, while immunoreactivity to serotonin, calcitonin, CGRP, PHI, and Leu-enkephalin was found in pulmonary endocrine cells. Numerous nerve fibers positive to NSE, PGP9.5, chromogranin, tyrosine hydroxylase, calcitonin, CGRP, bombesin, substance P, VIP, NPY, and PYY were found in the lungs. In addition, neurons positive to NSE and PGP9.5 were also found. Immunoreactivities to PHI and PYY in cells and to NSE, PGP9.5, chromogranin, tyrosine hydroxylase, calcitonin, CGRP, and PYY in nerves, were reported first in the respiratory system of reptiles.

Colocalization of immunoreactivities to serotonin, calcitonin and CGRP in endocrine pulmonary cells of the iberian lizard Podarcis hispanica (Reptilia)

The coexistence of immunoreactivities to serotonin (5HT), calcitonin (CT) and calcitonin gene-related peptide (CGRP) was studied in pulmonary endocrine cells of the Iberian lizard by immunocytochemistry and in semithin/thin sections under light and electron microscope. Immunostaining of serial sections revealed coexistence of 5HT/CT/CGRP immunoreactivities in some cells, while in others only 5HT/CT or CGRP immunoreactivities were found. Appropriate absorption controls excluded crossreactivity between the antisera used. Ultrastructurally, cells immunoreactive to 5HT/CT and CGRP share similar features, with round or slightly ovoid secretory granules of mean diameter from 165 to 180 nm. The possible functional significance of the copresence of 5HT, CT and CGRP is discussed.

Effects of inhaled lignocaine and adrenaline on capsaicin-induced cough in humans.

The hypothesis that adrenaline can augment and/or prolong the antitussive effect of nebulised lignocaine was examined. The effect of inhaled lignocaine alone (20 mg) and in combination with adrenaline (400 micrograms) was studied on capsaicin-induced cough in 10 healthy subjects. Cough was significantly reduced between five and 25 minutes by lignocaine. Adrenaline alone had no inhibitory effect and it neither augmented nor prolonged the antitussive effect of lignocaine. The subjective anaesthesia by lignocaine was short lasting (less than 15 minutes) and not altered by adrenaline, suggesting different sensory mechanisms for anaesthesia and cough suppression. Plasma concentrations of lignocaine were low (< 30 ng/ml), not altered by adrenaline, and did not correlate with the local anaesthetic or the antitussive effect. Lignocaine acts locally in the oropharynx and airways and adrenaline does not alter the effect or absorption of nebulised lignocaine on the human respiratory mucosa.

Pretransplant clinicopathological correlation in end-stage primary pulmonary hypertension

The aim of the study was to see if there was any correlation between the histopathology, ultrastructure, pulmonary endocrinology and clinical manifestations of end-stage primary pulmonary hypertension. Twenty patients undergoing heart-lung transplantation for the disease were studied. The nature and duration of symptoms and signs, results of haematological, electrocardiographic, radiographic, echocardiographic and haemodynamic studies, and the response of patients to vasodilators were compared with data from histopathological and ultrastructural study of lungs removed at transplantation. Length of clinical history and clinical evidence of severe disease were not necessarily associated with advanced histopathology, nor did the presence of small, contracted muscular pulmonary arteries imply responsiveness to vasodilators. Numbers of gastrin-releasing peptide-containing pulmonary endocrine cells were greater in lungs in which there was activity of myofibroblasts in pulmonary arterial vessels, and correlated negatively with mean pulmonary artery pressure and pulmonary artery systolic pressure. Whereas the prognosis of primary pulmonary hypertension cannot as yet be defined by other than its clinical manifestations, intimal proliferation as well as vasoconstriction may be important in its pathogenesis. The release of gastrin-releasing peptide from pulmonary endocrine cells may possibly be involved in this process.