Pulmonary pharmacology最新文献

Summary: The bronchial epithelium produces cytokines that could contribute to inflammatory events in airways. In this study we determined the basal and TNFα stimulated productions of GM-CSF and IL-8 by human bronchial epithelial cells (HBEC) collected from 12 control and six asthmatic patients. Spontaneous and TNFα-induced GM-CSF or IL-8 released levels increased significantly with time. Epithelial cells from asthmatic patients spontaneously released high levels of GM-CSF (24 h), TNFα potentiated GM-CSF and IL-8 release in control subjects and only the IL-8 production in asthmatics. Nedocromil sodium, an antiinflammatory drug, and salbutamol, a beta2-agonist, are commonly used in asthma. They were evaluated on the spontaneous and TNF-induced expression of GM-CSF and IL-8 in cultured bronchial epithelial cells. Nedocromil sodium, at the concentration of 10^-6 M, reduced the TNF-induced increase in GM-CSF but not the IL-8 release. Salbutamol, at the concentration of 10^-6 or 10^-5 M, did not affect the constitutive or stimulated production of both cytokines.

Summary: To determine the role of M1 muscarinic receptors in the response of the pulmonary parenchyma to inhaled methacholine (MCh), 20 mongrel, out-bred puppies, 8-10 weeks of age were challenged following pretreatment with either saline (control), UH-AH37 (a combined M1 & M3 receptor blocker), or pirenzepine (a relatively selective M1 receptor blocker). In addition, eight fox hound-beagle puppies, born and raised in a clean animal house, were studied. Relatively selective doses of pirenzepine produced a dose-dependent shift to the right of the parenchymal dose-response curves (P=0.031), with no effect on the airway dose-response curve (P=0.102). The fox hound-beagle puppies showed less parenchymal response (P<0.0005), but equivalent airway response (P=0.468), to MCh compared with the mongrel puppies. High doses of pirenzepine (10000 μg/kg) and UH-AH37 (3 mg/kg) markedly inhibited both the parenchymal and airway responses to MCh. Data from the present study demonstrate that: (1) while both the airway and pulmonary parenchyma respond to inhaled MCh, the mechanisms by which they respond differ; (2) stimulation of M1 subtype muscarinic receptors are responsible, at least partly, for the parenchymal response; and (3) experimental conditions, such as the breed and housing conditions of animals, may have major influences on the parenchymal response to inhalational challenge tests.

Summary: We have investigated the effects of the neutral endopeptidase inhibitor, SCH 42354, on the vasoreactivity of atrial natriuretic peptide (ANP) in rat isolated pulmonary resistance vessels (PRV) and isolated perfused lungs (IPL). PRV (n=37) were mounted onto the jaws of a myograph and precontracted with PGF_2α (100 μM). Concentration-responses to ANP (0.17 to 340 nM) were determined before and after the addition of SCH 42354 (10, 30 and 100 nM). Each concentration of SCH 42354 caused a significant increase in potency (—log EC₅₀) of ANP in isolated PRV.

Lungs from normoxic rats (n=13) were isolated and perfused with whole blood. An increase in pulmonary artery pressure was achieved by ventilating with an hypoxic gas mixture and concentration-responses obtained by incremental additions of ANP (40 nM to 12 μM), before and after the addition of SCH 42354 (100 nM). SCH 42354 significantly increased the potency (—log EC₅₀) of ANP in the rat IPL. ANP is partly metabolized by NEP. That an inhibitor of NEP increased the potency of ANP in isolated pulmonary vessels, and in isolated perfused whole lungs, suggested that SCH 42354 may be having a local action within the pulmonary vasculature.

Summary: The densities of airway binding sites for Vasoactive intestinal polypeptide (VIP) were determined using ¹²⁵I-labelled VIP (IVIP) and the technique of autoradiography applied to cryostat sections. Tissue studied included: grossly normal airway tissue taken from lungs resected for bronchial carcinoma (Ca; n=11) and lungs removed at transplant from patients with cystic fibrosis (CF; n=7). Lung tissue obtained at post-mortem in cases of fatal asthma (n=3) or lobes resected for bronchiectasis (n=3) were taken as further disease controls. In the Ca controls there was dense IVIP labelling, of alveolar wall, blood vessels, airway epithelium, submucosal glands, and bronchial smooth muscle: labelling of bronchiolar smooth muscle was sparse. In comparison with the Ca controls, IVIP labelling of all tissue structures in CF, with the exception of bronchial smooth muscle, was reduced (P<0.01). The most striking reductions were associated with airway epithelium and alveolar wall. These reductions showed a similar trend in bronchiectasis but did not achieve statistical significance. There was no such change in lung tissue obtained from the cases of fatal asthma where labelling of bronchial smooth muscle and all other structures was similar to that of the Ca controls. It is likely that the reduction of VIP binding sites in CF is secondary to infection and inflammation.

Summary: The current treatment of airway obstruction using β-agonists and theophylline is designed to increase intracellular level of cAMP. Experimental data show that cGMP and cAMP induce functionally additive relaxation of airways. Nitrates relax smooth muscle through the activation of guanylate cyclase. We wondered whether an additive effect of nitroglycerin (NTG) on β₂-agonist-induced bronchodilatation was present in asthmatic patients.

To this aim we evaluated the acute bronchodilating effect of inhaled salbutamol (200 μg MDI) in 10 asthmatics, pre-treated with inhaled NTG or placebo, in a double-blind cross-over design. FEV₁ after NTG was higher than that obtained after placebo (2197±175 vs. 1981±155 ml, P<0.001). Mean FEV₁ obtained 5 min after salbutamol was higher when patients were pre-treated with NTG than placebo (2694±217 vs. 2440±228 ml respectively, P<0.001). The bronchodilatation due to salbutamol was identical whether NTG or placebo was inhaled first, respectively at 458±68 and 497±44 ml after 5 min. After 15 min FEV₁ was higher than baseline, but no significant difference was still present between the value observed after pre-treatment with NTG or placebo (2554±235 and 2551±205 ml respectively).

In conclusion, in asthmatics nebulized NTG produces a moderate and short-lasting bronchodilatation, which is additive with that produced by salbutamol.

Summary: Calcium antagonists have been claimed to decrease the pulmonary artery pressure and increase oxygen uptake and cardiac output in patients with chronic obstructive pulmonary disease (COPD). This should tend to decrease the plasma levels of catecholamines. The purpose of the present study was to assess the effects of the vasodilating calcium antagonist, isradipine, on resting and exercise levels of catecholamines in patients with COPD. Eighteen patients with severe respiratory insufficiency (FEV₁ <1.01) were investigated. During maximum exercise, the baseline levels of plasma noradrenaline rose from 2.27 nmol/l (0.41-7.66: mean, range) to 3.86 nmol/l (1.3-12.2) (P=0.0002) and plasma adrenaline rose from 0.39 nmol/l (0.07-1.02) to 0.64 nmol/l (0.07-1.77) (P=0.0001). The patients were randomly allocated to receive either capsules of placebo or capsules of 5 mg of isradipine and were reinvestigated after 2 h and 3 months. There was no significant difference between the two groups concerning the change in plasma catecholamines, neither at rest nor at exhaustion. Furthermore, the increase in catecholamines during exercise in the two groups did not differ from each other, neither before administration of isradipine nor after. In conclusion, a vasodilating calcium antagonist did not alter the resting level or exercise induced increase in plasma catecholamines.

Summary: Cryopreservation has been successfully used in the in vitro study of pharmacological responses of animal tissues and, to a limited extent, of human tissue. In this study, we examined the effect of cryopreservation on reactivity of human bronchus which was stored for a period of up to 3 weeks. Thirty-two bronchial rings were obtained from each of four transplantation donors (four male, aged 32±15 years SD). Eight rings from each patient were studied on day 0 (the day of retrieval) and an additional eight on each of days 7, 14 and 21, after cryopreservation in 1.8 M dimethyl surfoxide in 1 ml foetal bovine serum at -190°C. On day 0, all tissues from all patients contracted in response to either histamine or carbachol or relaxed in response to isoprenaline or levcromakalim. There was no significant difference in the mean T_max or pD₂ values for any agonist on days 7, 14 and 21 when responses were compared with those obtained on day 0. The major change induced by cryopreservation was observed in the response to antigen. Tissues from three of the four donors contracted to the administration of Dermatophagoides pteronyssinus on day 0. However, when tissues from these same donors were studied on days 7, 14 and 21, they did not contract to this antigen. The results of this study indicate that human bronchial tissue may be successfully cryopreserved to maintain contractile and relaxant responses to various agonists. However, the response to antigen in tissues, which on day 0 of study were determined to be sensitized, was not present after cryopreservation.

Summary: Although tamour necrosis factor α (TNFα) may be involved in the pathology of asthma, little is known about its role in mediator release from inflammatory cells in human lung. We investigated whether TNFα induced histamine release from mast cells in human chopped lung tissue and whether it modulated antigen-induced release of histamine and leukotrienes C₄/D₄/E₄ from passively sensitized lung tissue. Spontaneous histamine release in the presence of 1 nM TNFα for up to 4 h at 37°C was not significantly different from spontaneous histamine release alone (6.1±1.3% and 6.1±1.5% of total tissue histamine at 4 h respectively; n=3). Lung tissue was passively sensitized to the house dust mite Dermatophagoides pteronyssinus by incubating it in serum from an atopic volunteer donor for 3 h at 37°C. Treatment of the sensitized lung tissue with 1 nM TNFα for 60 min prior to challenge with a low concentration (1.8 AU) of D. pteronyssinus caused a significant increase in the amount of histamine release induced by the antigen from 0.2±0.6% to 1.9±1.0% of total tissue histamine (P=0.045, n=6). The release of leukotriene C₄/D₄/E₄ induced by the same concentration of antigen was not significantly changed by the TNFα treatment (39.5±9.1 and 55.6±17.7 pg/100 μl supernatant sample respectively; n=6). These results suggest that TNFα may be involved in potentiation of histamine release in allergic asthma, particularly in the presence of low antigen concentrations.

Summary: The role of airway inflammation, induced by weekly antigen challenge, in the airway hyperresponsiveness to vagal (whole and NANC components) nerve stimulation and to neurotransmitters (acetylcholine and selective agonists for tachykinin NK1 and NK2 receptors) has been studied in the guinea-pig. Primarily, the time course (3, 7 and 14 days following the last challenge) of the effects of repeated aerosol antigen challenge on airway inflammation and bronchoalveolar fluid cellular composition was investigated. At 7 days following the last antigen challenge a maximal (as compared to 3 and 14 days) inflammatory response, in terms of a diffuse mild to marked infiltration of eosinophils, neutrophils and lymphocytes, was evident throughout pulmonary tissues. Only at this time some evidence of eosinophilia and neutropenia was detectable in BAL fluids. In these animals there was a normal bronchial responsiveness to iv administration of acetylcholine, selective synthetic agonists for the tachykinin NK2 receptors and capsaicin. On the other hand a remarkable airways hyperresponsiveness to iv administration of selective agonists for tachykinin NK1 receptors, as well as electrical stimulation of the vagal nerves (in presence and in absence of atropine), was detected. As a whole, these data indicate that at the peak of the inflammatory airway response following multiple antigen challenge there is a selective hyperresponsiveness to stimulation of vagal (mainly the non-adrenergic, non-cholinergic component) nerves associated with an increase in tachykinins (NK-1)-mediated bronchospasm.