Both inhaled histamine and hypertonic saline increase airway reactivity in non-sensitised rabbits.
(25/896)
BACKGROUND: Asthmatics react with bronchoconstriction upon a variety of stimuli, i.e. exercise and hypertonic aerosol challenge. We have previously shown that hyperventilation with dry gas in a rabbit model resulted in a change of the ion content of the tracheal wall. This was followed by a hyperreactive response to histamine. OBJECTIVE: We hypothesised that nebulisation with 3.6% hypertonic saline will be accompanied by a hyperreactive response to histamine in a rabbit model. METHODS: Anaesthetised rabbits were given histamine after nebulisation with hypertonic saline. In addition, repeat nebulisation with hypertonic saline was given with or without histamine between these nebulisations. RESULTS: There was a different response to histamine 10 mg x ml(-1) whether hypertonic saline had been given or not (p < 0.001). Histamine nebulisation, given after hypertonic saline, caused an increase from baseline in resistance of 65 +/- 12 cm H(2)O.litre(-1) x s (mean +/- SEM, p < 0. 001) and a decrease in compliance of 2.3 +/- 0.4 ml x cm H(2)O(-1) (p < 0.001). The corresponding values for the control animals were 10 +/- 4 cm H(2)O.litre(-1) x s (n.s.) and 1.7 +/- 0.2 ml x cm H(2)O(-1) (p < 0.001). At a second nebulisation with hypertonic saline, with a histamine challenge 30 min before, the resistance increased from baseline by 35 +/- 10 cm H(2)O x litre(-1) x s (p < 0.01). This was not observed when no histamine had been given between the hypertonic saline nebulisations. CONCLUSIONS: This study in rabbits shows that hypertonic solutions cause an increase in the responsiveness to histamine and that histamine causes an increase in responsiveness to hypertonic saline. This is similar to the response of asthmatics to hypertonic saline. (+info)
Increased airway responsiveness to acetaldehyde in asthmatic subjects with alcohol-induced bronchoconstriction.
(26/896)
Bronchial responsiveness to acetaldehyde, a main factor in alcohol-induced bronchoconstriction, and methacholine were compared between 10 subjects with alcohol-induced bronchoconstriction and 16 asthmatic subjects without alcohol sensitivity. In the alcohol-sensitive group, the geometric mean (geometric SEM (GSEM)) of the provocative concentration of methacholine (PC20,meth) and acetaldehyde (PC20,acet) causing a 20% fall in forced expiratory volume in one second were 0.947 mg x mL(-1) (GSEM 0.139) and 21.0 mg x mL(-1) (GSEM 0.112), respectively, which were not significantly different from those in the nonalcohol-sensitive group, which were 0.634 mg x mL(-1) (GSEM 0.115) and 31.7 mg x mL(-1) (GSEM 0.077), respectively. The ratio of airway responsiveness to acetaldehyde relative to methacholine (log PC20,acet/PC20,meth) was 1.345+/-0.093 (mean+/-SEM) in the alcohol-sensitive group, which was significantly different from the value of 1.699+/-0.059 in the nonalcohol-sensitive group (p=0.0025). A significant correlation was observed between PC20,meth and PC20,acet in both the alcohol-sensitive group (r=-0.742, p=0.0115) and nonsensitive group (r=0.882, p<0.0001). In conclusion, the airways of asthmatic subjects with alcohol-induced bronchoconstriction have a selective hyperresponsiveness to acetaldehyde. (+info)
Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study.
(27/896)
The aim of the study was to assess the potential role of glucocorticoids (GC) in modulating systemic and pulmonary inflammatory responses in mechanically ventilated patients with severe pneumonia. Twenty mechanically ventilated patients with pneumonia treated at a respiratory intensive care unit (RICU) of a 1,000-bed teaching hospital were prospectively studied. All patients had received prior antimicrobial treatment. Eleven patients received GC (mean+/-SD dose of i.v. methylprednisolone 677+/-508 mg for 9+/-7 days), mainly for bronchial dilatation. Serum and bronchoalveolar lavage fluid (BALF) tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and C-reactive protein levels were measured in all patients. The inflammatory response was attenuated in patients receiving GC, both systemically (IL-6 1,089+/-342 versus 630+/-385 pg x mL(-1), p=0.03; C-reactive protein 34+/-5 versus 19+/-5 mg x L(-1), p=0.04) and locally in BALF (TNF-alpha 118+/-50 versus 24+/-5 pg x mL(-1), p= 0.05; neutrophil count: 2.4+/-1.1 x 10(9) cells x L(-1) (93+/-3%) versus 1.9+/-1.8 x 10(9) cells x L(-1) (57+/-16%), p=0.03). Four of the 11 (36%) patients receiving GC died compared to six (67%) who were not receiving GC (p=0.37). The present pilot study suggests that glucocorticoids decrease systemic and lung inflammatory responses in mechanically ventilated patients with severe pneumonia receiving antimicrobial treatment. (+info)
Tolerance to beta-agonists during acute bronchoconstriction.
(28/896)
Previous reports suggest that regular use of beta-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction. Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 microg, b.i.d.), both drugs or placebo in a randomized, double-blind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 microg at 5 min intervals) was then measured. Dose-response curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates. There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide. Significant tolerance to the bronchodilator effect of inhaled beta-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled beta-agonists may lead to a reduced response to emergency beta-agonist treatment during asthma exacerbations. (+info)
Dynamic hyperinflation and flow limitation during methacholine-induced bronchoconstriction in asthma.
(29/896)
Although persistent activation of the inspiratory muscles and narrowing of the glottic aperture during expiration have been indicated as relevant mechanisms leading to dynamic hyperinflation in acute asthma, expiratory flow limitation (EFL) has recently been proposed as a possible triggering factor for increasing endexpiratory lung volume (EELV). To establish whether the attainment of maximal flow rate during tidal expiration could elicit dynamic elevation of EELV, breathing pattern, change in EELV by measuring inspiratory capacity (IC) and occurrence of EFL by the negative expiratory pressure (NEP) method were monitored in 10 stable asthmatic subjects during methacholine-induced, progressive bronchoconstriction in seated position. Change in dyspnoea was scored using the Borg scale. At maximum response forced expiratory volume in one second (FEV1) fell on average by 45+/-2% (p<0.001 versus control), while IC decreased 29+/-2%, (by 0.89+/-0.07 L, (p<0.01 versus control)). Only 2 subjects exhibited EFL at the end of methacholine challenge. In 7 subjects EELV started to increase before the occurrence of EFL. Dyspnoea, which increased from 0.2+/-0.1 to 5.5+/-1.0 (Borg scale) at maximum response (p<0.001), was significantly related to the level of bronchoconstriction as assessed by change in (delta)FEV1 (r=0.72; p<0.001) and to dynamic hyperinflation as measured by deltaIC (r=0.50; p<0.001). However, for both deltaFEV1 and deltaIC the slope of the relationship with increasing dyspnoea was highly variable among the subjects. It is concluded that in acute methacholine-induced bronchoconstriction, dynamic hyperinflation may occur in the absence of expiratory flow limitation and that expiratory flow limitation does not represent the triggering factor to generate dynamic hyperinflation. In these circumstances, dyspnoea appears to be related to the increase in end-expiratory lung volume and not to the onset of expiratory flow limitation. (+info)
Passive sensitization of human airways increases responsiveness to leukotriene C4.
(30/896)
Passive sensitization of human airways in vitro causes increased responsiveness to histamine and induces specific immunoglobulin (Ig)E-dependent contractile responsiveness to allergen. Leukotrienes (LTs) and, to a lesser extent, histamine are the major mediators of allergen-induced contraction. Since it is unclear whether passively sensitized airways are also hyperresponsive to cysteinyl leukotrienes, this study investigated the effect of passive sensitization on LTC4-, in addition to histamine- and allergen-induced contractions in vitro. Bronchial rings from nine nonatopic patients were sensitized overnight with serum containing high levels of total IgE (>250 U x mL(-1)) and allergen-specific IgE against Dermatophagoides farinae (fluorescence allergosorbent test) (FAST class > or =3). The potency (-log10 of the mediator concentration causing a half maximal response (pEC50) of histamine was significantly increased in serum-sensitized tissues compared to nonsensitized controls ((mean+/-SEM) pEC50 5.20+/-0.27 versus 5.64+/-0.18; p=0.02) and maximal contractions were enhanced (877+/-47 versus 543+/-51 mg; p<0.0001). Similarly, the potency of LTC4 was significantly increased in sensitized compared to nonsensitized bronchial rings (pEC50 9.37+/-0.20 versus 8.66+/-0.26; p=0.004); maximal contractions were also enhanced (811+/-57 versus 361+/-86 mg; p<0.0001). These data demonstrate that passive sensitization of human airways induces an increase not only in histamine but also in leukotriene responsiveness. Therefore, it might be speculated that allergen responses in sensitized airways are effected through a combination of increased mediator release from inflammatory cells and increased responsiveness of airway smooth muscle. (+info)
Endothelin-1 potentiates cholinergic nerve-mediated contraction in human isolated bronchus.
(31/896)
That endothelin-1(ET-1) plays a mediator role in asthma is consistent with reports of ET-1-induced potentiation of cholinergic nerve-mediated contraction in airways from various animal species. This study examined the effect of ET-1 on cholinergic contractions in human isolated bronchus. Macroscopically nondiseased human bronchial tissue was obtained from 23 patients with respiratory tumours. An electrical field stimulation (EFS) frequency that produced one third of the contraction at 30 Hz (EFS30) was estimated. The effect of ET-1 on these EFS-evoked contractions was assessed. EFS-evoked contractions were frequency-dependent and abolished by either atropine or tetrodotoxin. Thus, EFS-induced contractions were mediated by acetylcholine from cholinergic nerves. ET-1 (3 nM) potentiated EFS-evoked contractions by 10+/-2% EFS30 (p<0.05) without any significant effect on contractions induced by exogenous acetylcholine. Neither the ET(A) receptor-selective antagonist BQ-123 (3 microM) nor the ET(B) receptor-selective antagonist BQ-788 (10 microM) alone significantly altered ET-1-induced potentiation of EFS-evoked contractions. However, in the combined presence of both BQ-123 and BQ-788, ET-1-induced potentiation of EFS-evoked contractions was abolished. Thus, prejunctional endothelinA and endothelinB receptors appear to mediate endothelin-1-induced potentiation of electrical field stimulation-evoked cholinergic contractions in human bronchus. This suggests another potentially important mechanism through which endothelin-1 could increase bronchial tone in asthma. (+info)
Bronchodilation by pituitary adenylate cyclase-activating peptide and related peptides.
(32/896)
Pituitary adenylate cyclase-activating peptide (PACAP) is present in nerves in the vicinity of bronchial and vascular smooth muscle in the airways. At least one endogenous form of PACAP, PACAP 1-27, has high affinity binding sites in the lung, probably including cholinergic nerve terminals, bronchial smooth muscle, epithelial and mononuclear inflammatory cells. The mechanism of action for PACAP 1-27 and 1-38 in vivo involves endogenous catecholamines, peptidases and nitric oxide, depending on tissue type. Intracellularly, cyclic adenosine monophosphate (cAMP) as well as calcium and sodium mobilization is probably involved. PACAP 1-27 and 1-38 inhibit airway smooth muscle tone in vitro and in vivo. The inhibitory effect of PACAP 1-38 is more sustained than that of PACAP 1-27, in vitro as well as in vivo. PACAP 1-38 also causes more sustained inhibition of bronchoconstriction after inhalation in vivo, than does vasoactive intestinal peptide (VIP). PACAP 1-27 given intravenously virtually abolishes allergen-induced bronchoconstriction in vivo. Novel synthetic analogues of PACAP 1-27 cause more sustained inhibition of airway smooth muscle tone in vitro and in vivo than do PACAP 1-27 or 1-38. Both PACAP 1-27 and 1-38 inhibit arterial smooth muscle tone but, administration of PACAP 1-27, 1-38 or a structural analogue of PACAP 1-27 in the airways, induces no cardiovascular side effects at doses inhibiting bronchoconstriction. PACAP 1-38 enhances phagocytosis in macrophages and inhibits the release of the pro-inflammatory cytokine interleukin-2 in lymphocytes, suggesting antiinflammatory effects. It is concluded that pituitary adenylate cyclase-activating peptide 1-27 and 1-38, or structurally related molecules, may be useful as bronchodilators but their effect on human bronchial smooth muscle and on human inflammatory cells is in need of evaluation. (+info)