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PubMed1997

Association of anxiety with perception of histamine induced bronchoconstriction in patients with asthma.

BACKGROUND: The perception of bronchoconstriction varies among patients with asthma and this perception may be related to the covariation of sensory and affective aspects of dyspnoea. A study was performed to evaluate whether there are differences in the perception of histamine induced bronchoconstriction between anxious and non-anxious perceivers and whether anxious perception of bronchoconstriction can be predicted by higher levels of baseline anxiety. METHODS: Seventy eight asthmatic subjects referred for a histamine challenge test undertook baseline measures for anxiety symptomatology and forced expiratory volume in one second (FEV1) followed by perceived breathlessness (Borg scale), anxiety (SUDS), and FEV1 measurement before and during induced bronchoconstriction. Based on the correlation between Borg and SUDS scores, the patients were divided into anxious and non-anxious perceivers. RESULTS: Forty one patients reported no anxiety during the challenge test. The anxious perceivers (n = 20) had higher levels of perceived breathlessness and anxiety at 20% fall in FEV1 and were more accurate in their perception of airways obstruction than non-anxious perceivers (n = 58). However, they did not report higher baseline levels of anxiety symptomatology. CONCLUSIONS: Anxiety experienced during bronchial challenge testing may result from the accurate perception of physiological changes and further direct attention to airways obstruction.

Adult↗

PubMed1991

Thiol modification in H2O2- and thromboxane-induced vaso- and bronchoconstriction in rat perfused lung.

Hydrogen peroxide (H2O2), arachidonic acid (AA), and U-44069, a thromboxane analogue, all induced vaso- and bronchoconstriction in the isolated perfused rat lung. The role of protein sulfhydryl modifications in these processes was investigated. The thiol oxidizing agent diamide inhibited both vaso- and bronchoconstriction induced by H2O2, AA, or U-44069. Diamide had only a marginal effect on glutathione and protein thiol levels and no effect on lung mechanics. The diamide inhibition was reversible, and H2O2-induced vaso- and bronchoconstriction was almost maximal after 10 min of perfusion with buffer. The recovery was more rapid if dithiothreitol, a thiol reducing agent, was used in the buffer. H2O2- and AA-induced vaso- and bronchoconstriction is caused by thromboxane release. Diamide did not influence H2O2- or AA-dependent thromboxane formation, indicating that neither AA release nor AA metabolism to thromboxane is sensitive to thiol oxidation. Thus our results indicate that the site of diamide-induced thiol oxidation is the thromboxane receptor or its signal transduction.

Animals↗

PubMed1991

Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea.

To determine whether the intensity of dyspnea at a given level of respiratory motor output differs between bronchoconstriction and the presence of an external resistance, we compared the sensation of difficulty in breathing during isocapnic voluntary hyperventilation in six normal subjects. An external resistance of 1.9 cmH2O.1-1.s was applied during both inspiration and expiration. To induce bronchoconstriction, histamine aerosol (5 mg/ml) was inhaled until airway resistance (Raw) increased to a level approximately equal to the subject's control Raw plus the added external resistance. To clarify the role of vagal afferents on the genesis of dyspnea during both forms of obstruction to airflow, the effect of airway anesthesia by lidocaine aerosol inhalation was also examined after histamine and during external resistive loading. The sensation of difficulty in breathing was rated at 30-s intervals on a visual analog scale during isocapnic voluntary hyperpnea, in which the subjects were asked to copy an oscilloscope volume trace obtained previously during progressive hypercapnia. Histamine inhalation significantly increased the intensity of the dyspneic sensation over the equivalent external resistive load at the same levels of ventilation and occlusion pressure during voluntary hyperpnea. Inhaled lidocaine decreased the sensation of dyspnea during bronchoconstriction with no change in Raw, but it did not significantly change the sensation during external resistive loading. These results suggest that afferent vagal activity plays a role in the genesis of dyspnea during bronchoconstriction.

Adult↗

PubMed1993

A specific endothelin-1 antagonist blocks inhaled endothelin-1-induced bronchoconstriction in sheep.

In this study we used conscious sheep to compare the relative potencies of inhaled endothelin- (ET) 1 and ET-3 and to determine whether a newly described selective ET-1 receptor antagonist, [diaminopropionic acid1-Asp15]ET-1 ([Dpr1-Asp15]ET-1), when given as an aerosol blocks ET-1-induced bronchoconstriction. Partial concentration-response curves to ET-1 and ET-3 were obtained by measuring the change in pulmonary airflow resistance (RL) after aerosol challenge. Both ET-1 (n = 6) and ET-3 (n = 4) caused concentration-dependent (10(-10)-10(-7) bronchoconstriction, but ET-3 was 400-fold less potent than ET-1. Pretreatment (30 min) with 25 breaths of 5 x 10(-8) M [Dpr1-Asp15]ET-1 caused a 100-fold rightward shift of the ET-1 concentration-response curve. The activity of the ET-1 antagonist (25 breaths of 5 x 10(-8) M) was compared with that of various control peptides (25 breaths of 10(-8) M). ET-1 (50 breaths of 10(-7) M) caused an increase in RL of 133 +/- 33% (SE) over baseline. [Dpr1-Asp15]ET-1 significantly inhibited this response by 54%. No protection was seen with a monocyclic control peptide or a thrombin receptor peptide. There was, however, a small protective effect (38%, P < 0.05) seen with [Dpr1-Asp15]ET-3, a structurally homologous ET-3 antagonist. [Dpr1-Asp15]ET-1 had no effect on carbachol (n = 3) or leukotriene D4-induced bronchoconstriction. Thus inhaled ET-1 and, to a lesser extent, ET-3 cause concentration-dependent bronchoconstriction in conscious sheep.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗

PubMed1994

Effect of clonidine on induced cough and bronchoconstriction in guinea pigs and healthy humans.

We examined the effects of the alpha 2-receptor agonist clonidine, administered orally and by inhalation, on citric acid- and capsaicin-induced reflexes in guinea pigs and healthy human subjects. In groups (n = 8-10) of conscious guinea pigs, oral clonidine (10 and 100 micrograms/kg) was without effects, whereas inhaled clonidine (10-1,000 microM) caused a concentration-dependent inhibition of citric acid-induced cough (coughs during 3 min: control, 6.5 +/- 0.9; 1,000 microM clonidine, 1.7 +/- 1.0; P < 0.05) and reflex bronchoconstriction (time to onset of bronchoconstriction: control, 191 +/- 24 s; 1,000 microM clonidine, 317 +/- 33 s; P < 0.05). The inhibitory effect of inhaled clonidine on both reflexes was completely reversed by pretreatment with yohimbine but not with prazosin. In 12 healthy human volunteers, oral clonidine (150 mg) caused a significant fall in supine and erect systolic blood pressure and a significant increase in drowsiness as measured on a visual analogue scale 1 and 2 h after administration. Despite these effects, oral clonidine had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. In contrast to the effects in guinea pigs, inhaled clonidine (281 microM) had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. These data suggest that peripheral alpha 2-receptors exert an inhibitory effect on sensory neurotransmission in the guinea pig but not in the healthy human airway, indicating an important difference between the two species.

Administration, Inhalation↗

PubMed1997

Hyperpnea-induced bronchoconstriction is dependent on tachykinin-induced cysteinyl leukotriene synthesis.

The purpose of the study was to test the hypothesis that tachykinins mediate hyperpnea-induced induced bronchoconstriction indirectly by triggering cysteinyl leukotriene (LT) synthesis in the airways. Guinea pigs (350-600 g) were anesthetized with xylazine and pentobarbital sodium and received hyperpnea challenge (tidal volume 3.5-4.0 ml, frequency 150 breaths/min) with either humidified isocapnic gas (n = 6) or dry gas (n = 7). Dry gas challenge was performed on animals that received MK-571 (LTD4 antagonist; 2 mg/kg i.v.; n = 5), capsaicin (n = 4), neurokinin (NK) antagonists [NK1 (CP-99994) + NK2 (SR-48968) (1 mg/kg i.v.); n = 6], or the H1 antihistamine pyrilamine (2 mg/kg i.v.; n = 5). We measured the tracheal pressure and collected bile for 1 h before and 2 h after hyperpnea challenge. We examined the biliary excretion of cysteinyl LTs; the recovery of radioactivity in bile after instillation of 1 microCi [3H]LTC4 intratracheally averaged 24% within 4 h (n = 2). The major cysteinyl LT identified was LTD4 (32% recovery of radioactivity). Cysteinyl LTs were purified from bile of animals undergoing hyperpnea challenge by using reverse-phase high-pressure liquid chromatography and quantified by radioimmunoassay. There was a significant increase in the peak value of tracheal pressure after challenge, indicating bronchoconstriction in dry gas-challenged animals but not after humidified gas challenge. MK-571, capsaicin, and NK antagonists prevented the bronchoconstriction; pyrilamine did not. Cysteinyl LT levels in the bile after challenge were significantly increased from baseline in dry gas-challenged animals (P < 0.05) and were higher than in the animals challenged with humidified gas or dry gas-challenged animals treated with capsaicin or NK antagonists (P < 0.01). The results indicate that isocapnic dry gas hyperpnea-induced bronchoconstriction is LT mediated and the role of tachykinins in the response is indirect through release of LTs. Endogenous histamine does not contribute to the response.

Animals↗

PubMed1997

Adenosine modulates endothelin-induced bronchoconstriction in guinea pig airway.

The present study was designed to determine whether endogenous and exogenous adenosine modulates endothelin (ET)-induced bronchoconstriction. Exogenous adenosine enhances ET-induced bronchoconstriction. Following pretreatment with adenosine deaminase and theophylline to eliminate or antagonize endogenous adenosine, ET-1-induced bronchoconstriction was significantly attenuated, but not that of ET-3. In conclusion, this is the first report of an enhancement of ET-induced bronchoconstriction of guinea pig airways by endogenous and exogenous adenosine. Our findings may be useful in designing specific adenosine receptor antagonists as therapeutic agents in the management of bronchial asthma.

Acetylcholine↗

PubMed1995

Genetic susceptibility to atracurium-induced bronchoconstriction.

The goal of this study was to develop a murine model of atracurium-induced bronchoconstriction in which to evaluate the mechanism of action of this airway response. We evaluated nine inbred strains of mice for the development of atracurium-induced bronchoconstriction. The maximal difference in the magnitude of the airway response to atracurium noted between the highly responsive DBA/2 mice and the minimally responsive SJL mice was greater than 20-fold. This phenotype appears to reflect an intrinsic difference in the lungs of these animals because the extent of neuromuscular blockade was not significantly different in DBA/2 and SJL mice. Atracurium-induced airway hyperresponsiveness in DBA/2 mice was eliminated in a dose-dependent manner by pretreatment with atropine or pancuronium. These data are consistent with a postganglionic vagal efferent mechanism which produces a differential pulmonary response to this neuromuscular blocker. A genetic predisposition to atracurium-induced bronchoconstriction appears to exist in certain inbred strains of mice. Thus, a mouse model may be useful for mapping the gene(s) that control this trait and for suggesting responsible candidate genes. Our results suggest that the inbred laboratory mouse will be useful to study the mechanism by which atracurium produces bronchoconstriction.

Animals↗

PubMed1996

Detection of excessive bronchoconstriction in asthma.

Airway hyperresponsiveness is easily assessed by measuring the concentration or dose of an inhaled agonist that produces a defined response, e.g., PC20 or PD20. However, this measure does not assess excessive bronchoconstriction. We report the results of analyzing bronchial dose-response curves by measuring percent fall in vital capacity (delta FVC%) as the response rather than the PC20. In our analysis, delta FVC% was measured at the PC20, and therefore it was the dependent variable, whereas the concentration of agonist was the independent variable, in contrast to the usual bronchoprovocation tests in which the response is the independent variable and the dose is the dependent variable. We reasoned that a dose-dependent increase in gas trapping with histamine would detect excessive bronchoconstriction as a decrease in FVC; in contrast, PC20 measures only the ease of bronchoconstriction. In 10 patients with mild asthma the reproducibility of delta FVC% when FEV1 fell by 20%, i.e., at the PC20 concentration of histamine, taken from a greater than 6-s FVC on an otherwise standard histamine challenge test was comparable to that of PC20. In 10 healthy asymptomatic subjects there were only trivial falls (0.3%) in FVC to as much as 16 mg/ml histamine. In a retrospective study of 146 patients with mild asthma, the delta FVC% was normally distributed (13.2 +/- 5.5 SD%) and did not correlate with the number of beta 2-agonist prescriptions or the PC20, but it did correlate with the number of prescriptions written per month for oral prednisone (r = 0.55, p < 0.02). We conclude that delta FVC% when FEV1 falls by 20% is a safe method of detecting excessive bronchoconstriction, and it reveals that different asthmatics react in fundamentally different ways to the same agonist. This may be useful in detecting the asthmatic at risk for serious disease.

Adult↗

PubMed1996

The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics.

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.

Administration, Inhalation↗

PubMed1996

Inhaled tryptase causes bronchoconstriction in sheep via histamine release.

Allergen-induced bronchoconstriction involves mast cell activation. Tryptase is a mast cell serine protease that is released during this process, but little is known about the action of tryptase in the airway. The purpose of this study was to determine: (1) if aerosolized tryptase causes bronchoconstriction, and (2) the mechanism by which this occurs. We measured mean pulmonary flow resistance (RL) in five allergic sheep before and after consecutive inhalations of 100 and 500 ng tryptase (in 2 ml total volume). Inhaled tryptase at 100 and 500 ng increased RL (mean +/- SE) by 33 +/- 12 and 122 +/- 8% (p < 0.05) over baseline. The response was reproducible upon repeat challenges. These studies were repeated in the same animals after pretreatment with aerosolized APC 366 (9 mg/3 ml), a specific tryptase inhibitor. In APC-366-treated sheep, tryptase increased RL by 10 +/- 3 and 6 +/- 2% (p < 0.05 versus control values) at 100 and 500 ng, respectively. The response to tryptase was also blocked by pretreating the sheep intravenously with the histamine H1-antagonist chlorpheniramine (2 mg/kg), in which RL increased only 5 +/- 4 and 7 +/- 6% after 100 and 500 ng tryptase. APC 366, however, did not block histamine-induced bronchoconstriction. Consistent with these findings was the observation that segmental bronchial challenge with tryptase (1 microgram) resulted in a significant increase in histamine levels in bronchoalveolar lavage. Inhaled tryptase (500 ng) also caused airway hyperresponsiveness to aerosolized carbachol 2 h after tryptase challenge. This tryptase-induced airway hyperresponsiveness could be blocked either by pretreating the sheep with APC 366 (30 min before challenge) or by treating the sheep 30 min after challenge. These results indicate that inhaled tryptase causes bronchoconstriction and airway hyperresponsiveness in allergic sheep by an event that may involve mast cell activation.

Administration, Inhalation↗

PubMed1997

The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects.

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.

Adenosine↗

PubMed1997

Endothelin-1-induced bronchoconstriction in asthma.

Endothelin-1 (ET-1) has been indirectly implicated in the pathophysiology of asthma, and it is a potent bronchoconstrictor both in vitro and by inhalation in animal models in vivo. We examined the effect of inhaled ET-1 on airway tone in comparison with methacholine in eight asthmatics and five healthy volunteers in a double-blind randomized fashion. After a screening methacholine challenge each asthmatic had two ET-1 (doubling dose range, 0.96 to 15.36 nmol) and one methacholine (doubling dose range, 0.33 to 21.0 mumol) challenge, and normal subjects had a single ET-1 challenge. Inhalations were delivered using a dosimeter, and lung function measurements were made using constant-volume body plethysmography, with end points being a 35% fall in specific airway conductance (SGaw) and a 15% fall in FEV1. Samples for plasma ET-1 were taken before and after the inhalations, and pulse, blood pressure and oxygen saturation were monitored throughout the inhalations. All the asthmatic subjects displayed rapid-onset (< 5 min) dose-dependent bronchoconstriction to ET-1 across the dose range used, with mean (range) ET-1 PC35SGaw values of 5.15 (1.4 to 13.9) nmol, and 4.3 (1.2 to 8.3) nmol for the two ET-1 inhalations, and 0.42 (0.2 to 0.7) mumol for methacholine. Albuterol completely and rapidly reversed ET-1-induced bronchoconstriction, and in two patients not given albuterol, bronchoconstriction lasted 60 to 90 min. No significant bronchoconstriction was observed in any of the healthy volunteers across the ET-1 dose range used (mean PC35SGaw > 15.36 nmol). Oxygen saturation did not alter in either group, and plasma ET-1 did not change after ET-1 inhalation. Noninvasive blood pressure measurements revealed a fall in systolic blood pressure in normal subjects, with no change in asthmatics. Endothelin-1 is a potent bronchoconstrictor in asthma, with a bronchoconstrictor potency around 100 times that of methacholine in asthma. Asthmatics exhibit bronchial hyperreactivity to ET-1, and inhaled ET-1 can safely be given to asthmatics and normal subjects in the nebulized dose range 0.96 to 15.36 nmol.

Adult↗

PubMed1997

Eosinophilic leukocyte accumulation during vagally induced bronchoconstriction.

Eosinophilic leukocytes (eosinophils) are important effector cells in allergic inflammatory diseases such as asthma, in which significant accumulation of these cells is observed in the bronchial mucosa. However, there is little information about the relationships between bronchoconstriction and accumulation of eosinophils. We hypothesized that eosinophils are retained in the bronchial vasculature in the inner airway wall during bronchoconstriction because of deformation of the mucosal membrane. To test this hypothesis we induced unilateral bronchoconstriction in open chest guinea pigs by stimulating the right vagus nerve and compared the accumulation of eosinophils in the airway wall of the constricted and contralateral unconstricted lungs using histologic specimens. Results show that the density of eosinophils (number of cells/wall area) significantly increased in the inner wall and decreased in the adventitia of the constricted airways compared with the contralateral unconstricted airways. There was a positive relationship between the amount of smooth muscle shortening and the eosinophil density in the inner wall. On the other hand, this relationship was significantly negative in the adventitia. Atropine completely inhibited the eosinophil accumulation in the inner wall. These data suggest that eosinophils can accumulate in the airway inner wall during bronchoconstriction because of geometrical factors.

Animals↗

PubMed1997

The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma.

Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV1 < or = 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of < or = 4 ppm (PC8SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC8SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC8SRaw was significantly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC8SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO2-induced bronchoconstriction. We conclude that S02-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.

Adult↗

PubMed1998

Endogenous nitric oxide inhibits bronchoconstriction induced by cold-air inhalation in guinea pigs: role of kinins.

Inhalation of cold air in guinea pigs increases total pulmonary resistance (RL), an effect that is mediated by kinins and tachykinins. Bronchoconstriction induced by bradykinin (BK) inhalation in guinea pigs is markedly inhibited by nitric oxide (NO) release from the airway epithelium. We investigated whether endogenous NO modulates the increase in RL induced by inhalation of cold air. In anesthetized and artificially ventilated guinea pigs pretreated with atropine, cold-air inhalation (13 degrees C in the trachea) for 5 min did not increase RL. Pretreatment with intravenous N(G)-nitro-L-arginine methyl ester (L-NAME) (but not with its inactive enantiomer, D-NAME) increased RL, an effect reversed by L-Arg. The increase in RL induced by cold air after L-NAME was abolished by the tachykinin NK2-receptor antagonist SR 48968 or the kinin B2-receptor antagonist, HOE 140. After administration of SR 48968, inhalation of cold air reduced baseline airway tone. However, after HOE 140, cold-air inhalation did not affect baseline airway tone. L-NAME exaggerated the bronchoconstriction induced by BK. However, L-NAME did not affect capsaicin-induced bronchoconstriction. BK increased cyclic guanosine monophosphate (cGMP) levels in strips of guinea pig trachealis muscle in vitro, whereas the selective tachykinin NK2-receptor agonist [betaAla8]neurokinin A (4-10) was without effect. The present data suggest that bronchoconstriction induced by cold-air inhalation and mediated by kinin and tachykinin release is inhibited by endogenous NO, and that kinins, but not tachykinins or cold air alone, release bronchorelaxant NO.

Air↗

PubMed2001

Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil- and cyclooxygenase 2-dependent mechanism.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used to ameliorate neutropenia in patients after antineoplastic treatment. It has also been suggested as an adjunct treatment in septic patients; however, the recruitment and priming of leukocytes by GM-CSF bears the hazard of a hyperinflammatory response. In particular, the role of GM-CSF in pulmonary functions in septic lungs is still unclear. Therefore, we pretreated rats in vivo with GM-CSF (50 microg/kg, intravenous) and assessed the pulmonary functions of their subsequently prepared isolated perfused lungs when exposed to subtoxic concentrations of lipopolysaccharide (LPS, 2 microg/ml). These lungs showed enhanced expression of cyclooxygenase 2 (COX-2), a significant increase in thromboxane (TX) and tumor necrosis factor (TNF) release into the venous perfusate, and bronchoconstriction. COX-2 inhibition or blocking of the TX receptor abolished the GM-CSF/LPS-induced bronchoconstriction, but not the TNF release. Neutralizing antibodies against TNF did not prevent GM-CSF/LPS-induced bronchoconstriction. After GM-CSF pretreatment, massive neutrophil invasion into the lung occurred. Neutropenic rats were protected against GM-CSF/ LPS-induced lung injury. Similar results were obtained in rats pretreated with G-CSF instead of GM-CSF. We conclude that GM-CSF pretreatment exacerbates pulmonary injury by low-dose LPS via COX-2 expression, TX release, and bronchoconstriction by initiating neutrophil invasion and activation.

Animals↗

PubMed2001

Hyaluronic acid blocks porcine pancreatic elastase (PPE)-induced bronchoconstriction in sheep.

We previously showed that inhaled porcine pancreatic elastase (PPE) causes bronchoconstriction in sheep via a bradykinin-mediated mechanism. Hyaluronic acid (HA), in vitro, binds and inactivates airway tissue kallikrein (TK), the enzyme responsible for kinin generation. Therefore, we hypothesized that in vivo, HA should prevent PPE-induced bronchoconstriction by binding and inactivating TK. To test this, we measured pulmonary resistance (RL) in allergic sheep before and after inhalation of PPE alone (500 microg) and after pretreatment with either inhaled HA at 70 kD, designated low molecular weight (LMW)-HA or 200 kD, designated high molecular weight (HMW)-HA at different concentrations. Inhaled PPE increased RL 147 +/- 8% over baseline values and this effect was associated with a 111 +/- 28% increase in bronchoalveolar lavage fluid (BALF) TK activity. HA blocked the PPE-induced bronchoconstriction and the increase in BALF TK activity in a dose- dependent and molecular weight-dependent fashion. HA alone had no effect on RL. Instillation of PPE in the lung increased kinin concentrations in BALF, a result consistent with the PPE-induced increase in BALF TK activity. Our findings show that HA blocks PPE-induced bronchoconstriction in a dose-dependent and molecular weight-dependent fashion by a mechanism that may, in part, be related to inhibition of TK activity and the formation of kinins.

Adjuvants, Immunologic↗