Characterization of airway and vascular responses in murine lungs.
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1. We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. 2. Airways: The EC50 (microM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml(-1), respectively. Adenosine (< or =1 mM), bombesin (< or =100 microM), histamine (< or =10 mM), LTC4 (< or =1 microM), PAF (0.25 microM) and substance P (< or =100 microM) had only weak effects (<5% of Mch) on RL. 3. Vessels: The EC50 (microM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05+info)
Osmotic regulation of airway reactivity by epithelium.
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Inhalation of nonisotonic solutions can elicit pulmonary obstruction in asthmatic airways. We evaluated the hypothesis that the respiratory epithelium is involved in responses of the airways to nonisotonic solutions using the guinea pig isolated, perfused trachea preparation to restrict applied agents to the mucosal (intraluminal) or serosal (extraluminal) surface of the airway. In methacholine-contracted tracheae, intraluminally applied NaCl or KCl equipotently caused relaxation that was unaffected by the cyclo-oxygenase inhibitor, indomethacin, but was attenuated by removal of the epithelium and Na+ and Cl- channel blockers. Na+-K+-2Cl- cotransporter and nitric oxide synthase blockers caused a slight inhibition of relaxation, whereas Na+,K+-pump inhibition produced a small potentiation. Intraluminal hyperosmolar KCl and NaCl inhibited contractions in response to intra- or extraluminally applied methacholine, as well as neurogenic cholinergic contractions elicited with electric field stimulation (+/- indomethacin). Extraluminally applied NaCl and KCl elicited epithelium-dependent relaxation (which for KCl was followed by contraction). In contrast to the effects of hyperosmolarity, intraluminal hypo-osmolarity caused papaverine-inhibitable contractions (+/- epithelium). These findings suggest that the epithelium is an osmotic sensor which, through the release of epithelium-derived relaxing factor, can regulate airway diameter by modulating smooth muscle responsiveness and excitatory neurotransmission. (+info)
Changes in smooth muscle tone during osmotic challenge in relation to epithelial bioelectric events in guinea pig isolated trachea.
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The relationship between epithelial bioelectric events and epithelium-dependent relaxant and contractile responses of airway smooth muscle in response to hyperosmolar and hypo-osmolar solutions was investigated in guinea pig isolated trachea. Tracheae were perfused with normal or nonisosmotic modified Krebs-Henseleit solution while simultaneously monitoring transepithelial potential difference (VT) and contractile and relaxant responses of the muscle. Baseline VT was -10.1 to -13.3 mV (distal and proximal ends, respectively). Intraluminal amiloride (10(-4) M) induced a 3.7-mV depolarization, verifying that the VT was of epithelial origin. Extraluminal methacholine (3 x 10(-7) M; EC50) caused hyperpolarization and smooth muscle contraction; intraluminal methacholine had very little effect. Increasing intraluminal bath osmolarity via addition of 240 mOsM NaCl or KCl caused an immediate and prolonged depolarization and epithelium-dependent relaxation. Increasing intraluminal bath osmolarity with sucrose evoked similar responses, except that an immediate, transient hyperpolarization and contraction preceded the depolarization and relaxation. Increasing extraluminal bath osmolarity with 240 mOsM NaCl induced depolarization and a longer lasting epithelium-dependent relaxation, whereas extraluminally added 240 mOsM KCl induced a complex smooth muscle response (i.e., transient relaxation followed by contraction), which was accompanied by prolonged depolarization. Intraluminal hypo-osmolarity produced a transient hyperpolarization followed by depolarization along with contraction of the smooth muscle. Bioelectric responses always preceded smooth muscle responses. These results suggest that bioelectric events in the epithelium triggered by nonisosmotic solutions are associated with epithelium-dependent responses in tracheal smooth muscle. (+info)
Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats.
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BACKGROUND: It has previously been shown that M1 cholinergic receptors are involved in the parenchymal response to inhaled methacholine in puppies using the M1 selective antagonist pirenzepine. Although M3 receptors are responsible for acetylcholine induced bronchoconstriction in isolated rat lung, the role of M1 receptors has not been determined in the rat in vivo. METHODS: Anaesthetised, paralysed, open chested Brown Norway rats were mechanically ventilated and the femoral vein cannulated for intravenous injection of drugs. Low frequency forced oscillations were applied to measure lung input impedance (ZL) and computerised modelling enabled separation of ZL into airway and parenchymal components. Atropine (500 microg/kg iv) and pirenzepine (50, 100 or 200 microg/kg iv) were administered during steady state constriction generated by continuous inhalation (1 mg/ml) or intravenous (10 or 15 microg/kg/min) administration of methacholine. RESULTS: Continuous inhalation of methacholine produced a 185% increase in frequency dependent tissue resistance (G) which was effectively inhibited by atropine 500 microg/kg iv (p<0.01, n = 6). Pirenzepine (50, 100 or 200 microg/kg) had a minimal effect on the parenchymal response to inhaled methacholine. A 258% increase in airway resistance (Raw) was induced by continuous intravenous infusion of methacholine and this response was effectively abolished by pirenzepine (p<0.001, n = 5). Cutting the vagi in the cervical region did not alter baseline airway mechanics. Vagotomy did not affect lung responses to intravenous methacholine nor the ability of pirenzepine to reduce these responses. CONCLUSIONS: In the rat, M1-subtype receptors are functional in airways but not in the tissue. (+info)
Effect of methacholine challenge on cellular composition of sputum induction.
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BACKGROUND: Induced sputum and methacholine inhalation challenge are routinely used for the assessment of airway inflammation and airway hyperresponsiveness, respectively. This study investigates whether a methacholine challenge performed one hour before sputum induction alters the cellular and biochemical constituents of sputum. METHODS: Sixteen stable asthmatic patients with lung function within the normal range underwent two sputum inductions within one week. One hour before one of the sputum inductions a methacholine challenge was performed. RESULTS: There were no significant differences in total cell count, macrophages, neutrophils, eosinophils, lymphocytes, epithelial cells, ECP, and albumin between the two challenges. The repeatability of cell counts was good for all cells, ECP and albumin, but poor for total cells. CONCLUSIONS: In patients with stable asthma a methacholine challenge carried out one hour before sputum induction does not significantly alter the cellular and biochemical constituents of sputum. (+info)
Cough threshold in patients with chronic obstructive pulmonary disease.
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BACKGROUND: Cough is an important symptom of patients with chronic obstructive pulmonary disease (COPD). The cough threshold to citric acid and capsaicin in patients with COPD and in normal volunteers was measured, as well as bronchial hyperresponsiveness to methacholine. METHODS: Nineteen patients with COPD and 22 controls were recruited. Subjects underwent a methacholine bronchoprovocation test and a cough challenge to citric acid and capsaicin. RESULTS: The log citric acid cough threshold D2 (concentration causing two coughs) was significantly lower in patients with COPD (mean 2.17 versus 2.56, mean difference (95% CI) 0.39 (0.04 to 0.74), p = 0.02) but not for capsaicin cough D2 (0.66 versus 0.8, p = 0.41). Sixteen patients with COPD had bronchial hyperresponsiveness which was correlated with baseline FEV1 (r = 0.6, p = 0.01, 95% CI 0.15 to 0.84). CONCLUSIONS: Patients with COPD have a lower cough threshold to citric acid, possibly due to a differential effect of cigarette smoke on citric acid sensitive cough receptors. (+info)
Shifts in lung lymphocyte profiles correlate with the sequential development of acute allergic and chronic tolerant stages in a murine asthma model.
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T lymphocytes have a central regulatory role in the pathogenesis of asthma. We delineated the participation of lymphocytes in the acute allergic and chronic tolerant stages of a murine model of asthma by characterizing the various subsets of lymphocytes in bronchoalveolar lavage and lung tissue associated with these responses. Acute (10-day) aerosol challenge of immunized C57BL/6J mice with ovalbumin resulted in airway eosinophilia, histological evidence of peribronchial and perivascular airway inflammation, clusters of B cells and TCRgammadelta cells in lung tissue, increased serum IgE levels, and airway hyperresponsiveness to methacholine. In mice subjected to chronic (6-week) aerosol challenge with ovalbumin, airway inflammation and serum IgE levels were significantly attenuated and airway hyperresponsiveness was absent. The marked increases in lung B and T cell populations seen in the acute stage were also significantly reduced in the chronic stage of this model. Thus, acute ovalbumin challenge resulted in airway sensitization characteristic of asthma, whereas chronic ovalbumin challenge elicited a suppressed or tolerant state. The transition from antigenic sensitization to tolerance was accompanied by shifts in lymphocyte profiles in the lung and bronchoalveolar lavage fluid. (+info)
Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation.
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We determined the dose-response curves to inhaled methacholine (MCh) in 16 asthmatic and 8 healthy subjects with prohibition of deep inhalations (DIs) and with 5 DIs taken after each MCh dose. Flow was measured on partial expiratory flow-volume curves at an absolute lung volume (plethysmographically determined) equal to 25% of control forced vital capacity (FVC). Airway inflammation was assessed in asthmatic subjects by analysis of induced sputum. Even when DIs were prohibited, the dose of MCh causing a 50% decrease in forced partial flow at 25% of control FVC (PD(50)MCh) was lower in asthmatic than in healthy subjects (P < 0.0001). In healthy but not in asthmatic subjects, repeated DIs significantly decreased the maximum response to MCh [from 90 +/- 4 to 62 +/- 8 (SD) % of control, P < 0.001], increased PD(50)MCh (P < 0.005), without affecting the dose causing 50% of maximal response. In asthmatic subjects, neither PD(50)MCh when DIs were prohibited nor changes in PD(50)MCh induced by DIs were significantly correlated with inflammatory cell numbers or percentages in sputum. We conclude that 1) even when DIs are prohibited, the responsiveness to MCh is greater in asthmatic than in healthy subjects; 2) repeated DIs reduce airway responsiveness in healthy but not in asthmatic subjects; and 3) neither airway hyperresponsiveness nor the inability of DIs to relax constricted airways in asthmatic subjects is related to the presence of inflammatory cells in the airways. (+info)