Histamine-induced Airway Constriction Research Articles

Diammonium glycyrrhizinate inhibits histamine-induced airway smooth muscle cell activation and proliferation by regulating MAPK/FAK signal pathway and MMP-2 activity

Excessive proliferation of airway smooth muscle cells can cause airway problems. Mast cell-derived histamine induces bronchoconstriction. Glycyrrhizic acid is used to relieve COVID-19 airway symptoms from 2020 to now, but the mechanism of action is unknown. Then diammonium glycyrrhizinate is one of the derivatives of glycyrrhizic acid, the effects of diammonium glycyrrhizinate on histamine-induced airway smooth muscle cell proliferation is not discussed yet. This study was to establish a histamine/primary rat airway smooth muscle cell model, to investigate the effects of diammonium glycyrrhizinate on these cells, and to explore the potential mechanism of diammonium glycyrrhizinate in inhibiting histamine-induced airway constriction and deep airway injury. Cell viability and proliferation were assessed; matrix metalloproteinases-2 (MMP-2) activity was examined by gelatin zymography; cell cycle was detected by flow-cytometry, protein expressions of FAK were evaluated by fluorescence-immunocytochemistry; p38, Bcl-2, PCNA and GAPDH were evaluated by western blotting. Data show that diammonium glycyrrhizinate inhibited histamine–induced airway smooth muscle cell proliferation and MMP-2 activity; recovers histamine-induced airway smooth muscle cell cycle disorders, and restores the histamine-regulated intracellular signals. The present study suggests an underlying mechanism that diammonium glycyrrhizinate can relieve the airway symptom of COVID-19 patients by inhibiting histamine-induced over-activation/proliferation and regulating airway smooth muscle cell intracellular signaling pathways. The pharmaceutical potential of diammonium glycyrrhizinate requires attention.

Characteristics of AZD9708, a novel, selective β2-adrenoceptor agonist with rapid onset and long duration of action

Here we describe the pre-clinical pharmacological profile of AZD9708, a novel long-acting β2-adrenoceptor agonist that has potential as a once-daily therapy for asthma and chronic obstructive pulmonary disease (COPD).AZD9708 is a potent and selective agonist at the human β2-adrenoceptor, with selectivity over human β1- and β3-adrenoceptors of >500 and >24 fold, respectively. AZD9708 relaxes carbachol-induced contraction of human bronchial rings with a time to 90% of maximal relaxation of 13–20 min, similar to that seen with formoterol and quicker than salmeterol. In anesthetized guinea pigs, AZD9708 provides significant protection against histamine-induced airway constriction at 24 h after intratracheal and nebulized doses. This is longer than with intratracheal salmeterol, which is bronchoprotective for approximately 8 h, and formoterol, which is bronchoprotective for 8 and 12 h following nebulized and intratracheal dosing, respectively.AZD9708 also shows the potential for a greater therapeutic margin than widely used β2-adrenoceptor agonists such as formoterol. At a defined efficacy dose that provides 80% bronchoprotection (ED80), formoterol leads to a decrease in blood potassium levels in guinea pigs, whilst AZD9708 is not associated with significant reductions in potassium levels at doses up to 7 times the ED80. [14C]AZD9708 is associated with extensive protein binding in both human (mean 1.0% free) and rat (mean 2.6% free) plasma.This pharmacological profile indicates the potential of AZD9708 to become an important addition to the range of bronchodilators available for the treatment of patients with obstructive airways disease.

Effect of airways constriction on exhaled nitric oxide

While airway constriction has been shown to affect exhaled nitric oxide (NO), the mechanisms and location of constricted airways most likely to affect exhaled NO remain obscure. We studied the effects of histamine-induced airway constriction and ventilation heterogeneity on exhaled NO at 50 ml/s (Fe(NO,50)) and combined this with model simulations of Fe(NO,50) changes due to constriction of airways at various depths of the lung model. In 20 normal subjects, histamine induced a 26 +/- 15(SD)% Fe(NO,50) decrease, a 9 +/- 6% forced expiratory volume in 1 s (FEV(1)) decrease, a 19 +/- 9% mean forced midexpiratory flow between 25% and 75% forced vital capacity (FEF(25-75)) decrease, and a 94 +/- 119% increase in conductive ventilation heterogeneity. There was a significant correlation of Fe(NO,50) decrease with FEF(25-75) decrease (P = 0.006) but not with FEV(1) decrease or with increased ventilation heterogeneity. Simulations confirmed the negligible effect of ventilation heterogeneity on Fe(NO,50) and showed that the histamine-induced Fe(NO,50) decrease was due to constriction, with associated reduction in NO flux, of airways located proximal to generation 15. The model also indicated that the most marked effect of airways constriction on Fe(NO,50) is situated in generations 10-15 and that airway constriction beyond generation 15 markedly increases Fe(NO,50) due to interference with the NO backdiffusion effect. These mechanical factors should be considered when interpreting exhaled NO in lung disease.

Prevention of bronchoconstriction by an orally active local anesthetic.

Stimulation of airway irritant receptors produces reflex bronchoconstriction that can be prevented by pretreatment with anticholinergic drugs or local anesthetics delivered by aerosol or intravenously. We compared therapeutic doses of an orally administered local anesthetic, mexiletine hydrochloride, and intravenously administered lidocaine at blocking histamine-induced bronchoconstriction in five basenji-greyhound dogs, using high-resolution computed tomography (HRCT) to directly measure changes in airway size. In the dogs given placebo, a histamine infusion decreased airway area to 61 +/- 2% (mean +/- SEM) of control (p < 0.01). Mexiletine pretreatment completely prevented histamine-induced airway constriction, with an airway area that was 94 +/- 4% of the control value during the histamine infusion (p = 0.07 compared with baseline). Mexiletine serum levels were therapeutic (1.7 +/- 0.3 mg/L). Similarly, pretreatment with lidocaine significantly blunted the airway constriction provoked by intravenous histamine. In lidocaine-pretreated dogs, histamine decreased airway area to 79 +/- 4% of baseline (p < 0.01). As in the case of mexiletine, lidocaine serum levels were also therapeutic (2.4 +/- 0.3 mg/L). Mexiletine was more effective than lidocaine at preventing histamine-induced bronchoconstriction (p = 0.02). These data suggest that orally administered local anesthetics may be useful in preventing irritant-induced bronchoconstriction in humans.

Reversal of bronchoconstriction by inhaled nitric oxide. Histamine versus methacholine.

Using high-resolution CT (HRCT), which measures changes in innervated airways greater than 1 mm in diameter, we compared the ability of nitric oxide (NO) to dilate airways preconstricted with histamine and methacholine in five anesthetized dogs. After the airways were preconstricted, NO was inhaled in concentrations of 100, 200, and 400 ppm. Additionally, histamine was given with and without atropine and methylene blue. Data were analyzed by one-way analysis of variance. Histamine and methacholine decreased airway area to a similar extent: 60 +/- 3% (mean +/- SEM) and 63 +/- 3% of control, respectively (p = 0.85). Atropine completely reversed the histamine-induced constriction (255 +/- 19%). NO also completely reversed histamine-induced airway constriction in a dose-related fashion. The airway area went from 60 +/- 3% during histamine infusion to 85 +/- 5, 102 +/- 5, and 111 +/- 10% of control, respectively (p < 0.01), after doses of 100, 200, and 400 ppm NO. Methylene blue partially inhibited the reversal by 200 ppm NO of histamine-induced constriction. In contrast, NO only partially reversed methacholine-induced constriction. NO at 100, 200, and 400 ppm partially attenuated the methacholine-induced airway constriction. Airway area went from 63 +/- 3 to 67 +/- 3, 75 +/- 3, and 75 +/- 2% of control, respectively (p < 0.01). We conclude that NO relaxes canine conducting airways by indirect mechanisms as well as by directly relaxing the airway smooth muscle.

Airway Dimensions During Histamine-Induced Airway Constriction in Dogs

Airway Dimensions During Histamine-Induced Airway Constriction in Dogs

Effects of the tripeptide substance P antagonist, FR113680, on airway constriction and airway edema induced by neurokinins in guinea-pigs

FR113680 is a newly developed tripeptide substance P (SP) receptor antagonist. The effects of FR113680 on airway constriction and airway edema induced by neurokinins were investigated in guinea-pigs. In in vitro experiments, FR113680 inhibited the contraction of isolated guinea-pig trachea induced by SP and neurokinin A (NKA) in a dose-dependent manner with IC 50 values of 2.3 × 10 −6 and 1.5 × 10 −5 M, respectively. The tracheal contraction induced by histamine and acetylcholine was not affected by FR113680. FR113680 (5 × 10 −5 M) also significantly inhibited the atropine-resistant contraction of isolated guinea-pig bronchi induced by electrical field stimulation. In in vivo experiments, FR113680 given i.v. inhibited SP-induced airway constriction in guinea-pigs at doses of 1 and 10 mg kg −1. However, FR113680 only inhibited NKA- and capsaicin-induced airway constriction by 40–50% even at a dose of 10 mg kg −1. FR113680 also inhibited SP-induced airway edema in guinea-pigs with the same potency as it inhibited SP-induced airway constriction. Histamine-induced airway constriction and airway edema were not affected at a dose of 10 mg kg −1. These results suggest that FR113680 preferentially inhibits responses induced by NK 1 receptor activation (SP-induced airway constriction and airway edema), but is less effective on a NK 2 receptor-induced response (airway constriction by NKA and neurogenic stimulation).

Attenuation of Histamine-Induced Airway Constriction by Albuterol during Halothane Anesthesia

The effect of albuterol (a beta 2 specific adrenergic agonist) on airway reactivity to histamine aerosol challenge was evaluated during halothane anesthesia and thiopental-fentanyl anesthesia in five Basenji Greyhound dogs. Responses to histamine aerosol challenges (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/ml) were measured during thiopental-fentanyl anesthesia and during halothane anesthesia in the presence and absence of iv albuterol (2.5 micrograms/kg). Prior to aerosol challenges, baseline pulmonary resistance (RL) and dynamic compliance (Cdyn) did not differ in the four conditions. Albuterol significantly attenuated the pulmonary response to histamine during thiopental-fentanyl anesthesia. Although halothane itself significantly attenuated the pulmonary response to histamine, this response was further attenuated by the addition of albuterol. This study suggests that albuterol is effective in attenuating bronchoconstriction during both thiopental-fentanyl and halothane anesthesia. As the effects of albuterol and halothane on the airways are additive, beta-adrenergic agonists such as albuterol are the agents of choice to treat bronchospasm in patients anesthetized with inhalational anesthetics.

Aminophylline does not attenuate histamine-induced airway constriction during halothane anesthesia.

The effects of aminophylline on the release of endogenous catecholamines and on airway reactivity to aerosol histamine challenge were evaluated during halothane and thiopental/fentanyl anesthesia in basenji-greyhound dogs. Responses to histamine aerosol challenge (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/ml) were measured during six conditions: 1) thiopental/fentanyl anesthesia (control), 2) thiopental/fentanyl with aminophylline infusion, 3) halothane anesthesia (1.5 MAC), 4) halothane anesthesia with aminophylline infusion, 5) thiopental/fentanyl anesthesia after pretreatment with iv propranolol, and 6) thiopental/fentanyl anesthesia with aminophylline infusion after pretreatment with iv propranolol. Prior to aerosol challenge baseline pulmonary resistance (RL) did not differ in the six groups. Aminophylline significantly attenuated the pulmonary response to histamine and increased catecholamine concentrations during thiopental/fentanyl anesthesia. Although halothane itself significantly attenuated the pulmonary response to histamine, the administration of aminophylline during halothane anesthesia produced no additional protective effect and no increases in catecholamines were noted. Moreover, no protective effect was seen after aminophylline administration during thiopental/fentanyl anesthesia in the same dogs pretreated with propranolol. These data suggest that the protective effect of aminophylline on histamine reactivity results from release of endogenous catecholamines and that the use of aminophylline during halothane anesthesia, which blocks this release, is not warranted.

Mode of action of halothane on histamine-induced airway constriction in dogs with reactive airways.

To determine if clinical concentrations of halothane have direct relaxant effects on airway smooth muscle, the authors compared dose-response curves to histamine in the control state (thiopental) and during halothane anesthesia (1.0 and 1.5 MAC), in six basenji-greyhound (BG) dogs untreated and pretreated with atropine aerosols (10 mg X ml-1). Pulmonary resistance (RL) and dynamic compliance (Cdyn) were continuously monitored. Baseline airway tone was not significantly different during thiopental, halothane (1.0 MAC and 1.5 MAC), and after atropine aerosol administration. During thiopental anesthesia, histamine produced dose-related increases in RL and decreases in Cdyn. Both halothane and atropine significantly attenuated the bronchoconstriction induced by histamine 1 mg X ml-1. There was no significant differences in the extent of antagonism of histamine-related bronchoconstriction between halothane (1.0 MAC and 1.5 MAC) and the atropine aerosol. Moreover, in four dogs halothane anesthesia in the presence of atropine offered no additional protection compared with atropine alone. Because the protection afforded by halothane was not greater than that of atropine pretreatment alone, and the addition of halothane to atropine failed to increase the protection, it is concluded that block of vagal reflexes was the major action of halothane responsible for the attenuation of histamine-induced bronchoconstriction.

Noninvasive detection of airway constriction in awake guinea pigs.

Tidal volume measured by the barometric method is very sensitive to increases in compression and expansion of alveolar gas, such as would be expected to occur during airway narrowing or closure. By comparing a barometric method tidal volume signal (VT') with a reference tidal volume (VT) obtained with a head-out pressure plethysmograph, a simple index related to gas compressibility effects was calculated (VT/VT'). Changes in this index were compared with decreases in dynamic compliance (Cdyn) during histamine aerosol challenge of 15 Charles River Hartley guinea pigs. Decreases in VT/VT' occurred during all aerosol challenges and were correlated with decreases in Cdyn (r = 0.84, P less than 0.001). Decreases in VT/VT' were most marked at Cdyn values of less than 50% of base line. At Cdyn of less than 15% of base line, VT' was 3.1-4.8 times the VT reference signal. No increase in total pulmonary resistance was noted, and Cdyn and VT/VT' returned to base line after histamine exposure was stopped. We conclude that gas compressibility effects become substantial during histamine-induced airway constriction in the guinea pig and that the VT/VT' ratio appears to provide a simple noninvasive method of detecting these changes.

Interrelatinoship between alpha- and beta-adrenergic agonists and histamine in canine airways

To determine the interrelationship between adrenergic receptors in airway smooth muscle and histamine-induced airway constriction, we studied the responses of 26 parasympathectomized dogs to selective and mixed alpha- and beta-adrenergic stimulation in situ by means of an isometric tracheal smoth-muscle preparation. Intra-arterial (IA) phenylephrine (PE) caused dose-related tracheal contraction beginning at 10 −8 mol; maximal active tension was 9.47 ± 2.2 gm F/cm (mean ± SD) at 10 −5 mol. Pretreatment with propranolol augmented tracheal contraction to PE (maximum 35.5 ± 3.2 gm F/cm). The contractile resposne to PE was blocked with a dose of phentolamine (200 μg/kg IA), which did not alter the respionse to acetylcholine. Isoproterenol (ISO) caused dose-related tarcheal relaxation beginning at 4.2 × 10 −11 mol (maximum 43.2 ± 19.6 gm F/cm). Norepinephrine (NE) also caused tracheal relaxation beginning at 1.2 × 10 −6 mol, which was less than relaxation caused by ISO. Prestimulation with histamine did not augment the contractile response to PE but reduced maximal tracheal relaxation to NE (p < 0.001). It is concluded that selective alpha-adrenergic stimulation causes tracheal contraction. However, nonselective stimulation results in tracheal relaxation, even with a weak beat-agonist such as NE. Histamine does not augment alpha-adrenergic contraction as previously suggested but causes physiologic antagonism of beta-adrenergic relaxation of tracheal muscle.

Inhibition of histamine-induced airway constriction by ascorbic acid

We studied the effect of ascorbic acid on histamine-induced airway constriction in 17 healthy subjects; we also investigated its effect on guinea pig tracheal strips in vitro. Ventilatory function was measured by recording partial expiratory flow-volume (PEFV) curves on which maximum flow rates at 50 per cent VC and at 25 per cent VC were calculated. Following oral administration of 500 mg. ascorbic acid, the mean reductions of V̇ max at 50 per cent VC and V̇ max at 25 per cent VC after histamine inhalation were significantly smaller in comparison with placebo administration (P < 0.01). In the guinea pig trachea preparation, ascorbic acid reduced contractions induced by histamine and relaxed this tissue in the absence of other agents. Propranolol did not block the effect of ascorbic acid in man (80 mg. orally), but in vitro relaxations of tracheal strips by ascorbic acid were reduced by 2.5 μg propranolol. Ascorbic acid probably has a direct effect on airway smooth muscle; in the guinea pig trachea its effect may be mediated by γ-adrenergic receptors.