Modulation Of Airway Responsiveness Research Articles

Modulation of airway responses by prostaglandins in young and fully grown rabbits

Maturational changes have been noted in neurally mediated contractile and relaxant responses in airways from New Zealand White rabbits. In this study, we focused on prostaglandins with bronchoprotective properties as potential modulators of airway tone in maturing rabbits. Tracheal rings from 1-, 2-, and 13-wk-old rabbits were assessed for neurally mediated contractile and relaxant responses produced by electrical field stimulation (EFS) of nerves in the presence and absence of the prostaglandin inhibitor, indomethacin (Indo). We also measured EFS-induced release of prostaglandin E(2) (PGE(2)) and the stable metabolite of prostacyclin, 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)). In the presence of Indo, EFS produced significant increases in contractile responses in segments from 1- and 2-wk-old animals but not in segments from 13-wk adult rabbits. Tracheal rings from 1- and 2-wk-old animals precontracted with neurokinin A (NKA) relaxed 100% in response to EFS when Indo was not in the bath. In rings from 13-wk-old animals, relaxation was 40%. With Indo, relaxation was abolished in 1-wk-old animals and reduced to 30% in the 2- and 13-wk-old groups. Buffer from baths collected after EFS had significant increases in PGE(2) and 6-keto-PGF(1alpha) released from tissues from 1- vs. 2- and 13-wk-old animals. Dose response curves to PGE(2) using tissues precontracted to NKA showed significant increases in relaxant responses in 1- and 2- vs. 13-wk-old rabbits. In rabbit airways, this study demonstrates enhanced modulation of airway tone by PGE(2) and greater release of the bronchoprotective prostaglandins PGE(2) and prostacyclin early in life.

Modulation of airway responsiveness by anionic and cationic polyelectrolyte substances

To elucidate the effects of anionic and cationic polyelectrolyte substance on bronchoconstriction, we examined the serial changes in respiratory resistance (Rrs) in ovalbumin-sensitized guinea pigs after antigen exposure with or without preinhalation of low-molecular-weight heparin, poly- l-glutamic acid, poly- l-lysine and dextran, and with or without oral intake of dalteparin. Both immediate and late responses after antigen exposure were significantly decreased after pretreatment with inhaled low-molecular-weight heparin and poly- l-glutamic acid compared with saline alone. The late response was significantly decreased after pretreatment with oral dalteparin. Both low-molecular-weight heparin and poly- l-glutamic acid significantly decreased the airway response to methacholine in sensitized guinea pigs. In sensitized guinea pigs, the airway response to methacholine was significantly increased after pretreatment with inhaled poly- l-lysine. Pretreatment with inhaled low-molecular-weight heparin before poly- l-lysine exposure significantly suppressed the airway hyperresponsiveness after inhaled poly- l-lysine. These findings indicated that the “cationic–anionic interaction” plays an important role in airway responsiveness.

Pituitary adenylate cyclase activating peptide regulates neurally mediated airway responses.

To clarify the protective effects of pituitary adenylate cyclase activating peptide (PACAP) on airway narrowing, we examined the effects of PACAP on smooth muscle contraction and plasma extravasation in guinea-pig airways. Smooth muscle contraction evoked by electrical field stimulation (EFS) or exogenously applied acetylcholine (ACh) or substance P (SP) was measured before and after PACAP in vitro. The effect of PACAP on airway plasma extravasation was also measured in vivo. In trachea, PACAP (10(-9) - 10(-7) M) significantly suppressed smooth muscle contraction evoked by EFS without affecting ACh sensitivity, suggesting that PACAP inhibits cholinergic neuroeffector transmission. In the main bronchi, PACAP (10(-9) - 10(-8) M) significantly suppressed the contraction evoked by EFS without affecting SP sensitivity in the presence of atropine, suggesting that PACAP inhibits SP release from excitatory nonadrenergic noncholinergic (eNANC) nerves. In animals treated with atropine and propranolol, PACAP attenuated the increase in plasma extravasation induced by electrical vagus stimulation or by SP. These results suggest that pituitary adenylate cyclase activating peptide may play a role in modulation of airway responses through inhibition of cholinergic and noncholinergic mechanisms.

Modulation of airway responsiveness by the airway epithelium in humans: putative mechanisms

Modulation of airway responsiveness by the airway epithelium in humans: putative mechanisms

Modulation of airway responsiveness by the airway epithelium in humans: putative mechanisms

Modulation of airway responsiveness by the airway epithelium in humans: putative mechanisms

The Effect of a Nitric Oxide Synthase Inhibitor on the Modulation of Airway Responsiveness in Rats

The Effect of a Nitric Oxide Synthase Inhibitor on the Modulation of Airway Responsiveness in Rats

The effect of a nitric oxide synthase inhibitor on the modulation of airway responsiveness in rats.

The possible role of nitric oxide (NO) in the regulation of airway tone remains to be fully explored. In the present study we examined the effect of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on airway responsiveness in rats. The effect of L-NAME on endotoxin (lipopolysaccharide; LPS)-induced changes in airway responsiveness was also evaluated. L-NAME (1 mg/kg given intravenously) caused a 33.3 +/- 6.9% increase in blood pressure, but did not influence baseline airway tone or the provocative dose of carbachol causing a 50% increase in pulmonary resistance (RL)(PD50RL). Exposure of F344 rats to LPS induced a transient increase in airway responsiveness at 90 min after exposure, followed by a significant hyporesponsiveness between 9 and 12 h after exposure. L-NAME (1 mg/kg intravenously) did not influence the increase in responsiveness but inhibited the LPS-induced hyporesponsiveness; in LPS-exposed, L-NAME-treated animals, the PD50RL for carbachol was 3.0 +/- 0.1, versus 4.8 +/- 0.3 micrograms/kg in the LPS-exposed, placebo-pretreated group (p < 0.05). The effect of L-NAME was abolished by pretreatment with L-arginine but not with D-arginine. L-NAME did not influence the LPS-induced increase of neutrophils in bronchoalveolar lavage fluid (BALF). These results suggest that in rats, consitutive NO synthesis does not contribute either to basal airway tone or to the basal degree of airway responsiveness, but that inducible NO synthesis mediates endotoxin-induced hyporesponsiveness.

The epithelial barrier and airway responsiveness.

Epithelial injury and bronchial hyperresponsiveness are commonly associated with airway disease, and are widely considered to occur as the result of inflammatory changes in the airway wall. Mechanistically, the airway epithelium may influence the sensitivity of the airways to provocative stimuli through its primary function as a cellular barrier between the air and the interstitium, or by liberating a variety of bronchoactive mediators, e.g., lipoxygenase and cyclooxygenase products, nitric oxide, and an epithelium-derived relaxing factor (EpDIF). Much attention has focused on the latter function of the epithelium, particularly the putative EpDIF, which has an action considered to be analogous to that of endothelium-derived relaxing factor in blood vessels. The modulation of airway calibre by the epithelium has recently been investigated in vitro using tubular preparations of bronchi, where removal of, or damage to, the epithelium increases the sensitivity to agonists by several orders of magnitude. This contrasts with the effect of removing the epithelium on strips or rings of airway wall, where the increase in sensitivity is small and rather variable, but this has been the primary observation for proposing a putative EpDIF. This review evaluates the barrier or protective function of the airway epithelium and the major role it plays in the modulation of airway responsiveness. A role of a putative EpDIF seems, at best, to be of minor functional significance.

Contribution of the vagal nerve on histamine-induced bronchoconstriction in guinea-pigs

Recently, it has been suggested that the peripheral vagal nerve might participate in the bronchoconstriction locally in addition to the concept of "vagal reflex". We investigated the contribution of the vagal nerve on the modulation of airway responses to histamine (8 micrograms/kg, iv) in anesthetized and mechanically ventilated guinea-pigs. Airway responses were assessed by measurement of pulmonary resistance (RL). To determine whether the vagal nerve mediates excitatory effects by "vagal reflex" in guinea-pigs, we investigated the effects of vagotomy or hexamethonium (2 mg/kg, iv). Increase in RL induced by histamine was significantly enhanced after the vagotomy or the treatment of hexamethonium. Histamine-induced bronchoconstriction was also enhanced by the vagotomy in the animals after the administration of propranolol (1 mg/kg, iv). To determine whether the peripheral vagal nerve may play any role in the vagotomized animals, we investigated the effect of atropine (1 mg/kg, iv). Atropine reduced histamine-induced bronchoconstriction significantly in the vagotomized guinea-pigs or in the animals treated with hexamethonium. We conclude that the vagal nerve mainly exerts on inhibitory role through the central nervous system, and that the peripheral vagal nerve distal to ganglion plays an excitatory effects by releasing acetylcholine from the terminals in histamine-induced bronchoconstriction in guinea-pigs.

A PAF antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep.

We studied the effects of WEB-2086, a specific antagonist of platelet-activating factor (PAF), on the development of antigen-induced airway hyperresponsiveness and inflammation in sheep (n = 8). For these studies, airway responsiveness was determined from slopes of carbachol dose-response curves (DRC) performed at base line (prechallenge) and 2 h after Ascaris suum antigen challenges in the following three protocols: 1) antigen challenge alone (control trial), 2) WEB-2086 (1 mg/kg iv) given 30 min before antigen challenge (WEB pretreatment), and 3) WEB-2086 given 2 h after antigen challenge, immediately before the postchallenge DRC (WEB posttreatment). Airway inflammation was assessed by bronchoalveolar lavage (BAL) before antigen challenge and after the postchallenge DRC for each trial. A. suum challenge resulted in acute increases in specific lung resistance that were not different among the three trials. Antigen challenge (control trial) caused a 93% increase (P less than 0.05) in the slope of the carbachol DRC when compared with the prechallenge value. WEB pretreatment (1 mg/kg) reduced (P less than 0.05) this antigen-induced hyperresponsiveness, whereas pretreatment with a 3-mg/kg dose completely prevented it. WEB posttreatment was ineffective in blocking this hyperresponsiveness. BAL neutrophils increased after antigen challenge in the control trial and when WEB-2086 was given after antigen challenge (P less than 0.05). Pretreatment with WEB-2086 (1 or 3 mg/kg) prevented this neutrophilia. This study provides indirect evidence for antigen-induced PAF release in vivo and for a role of endogenous PAF in the modulation of airway responsiveness and airway inflammation after antigen-induced bronchoconstriction in sheep.

Modulation of the bronchomotor effects of chemical mediators by prostaglandin F2 alpha in asthmatic subjects.

Prostaglandin F2 alpha (PGF2 alpha) is generated by human lung tissue in response to a number of stimuli and is widely viewed as a bronchoconstrictor mediator. We have shown that aerosolized PGF2 alpha in concentrations between 1 and 100 micrograms/ml caused dose-related bronchoconstriction, but that continued stimulation at higher concentrations resulted in a partial return of pulmonary function toward control, suggesting that airways were refractory to further stimulation. To explore the mechanism and specificity of airway refractoriness induced by PGF2 alpha, we examined bronchomotor responses evoked by repeated PGF2 alpha stimulation, repeated histamine stimulation, and PGF2 alpha stimulation followed by histamine. Studies were carried out on 3 separate days in 7 subjects with allergic asthma. For each subject the aerosol concentration of each agonist remained constant throughout the study. Responses were measured as the percent change in FEV1 versus time, and comparisons were made between the first and second agonist challenge of each study day. We found that prior stimulation with PGF2 alpha resulted in diminished airway responsiveness, not only to PGF2 alpha but to histamine as well. In contrast, similar refractoriness could not be induced by repeated histamine stimulation, indicating that the PGF2 alpha-induced decrease in responsiveness was not a nonspecific effect of bronchoconstriction per se. Further, the finding that PGF2 alpha caused a decrease in the response to histamine suggests that diminished airway responsiveness was not due to down-regulation of specific PGF2 alpha receptors. Our findings suggest that in addition to its bronchoconstrictor properties, PGF2 alpha may play a role in the modulation of acute airway responses.