Repeated antigen challenge induces airway hyperresponsiveness with tissue eosinophilia in guinea pigs

1989 ◽  
Vol 67 (3) ◽  
pp. 1133-1139 ◽  
Author(s):  
K. Ishida ◽  
L. J. Kelly ◽  
R. J. Thomson ◽  
L. L. Beattie ◽  
R. R. Schellenberg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Blood Gas Analysis ◽  
Neutrophil Infiltration ◽  
Gas Analysis ◽  
Antigen Challenge ◽  
Response Curves ◽  
Tissue Eosinophilia ◽  
Antigenic Exposure

To test the hypothesis that the development of airway hyperresponsiveness (AHR) lasting greater than or equal to 3 days after the last antigenic exposure required repeated mediator release, we compared dose-response changes in lung resistance (RL) to acetylcholine (ACh) in animals sensitized with 1% ovalbumin (OA), 4% Bordatella pertussis aerosol and subsequently challenged with 0.5% OA aerosol twice weekly for 4–6 wk vs. animals receiving saline aerosol instead of OA. Despite antihistamine pretreatment, each OA challenge produced cyanosis and inspiratory indrawing. Blood gas analysis in six guinea pigs revealed an immediate fall in arterial PO2 (PaO2) from 104.3 +/- 4.9 to 35.4 +/- 2.2 Torr after a 1-min exposure to aerosolized OA. ACh dose-response measurements of RL 3 days after the last OA challenge demonstrated a leftward shift and an increased magnitude of response. These differences were less marked at 7 days, and by 14 days after the last OA challenge, ACh dose-response curves were not different from those of control guinea pigs. Sensitization without repeated antigen challenge did not cause hyperresponsiveness. Morphometric analysis showed significantly increased numbers of eosinophils in the epithelium of airways in hyperresponsive guinea pigs, without neutrophil infiltration or alterations in epithelium and airway wall areas. We conclude that repeated antigenic challenge, but not sensitization alone, causes prolonged AHR in guinea pigs, which is associated with tissue eosinophilia.

scholarly journals Reduced Airway Hyperresponsiveness by Phosphodiesterase 3 and 4 Inhibitors in Guinea-Pigs

1999 ◽  
Vol 8 (3) ◽  
pp. 153-157 ◽  
Author(s):  
Nöella Germain ◽  
Elisabeth Boichot ◽  
Jean-Michel Planquois ◽  
Vincent Lagente
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Response Curve ◽  
Pde5 Inhibitor ◽  
Pde4 Inhibitor ◽  
Potential Utility ◽  
Phosphodiesterase 3 ◽  
Pde Inhibitors ◽  
Pde3 Inhibitor

The aim of the present study was to compare the effects of selective phosphodiesterase (PDE) 3, 4 and 5 inhibitors on antigen-induced airway hyperresponsiveness in sensitized guinea-pigs. When the sensitized guinea-pigs were orally pre-treated with the selective PDE4 inhibitor, Ro 20-1724 (30 mg/kg), and studied 48 h after OA, a significant reduction (p<0.01) of the leftward shift of the dose-response curve to ACh was noted, whereas it was ineffective at the lower dose (10 mg/kg). Administration of the selective PDE3 inhibitor, milrinone (30 mg/kg) also elicited a significant reduction (p<0.01) of the airway hyperresponsiveness, whereas the PDE5 inhibitor zaprinast (30 mg/kg) was ineffective. These results show that both PDE3 and PDE4 inhibitors are able to inhibit the antigen-induced airway hyperresponsiveness in sensitized guinea-pigs and support the potential utility of selective PDE inhibitors in the treatment of asthma.

Mechanical response of pulmonary artery under aerobic and hypoxic conditions

1977 ◽  
Vol 42 (3) ◽  
pp. 438-443
Author(s):  
J. F. Souhrada ◽  
D. W. Dickey
Keyword(s):  
Pulmonary Artery ◽  
Dose Response ◽  
Guinea Pigs ◽  
Main Pulmonary Artery ◽  
Maximal Response ◽  
Response Curves ◽  
Aerobic Conditions ◽  
Experimental Medium ◽  
Hypoxic Conditions ◽  
Dose Response Curves

The present study demonstrates the reactivity of isolated main pulmonary artery (MPA) from guinea pigs and rats to two vasoactive drugs, norepinephrine (NE) and histamine (H), in substrate-rich and substrate-free medium, under both aerobic (PO2 = 95 +/- 0.5 Torr) and hypoxic conditions (PO2 = 30 +/- 1 Torr). The sensitivity of MPA from guinea pigs to NE and H during aerobic conditions is not significantly affected by the absence of substrate in the experimental medium. Furthermore, it is demonstrated that in the substrate-rich experimental medium (5.5 mM glucose), the reactivity of MPA from guinea pigs to NE and H is not significantly affected by acute hypoxia as compared with the response of MPA during aerobic conditions. These experiments contrast with data obtained when substrate is absent from the experimental medium. The dose-response curves of MPA from guinea pigs to NE and H under this condition were significantly blunted during hypoxia. Following the completion of the dose-response curves during aerobic conditions, with both NE and H, spontaneous mechanical activities were seen in the guinea pig MPA. On the other hand, it was demonstrated that during aerobic and hypoxic conditions MPA's isolated from rats exhibit no physiological response to histamine even when administered in the dose required to produce the maximal response in MPA isolated from guinea pigs. The sensitivity of MPA from rats to NE during aerobic conditions is not significantly affected by the absence of substrate in the experimental medium. However, when the preparation was exposed to hypoxia, the presence of substrate failed to maintain the reactivity of MPA to norepinephrine. In addition, MPA isolated from rats demonstrated a smaller contractile response to NE than those from guinea pigs. Furthermore, no spontaneous mechanical activities were observed after norepinephrine or histamine administration. The present study, in addition to pointing out species differences, shows the important role of exogenous substrate in maintaining the reactivity of pulmonary vascular smooth muscle during hypoxia.

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

1989 ◽  
Vol 67 (1) ◽  
pp. 406-413 ◽  
Author(s):  
M. Soler ◽  
M. W. Sielczak ◽  
W. M. Abraham
Keyword(s):  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Indirect Evidence ◽  
Airway Responsiveness ◽  
Antigen Challenge ◽  
Base Line ◽  
Response Curves ◽  
Challenge Control ◽  
Web 2086

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.

Increased in vitro responses of tracheal smooth muscle from hyperresponsive guinea pigs

1990 ◽  
Vol 68 (4) ◽  
pp. 1316-1320 ◽  
Author(s):  
K. Ishida ◽  
P. D. Pare ◽  
R. J. Thomson ◽  
R. R. Schellenberg
Keyword(s):  
Smooth Muscle ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Contractile Activity ◽  
Tracheobronchial Tree ◽  
Force Generation ◽  
Tracheal Smooth Muscle ◽  
Antigen Challenge

Repeated aerosol antigen challenge of previously sensitized guinea pigs induces airway hyperresponsiveness to inhaled acetylcholine. To determine the mechanism producing these airway changes and assuming that changes in the trachealis muscle reflect changes in muscle of the entire tracheobronchial tree, we examined the in vitro smooth muscle mechanics and morphometric parameters of tracheae from guinea pigs demonstrating hyperresponsiveness in vivo vs. tracheae from control guinea pigs. No differences between these groups were found in luminal volume at zero transmural pressure, passive pressure-volume characteristics, or area of airway wall. Smooth muscle areas were slightly less in tracheae from hyperresponsive guinea pigs. Tracheae from hyperresponsive guinea pigs had both significantly increased isovolumetric force generation and isobaric shortening compared with tracheae from controls when evaluated over the range of transmural pressures from -40 to 40 cmH2O. We conclude that the in vivo airway hyperresponsiveness induced with repeated antigen challenge is associated with both increased force generation and shortening of tracheal smooth muscle without increased muscle mass, suggesting enhanced contractile activity.

Nedocromil sodium in allergen-induced bronchial responses and airway hyperresponsiveness in allergic sheep

1988 ◽  
Vol 65 (3) ◽  
pp. 1062-1068 ◽  
Author(s):  
W. M. Abraham ◽  
J. S. Stevenson ◽  
M. Eldridge ◽  
R. Garrido ◽  
L. Nieves
Keyword(s):  
Airway Hyperresponsiveness ◽  
Airway Disease ◽  
Early Response ◽  
Nedocromil Sodium ◽  
Antigen Challenge ◽  
Late Response ◽  
Base Line ◽  
Response Curves ◽  
Lung Resistance ◽  
Placebo Trial

We examined the effects of nedocromil sodium, a new drug developed for the treatment of reversible obstructive airway disease, on allergen-induced early and late bronchial responses and the development of airway hyperresponsiveness 24 h after challenge in nine allergic sheep. On occasions greater than 2 wk apart the sheep were treated with 1) placebo aerosol (buffered saline) before and 3 h after antigen challenge, 2) an aerosol of nedocromil sodium (1 mg/kg in 3 ml buffered saline) before antigen challenge and placebo 3 h after challenge, and 3) placebo aerosol before and nedocromil sodium aerosol 3 h after challenge. Early and late bronchial responses were determined by measuring specific lung resistance (sRL) before and periodically after challenge. Airway responsiveness was assessed by determining from dose-response curves the carbachol concentration (in % wt/vol) that increased sRL to 5 cmH2O/s. In the placebo trial, antigen challenge resulted in early and late increases in sRL over a base line of 353 +/- 32 and 131 +/- 17% (SE), respectively. Both early and late increases in sRL were blocked (P less than 0.05) when the sheep were pretreated with nedocromil sodium. When nedocromil was given after the early response, the late response was reduced significantly. Eight of nine sheep developed airway hyperresponsiveness 24 h after antigen challenge. In these eight sheep, carbachol concentration before antigen challenge was 2.6 +/- 0.3%, 24 h later carbachol concentration was significantly lower (1.8 +/- 0.3%). Both nedocromil sodium treatments blocked (P less than 0.05) this antigen-induced airway hyperresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine dose-response curves in guinea pigs

1985 ◽  
Vol 58 (2) ◽  
pp. 625-634 ◽  
Author(s):  
W. C. Hulbert ◽  
T. McLean ◽  
B. Wiggs ◽  
P. D. Pare ◽  
J. C. Hogg
Keyword(s):  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Dynamic Compliance ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Mechanically Ventilated ◽  
Dose Response Curves ◽  
The Right

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51–82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

Time course of airway hyperresponsiveness induced by ozone in dogs

1983 ◽  
Vol 55 (4) ◽  
pp. 1232-1236 ◽  
Author(s):  
M. J. Holtzman ◽  
L. M. Fabbri ◽  
B. E. Skoogh ◽  
P. M. O'Byrne ◽  
E. H. Walters ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Dose Response ◽  
Airway Hyperresponsiveness ◽  
Time Course ◽  
Airway Responsiveness ◽  
Exposure Chamber ◽  
Ozone Exposure ◽  
Acute Inflammatory Response ◽  
Pulmonary Resistance ◽  
Response Curves

To better understand the mechanism of ozone-induced airway hyperresponsiveness we determined the time course of the ozone effect in dogs. To do this we assessed airway responsiveness before ozone exposure and then at 1 h, 1 day, and 1 wk after ozone exposure. To assess responsiveness we anesthetized the dogs and obtained dose-response curves of increasing concentrations of acetylcholine or histamine aerosols delivered to the airways vs. pulmonary resistance. Ozone exposures were carried out with the dogs awake and at rest in an exposure chamber for 2 h breathing either through the nose and mouth at a level of 2.2 ppm or through a tracheostomy at a level of 1.0 ppm. For both acetylcholine and histamine and for both routes of ozone delivery airway responsiveness increased most markedly at 1 h after ozone, increased to a lesser degree 1 day later, and returned to control levels by 1 wk. The results are similar to our previous studies in humans that showed that ozone-induced hyperresponsiveness occurs shortly after exposure and is rapidly reversible and suggest that the ozone effect is linked to an acute inflammatory response in the airways.

Enhanced airway responses to substance P after repeated challenge in guinea pigs

1989 ◽  
Vol 66 (2) ◽  
pp. 955-961 ◽  
Author(s):  
S. A. Shore ◽  
J. M. Drazen
Keyword(s):  
Substance P ◽  
Dose Response ◽  
Guinea Pigs ◽  
Response Curve ◽  
Enzyme Inhibitor ◽  
Dose Response Curve ◽  
Base Line ◽  
Response Curves ◽  
Dose Response Curves ◽  
Airway Responses

We performed three consecutive dose-response curves to rapid intravenous infusions of substance P (SP) in anesthetized, mechanically ventilated guinea pigs. The dose of SP required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002) and 3.3-fold (P less than 0.001) on the second and third dose-response curves, respectively, compared with the first. SP did not alter airway responses to intravenous histamine but did cause a significant (3.7-fold) decrease in ED50GL for dose-response curves to intravenous capsaicin, an agent that causes bronchoconstriction by release of endogenous tachykinins. The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a marked enhancement of airway responses to SP observed on the first dose-response curve but did not alter the enhancement of SP-induced airway responses produced by repeated SP challenge. The anticholinergic atropine (5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the first SP dose-response curve. Atropine and mepyramine did not prevent the enhancement of SP responses observed with repeated challenge, but after pretreatment with either indomethacin or acetylsalicylic acid, dose-response curves to SP were reproducible. Our results indicate that airway responses to intravenous SP are enhanced with repeated SP challenge and suggest that cyclooxygenase products of arachidonic acid metabolism are involved in the mediation of this phenomenon.

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