Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses

Allergic sheep respond to inhaled Ascaris suum antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D4 (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct then dual responders should demonstrate increased airway responses to inhaled LTD4 and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen. To test this we used animals from both groups with the same degree of non-specific airway responsiveness to carbachol and determined their airway responses to controlled inhalation challenges with synthetic LTD4 and Ascaris suum antigen. Airway responsiveness to carbachol was determined by measuring the change in specific lung resistance (SRL) to increasing concentrations of carbachol aerosol, and then identifying, by linear interpolation, the provocative carbachol concentration which produced a 150% increase (PC150) in SRL. Airway responses to LTD4, and antigen were determined by measuring the percentage change in SRL after a controlled inhalation challenge with either aerosol. Airway responsiveness to carbachol was not different between the two groups. There was, however, a difference (p less than 0.05) in the airway response to the same dose of LTD4 in the two groups. Dual responders showed a 297 +/- 72% increase in SRL as compared to a 90 +/- 13% increase in SRL in the acute responders. Dual responders also showed a greater immediate and more prolonged response to antigen than did acute responders. These results suggest that increased responsiveness to LTD4 may be one factor which may distinguish dual responders from acute responders.     

Production of early and late pulmonary responses with inhaled leukotriene D4 in allergic sheep

Some allergic sheep respond to inhalation of Ascaris suum antigen with both immediate and late increases in airflow resistance (late response). The mechanism of the late response is unknown but recent evidence suggests that the initial generation of slow-reacting substance of anaphylaxis (SRS-A) immediately after antigen challenge is a necessary pre-requisite for the physiologic expression of this late response. Based on this evidence we hypothesized that airway challenge with leukotriene D4 (LTD4), an active component of SRS-A would produce acute and late airway responses in allergic sheep similar to those observed with antigen. In five allergic sheep with documented early and late pulmonary responses to Ascaris suum antigen, inhalation of leukotriene D4 aerosol (delivered dose (mean +/- SE) 0.55 +/- 0.08 ug) resulted in significant early and late increases in specific lung resistance (SRL). In three allergic sheep which only demonstrated acute responses to antigen, LTD4 aerosol (delivered dose 0.59 +/- 0.09 ug) only produced an acute increase in SRL. In the late responders pretreatment with aerosol cromolyn sodium (1 mg/kg) did not affect the acute response but blunted the late increase in SRL. Pretreatment with aerosol FPL-57231 (1% w/v solution) completely blocked both the acute and late responses. These data support the hypothesis that initial release of LTD4 in the airways of sensitive animals is important for the physiologic expression of the late response.     

Modification of bronchial blood flow during allergic airway responses

Ascaris suum antigen effects on mean airflow resistance (RL) and bronchial arterial blood flow (Qbr) were studied in allergic anesthetized sheep with documented airway responses. Qbr was measured with electromagnetic flow probes, and supplemental O2 prevented antigen-induced hypoxemia. Aerosol challenge with this specific antigen increased RL and Qbr significantly. Cromolyn sodium aerosol pretreatment prevented antigen-induced increases in RL but not in Qbr. Intravenous cromolyn, however, prevented increases in Qbr and RL, suggesting a role for mast cell degranulation in both bronchomotor and bronchovascular responses to antigen. Antigen-induced increases in Qbr were not solely attributable to histamine release. Indomethacin pretreatment attenuated the antigen-induced increase in Qbr, thus suggesting that vasodilator cyclooxygenase products contribute to the vascular response. Antigen challenge significantly decreased Qbr after indomethacin and metiamide pretreatment, which suggests that vasoconstrictor substances released after antigen exposure also modulate Qbr; however, released vasodilators overshadow vasoconstrictor effects. Thus antigen challenge affects Qbr by locally releasing histamine and vasodilator prostaglandins as well as vasoconstrictor substances. These effects were independent of antigen-induced changes in systemic and pulmonary hemodynamics.     

Indomethacin and FPL-57231 inhibit antigen-induced airway hyperresponsiveness in sheep

We compared the development of antigen-induced airway hyperresponsiveness (AHR) 24 h after challenge with Ascaris suum antigen in allergic sheep with acute (n = 7) and with dual (n = 7) airway responses and then attempted to modify this AHR. Cholinergic airway responsiveness was determined by measuring the carbachol dose required to increase specific lung resistance (sRL) 150% (i.e., PC150). Subsequently the sheep were challenged with antigen and sRL was measured at predetermined times to document the presence or absence of a late response. PC150 was redetermined 24 h later followed by bronchoalveolar lavage (BAL) to assess inflammation. Only dual responders developed AHR (PC150 decreased, P less than 0.05). There were no significant differences in BAL between the two groups. Six dual responders were then, on separate occasions (greater than or equal to 3 wk), pretreated with placebo, indomethacin (2 mg/kg iv), or a leukotriene antagonist, FPL-57231 (30 mg inhaled). Neither agent significantly affected the acute response to antigen. Only FPL pretreatment blocked the late response, but both agents blocked the antigen-induced AHR 24 h later. BAL at 24 h showed no significant differences. These results indicate that only dual responders develop AHR 24 h after antigen challenge. This AHR appears independent of the late increase in sRL or the severity of pulmonary inflammation. AHR appears to be sensitive to agents that interfere with the early release or actions of cyclooxygenase and lipoxygenase metabolites in dual responders.     

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

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)     

Inhibition of allergic late airway responses by inhaled heparin-derived oligosaccharides.

Inhaled heparin has been shown to inhibit allergic bronchoconstriction in sheep that develop only acute responses to antigen (acute responders) but was ineffective in sheep that develop both acute and late airway responses (LAR) (dual responders). Because the antiallergic activity of heparin is molecular-weight dependent, we hypothesized that heparin-derived oligosaccharides (<2, 500) with potential anti-inflammatory activity may attenuate the LAR in the dual-responder sheep. Specific lung resistance was measured in 24 dual-responder sheep before and serially for 8 h after challenge with Ascaris suum antigen for demonstration of early airway response (EAR) and LAR, without and after treatment with inhaled medium-, low-, and ultralow-molecular-weight (ULMW) heparins and "non-anticoagulant" fractions (NAF) of heparin. Airway responsiveness was estimated before and 24 h postantigen as the cumulative provocating dose of carbachol that increased specific lung resistance by 400%. Only ULMW heparins caused a dose-dependent inhibition of antigen-induced EAR and LAR and postantigen airway hyperresponsiveness (AHR), whereas low- and medium-molecular-weight heparins were ineffective. The effects of ULMW heparin and ULMW NAF-heparin were comparable and inhibited the LAR and AHR even when administered "after" the antigen challenge. The ULMW NAF-heparin failed to inhibit the bronchoconstrictor response to histamine, carbachol, and leukotriene D(4), excluding a direct effect on airway smooth muscle. In six sheep, segmental antigen challenge caused a marked increase in bronchoalveolar lavage histamine, which was not prevented by inhaled ULMW NAF-heparin. The results of this study in the dual-responder sheep demonstrate that 1) the antiallergic activity of inhaled "fractionated" heparins is molecular-weight dependent, 2) only ULMW heparins inhibit the antigen-induced EAR and LAR and postantigen AHR, and 3) the antiallergic activity is mediated by nonanticoagulant fractions and resides in the ULMW chains of <2,500.     

Effect of left atrial pressure on bronchial vascular hemodynamics

We studied the bronchial vascular response to downstream pressure elevation by increasing left atrial pressure (Pla) and mean airway pressure (Paw) with positive end-expiratory pressure (PEEP). In seven pentobarbital-anesthetized ventilated sheep, we cannulated and perfused the bronchial branch of the bronchoesophageal artery. Steady-state bronchial artery pressure- (Pba) flow (Qba) relationships were obtained as Pla was increased by inflating a balloon catheter in the left atrium. Bronchial vascular resistance (BVR), determined by the inverse slope of the Pba-Qba relationship, increased significantly from 3.2 +/- 0.3 (SE) mmHg.ml-1.min-1 at a Pla of 2.9 +/- 0.7 mmHg to 5.1 +/- 0.5 mmHg.ml-1.min-1 at a Pla of 20.1 +/- 2.0 mmHg (P = 0.0007). Under control Qba (23.3 +/- 1.2 ml/min), these changes in BVR represent a 3.6 +/- 0.7-mmHg increase in Pba per mmHg increase in Pla. The zero-flow pressure increased 1.3 +/- 0.2 mmHg/mmHg increase in Pla. After infusion of papaverine, a smooth muscle paralytic agent, directly into the bronchial artery, BVR decreased significantly to 1.3 +/- 0.7 mmHg.ml-1.min-1 (P = 0.0004). Under these dilated conditions, BVR was unaltered by increases in Pla. After papaverine administration, Pba increased 0.9 +/- 0.1 and 1.2 +/- 0.1 mmHg/mmHg increase in Pla during control and zero-flow conditions, respectively. Thus the effect of Pla elevation on BVR appears to be dependent on active smooth muscle responses. Paw elevation had similar effects on Pba. Under control Qba, Pba increased 2.2 +/- 0.4 mmHg/mmHg increase in Paw.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of an orally active leukotriene (LT) D4 antagonist WY-48, 252 on LTD4 and antigen-induced bronchoconstrictions in allergic sheep

In this study we examined the effects of a new orally active leukotriene (LT) D4 receptor antagonist, WY-48,252 (1,1,1-trifluoro-N-[3-(2-quinolinylmethoxy)phenyl]methanesulfonamide), on LTD4-induced bronchoconstriction and antigen-induced early and late responses in allergic sheep. For all studies WY-48,252 10 mg/kg, was administered via intragastric tube 1 h prior to airway challenge. In seven sheep, airway challenge with LTD4 [delivered dose mean +/- SE, 53 +/- 2 micrograms] resulted in an immediate increase in SRL to 600 +/- 18% over baseline. When these same sheep were treated with WY-48,252, airway challenge with LTD4 (delivered dose, 61 +/- 5 micrograms) resulted in only a 220 +/- 50% increase in SRL (p less than 0.05 vs placebo). The drug had no effect on baseline SRL. WY-48,252 was also effective in reducing early responses and blocking late responses to inhaled antigen in allergic sheep (n = 7). In the control trial, airway challenge with Ascaris suum antigen resulted in immediate and late (i.e. 6-8 h) increases in SRL of 499% and 138% over baseline (both responses, p less than 0.05). When these same sheep were pretreated with WY-48,252 the immediate antigen-induced increase in SRL was 171% and the late response was 49% over baseline (both responses p less than 0.05 vs control). These results indicate that WY-48,252 is a LTD4 antagonist in allergic sheep. The ability of this compound to modify antigen-induced early responses and to block antigen-induced late responses suggests that the generation of LTD4 during airway anaphylaxis contributes to both responses.     

Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses

Allergic sheep respond to inhaled antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D₄ (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct than dual responders should demonstrate increased airway responses to inhaled LTD₄ and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen. To test this we used animals from both groups with the same degree of non-specific airway responsiveness to carbachol and determined their airway responses to controlled inhlation challenges with synthetic LTD₄ and antigen. Airway responsiveness to carbachol was determined by measuring the change in specific lung resistance (SR_L) to increasing concentrations of carbachol aerosol, and then identifying, by linear interpolation, the provocative carbachol concentration which produced a 150% increase (PC₁₅₀) in SR_L. Airway responses to LTD₄, and antigen were determined by measuring the percentage change in SR_L after a controlled inhlation challenge with either aerosol. Airway responsiveness to carbachol was not different between the two groups. There was, however, a difference (p<0.05) in the airway response to the same dose of LTD₄ in the two groups. Dual responders showed a 297±72% increase in SR_L as compared to a 90±13% increase in SR_L in the acute responders. Dual responders also showed a greater immediate and more prolonged response to antigen than did acute responders. These results suggest that increased responsiveness to LTD₄ may be one factor which may distinguish dual responders from acute responders.     

Late phase bronchial obstruction following nonimmunologic mast cell degranulation

Immunologic degranulation of airway mast cells after antigen inhalation produces early and late airway obstructions in allergic sheep. In this study we determined whether nonimmunologic degranulation of airway mast cells by inhalation of compound 48/80 had similar effects. In five sheep, pulmonary flow resistance (RL), thoracic gas volume (Vtg), and arterial O2 tension (Pao2) were determined prior to and at predetermined times after inhalation of 48/80 aerosol. Immediately after challenge mean specific lung resistance (sRL = RL X Vtg) increased by 259% and mean Pao2 decreased by 29%. All values returned to normal by 3 h. By 5-h postchallenge sRL again increased significantly; this second increase in sRL (92% above base line) was maximal at 7 h and was accompanied by a 17% drop in Pao2. In these same sheep inhalation of Ascaris suum antigen produced comparable early changes in sRL, but the onset of the late response was somewhat delayed and more pronounced. In a second group of sheep (n = 5), pretreatment with the mast cell stabilizer cromolyn sodium prevented both early and late responses by compound 48/80. Pretreatment with the histamine H1-antagonist chlorpheniramine had no significant effect on either response, whereas pretreatment with FPL 55712, an antagonist of slow-reacting substance of anaphylaxis (SRS-A), slightly but not significantly attenuated the early response and completely prevented the late response. We conclude that, like immunologic stimuli, nonimmunologic mast cell degranulation produces early and late bronchial obstructions in allergic sheep; that these responses are mediator dependent; and that while histamine and SRS-A contribute to the early response, it is the early appearance of SRS-A which is an important prerequisite for the late response.     

Production of early and late pulmonary responses with inhaled leukotriene D4 in allergic sheep

Some allergic sheep respond to inhalation of antigen with both immediate and late increases in airflow resistance (late response). The mechanism of the late response is unknown but recent evidence suggests that the initial generation of slow-reacting substance of anaphylaxis (SRS-A) immediately after antigen challenge is a necessary pre-requisite for the physiologic expression of this late response. Based on this evidence we hypothesized that airway challenge with leukotriene D₄ (LTD₄), an active component of SRS-A would produce acute and late airway responses in allergenic sheep similar to those observed with antigen. In five allergic sheep with documented early and late pulmonary responses to antigen, inhalation of leukotriene D₄ aerosol (delivered dose {mean ±SE} 0.55±0.08 ug) resulted in significant early and late increases in specific lung resistance (SR_L). In three allergic sheep which only demonstrated acute responses to antigen, LTD₄ aerosol (delivered dose 0.59±0.09ug) only produced an acute increase in SR_L. In the late responders pretreatment with aerosol cromolyn sodium (1 mg/kg) did not affect the acute response but blunted the late increase in SR_L. Pretreatment with aerosol FPL-57231 (1% w/v solution) completely blocked both the acute and late responses. These data support the hypothesis that initial release of LTD₄ in the airways of sensitive animals is important for the physiologic expression of the late response.     

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.     

TNF-alpha induced bronchial vasoconstriction

The pro-inflammatory characteristics of tumor necrosis factor-alpha (TNF-alpha) have been extensively characterized in in vitro systems. Furthermore, this cytokine has been shown to play a pivotal role in airways inflammation in asthma. Since the airway vasculature also performs an essential function in inflammatory cell transit to the airways, experiments were performed to determine the effects of TNF-alpha on bronchial vascular resistance (BVR). In anesthetized, ventilated sheep, the bronchial artery (BA) was cannulated and perfused with autologous blood. BVR was defined as inflow pressure/flow and averaged 6.3 +/- 0.2 mmHg. ml(-1). min(-1) (+/-SE) for the 25 sheep studied. Recombinant human TNF-alpha (10 microg for 20 or 40 min) infused directly into the BA resulted in a significant decrease in BVR to 87% of baseline (P < 0.05). This vasodilation was followed by a reversal of tone by 120 min and a sustained increase in BVR to 126% of baseline (P < 0.05). Since others have shown TNF-alpha caused coronary vasoconstriction through endothelial release of endothelin-1 (ET-1), an ET-1 antagonist was used to block bronchial vasoconstriction. BQ-123, a selective ET(A) receptor antagonist, was delivered to the bronchial vasculature prior to TNF-alpha challenge. Attenuation of bronchial vasoconstriction was observed at 120 min (P < 0.03). Thus TNF-alpha causes bronchial vasoconstriction by the secondary release of ET-1. Although TNF-alpha exerts pro-inflammatory actions on most cells of the airways, vasoactive properties of this cytokine likely further contribute to the inflammatory status of the airways.     

Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Effect of hypoxia on bronchial circulation

We studied the effect of systemic hypoxia on the bronchial vascular pressure-flow relationship in anesthetized ventilated sheep. The bronchial artery, a branch of the bronchoesophageal artery, was cannulated and perfused with a pump with blood from a femoral artery. Bronchial blood flow was set so bronchial arterial pressure approximated systemic arterial pressure. For the group of 25 sheep, control bronchial blood flow was 22 ml/min or 0.7 ml.min-1.kg-1. During the hypoxic exposure, animals were ventilated with a mixture of N2 and air to achieve an arterial PO2 (PaO2) of 30 or 45 Torr. For the more severe hypoxic challenge, bronchial vascular resistance (BVR), as determined by the slope of the linearized pressure-flow curve, decreased acutely from 3.8 +/- 0.4 mmHg.ml-1.min to 2.9 +/- 0.3 mmHg.ml-1.min after 5 min of hypoxia. However, this vasodilation was not sustained, and BVR measured at 30 min of hypoxia was 4.2 +/- 0.8 mmHg.ml-1.min. The zero flow intercept, an index of downstream pressure, remained unaltered during the hypoxic exposure. Under conditions of moderate hypoxia (PaO2 = 45 Torr), BVR decreased from 4.6 +/- 0.3 to 3.8 +/- 0.4 mmHg.ml-1.min at 5 min and remained dilated at 30 min (3.6 +/- 0.5 mmHg.ml-1.min). To determine whether dilator prostaglandins were responsible for the initial bronchial vascular dilation under conditions of severe hypoxia (PaO2 approximately equal to 30 Torr), we studied an additional group of animals with pretreatment with the cyclooxygenase inhibitors indomethacin (2 mg/kg) and ibuprofen (12.5 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Measurement of bronchial arterial blood flow and bronchovascular resistance in sheep

We studied the bronchial arterial blood flow (Qbr) and bronchial vascular resistance (BVR) in sheep prepared with carotid-bronchial artery shunt. Nine adult sheep were anesthetized, and through a left thoracotomy a heparinized Teflon-tipped Silastic catheter was introduced into the bronchial artery. The other end of the catheter was brought out through the chest wall and through a neck incision was introduced into the carotid artery. A reservoir filled with warm heparinized blood was connected to this shunt. The height of blood column in the reservoir was kept constant at 150 cm by adding more blood. Qbr was measured, after interrupting the carotid-bronchial artery flow, by the changes in the reservoir volume. The bronchial arterial back pressure (Pbr) was measured through the shunt when both carotid-bronchial artery and reservoir Qbr had been temporarily interrupted. The mean Qbr was 34.1 +/- 2.9 (SE) ml/min, Pbr = 17.5 +/- 3.3 cmH2O, BVR = 3.9 +/- 0.5 cmH2O X ml-1 X min, mean pulmonary arterial pressure = 21.5 +/- 3.6 cmH2O, and pulmonary capillary wedge pressure (Ppcw) = 14.3 +/- 3.7 cmH2O. We further studied the effect of increased left atrial pressure on these parameters by inflating a balloon in the left atrium. The left atrial balloon inflation increased Ppcw to 25.3 +/- 3.1 cmH2O, Qbr decreased to 21.8 +/- 2.4 ml/min (P less than 0.05), and BVR increased to 5.5 +/- 1.0 cmH2O.ml-1.min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central role of cyclooxygenase in the response of canine peripheral airways to antigen

We studied the effects of antigen aerosol challenge on the airways of the canine peripheral lung and examined the roles of cyclooxygenase products, histamine, and cholinergic activity in the responses. One-minute deliveries of 1:10,000 or 1:100,000 concentrations of Ascaris suum antigen aerosol through a wedged bronchoscope resulted in mean maximal increases in collateral system resistance (Rcs) of 415 and 177%, respectively, after 4-8 min. Repeated antigen challenge (1:100,000) resulted in significantly decreased responsiveness to antigen after the initial exposure (P less than 0.005). Bronchoalveolar lavage fluid obtained from the isolated, challenged segment had a significant increase in mean (+/- SE) prostaglandin D2 (PGD2) concentration vs. control (222.0 +/- 65.3 vs. 72.7 +/- 19.5 pg/ml; P less than 0.05); histamine concentrations were variable and not significantly different (4.1 +/- 2.6 vs. 1.2 +/- 0.2 ng/ml; P greater than 0.05). In nine experiments, cyclooxygenase inhibition significantly attenuated the antigen-induced increase in Rcs by 53.4% (P less than 0.001), and the concentration of PGD2 in lavage fluid was reduced by 96.0% (P less than 0.01). Blockade of histamine H1-receptors (n = 8) or cholinergic receptors (n = 7) did not significantly affect the airway response (P greater than 0.05). These data indicate that the canine peripheral lung responds in a dose-dependent manner to antigen aerosol challenge and exhibits characteristics of antigen tachyphylaxis. Results also suggest that cyclooxygenase products play a central role in the acute bronchoconstrictive response of the lung periphery.     

A possible role for PAF in allergen-induced late responses: modification by a selective antagonist

We determined whether platelet-activating factor (PAF) plays a role in allergen-induced airway responses by studying the effects of a selective PAF antagonist WEB-2086 on antigen-induced early and late airway responses in allergic sheep. In seven sheep, inhaled Ascaris suum produced significant early (282%) and late (176%) increases in specific lung resistance (sRL). WEB-2086 (1 mg/kg iv) given 20 min before antigen challenge did not affect the early response, but the peak late increase in sRL was only 37% over base line (P less than 0.05 vs. control). To study the mechanism by which PAF contributes to antigen-induced responses, we evaluated the effects of pharmacological probes on PAF-induced bronchoconstriction. Inhaled PAF (dose range 75-700 micrograms) caused reproducible (r = 0.781, P less than 0.05) increases in sRL in eight sheep. The PAF-induced bronchoconstriction was blocked by WEB-2086 (1 mg/kg iv) and by the leukotriene antagonist FPL-55712 (30 mg by aerosol); however, neither the cyclooxygenase blocker indomethacin (2 mg/kg iv) nor the histamine H1-antagonist chlorpheniramine (2 mg/kg iv) blocked the PAF response. WEB-2086, however, did not block bronchoconstriction induced by aerosol leukotriene D4, indicating that PAF acts indirectly through leukotrienes. Finally, we determined whether PAF could induce late airway responses. Inhaled PAF produced an immediate increase in sRL in all seven sheep tested, but late airway responses were observed in only three of the seven sheep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antigen stimulates glycoprotein secretion and alters ion fluxes in sheep trachea

We studied the effects of in vitro challenge with specific antigen (Ascaris suum antigen) on glycoprotein secretion and ion fluxes in tracheal tissues from allergic sheep. We mounted tissues in Perspex chambers and measured secretion of 35S- and 3H-labeled glycoproteins and fluxes of Cl- and Na+. In tissues from allergic sheep, A. suum antigen (25 micrograms protein X ml-1) increased glycoprotein secretion. A. suum antigen initially reversed net Cl- flux, causing net absorption of Cl- and of Na+. This was followed 15-30 min later by net secretion of Cl- and of Na+. Pretreatment of tissues with cromolyn (10(-4) M) greatly reduced the effects of A. suum antigen but did not abolish them. The cromolyn-resistant effects were nonspecific, because they were similar to those of in vitro challenges with nonspecific proteins, ovalbumin and ragweed in allergic sheep, and A. suum antigen in nonallergic sheep. We conclude that challenge with A. suum antigen results in mucus hypersecretion in airways of allergic sheep, by both specific and smaller nonspecific effects. Specific effects (cromolyn sensitive) are produced by mediators which are released from airway cells in response to A. suum challenge.     

Effects of antihistamines on the cardiopulmonary changes due to canine anaphylaxis

Histamine has long been considered to be an important chemical mediator in the pathogenesis of immediate hypersensitivity reactions. We evaluated the efficacy of antihistamines to determine the physiological role of histamine in canine anaphylaxis. Either a saline vehicle (control group), an H1 antihistamine (chlorpheniramine, 10 mg/kg), or this H1 antihistamine and an H2 antihistamine (cimetidine, 30 mg/kg) was administered to three separate groups of anesthetized dogs (n = 8). Cardiopulmonary responses and plasma histamine levels were measured after the separate intravenous injection of Ascaris suum antigen and histamine. Results were analyzed only from the animals demonstrating physiological responses or histamine release after antigen injection. In the control group, antigen produced a 43 +/- 15% (mean +/- SE) decrease in mean arterial blood pressure, a 34 +/- 13% fall in cardiac output, and a 19 +/- 9% decrease in lung compliance, whereas pulmonary vascular resistance increased 161 +/- 87% and airway resistance rose 114 +/- 66%. Similar physiological abnormalities were observed with histamine shock. However, peak plasma histamine levels were, in most cases, greater after histamine injection than after antigen injection. An H1 antihistamine alone or in combination with an H2 antihistamine did not alter the physiological changes associated with systemic anaphylaxis. In contrast, the combined use of H1 and H2 antihistamines prevented the cardiopulmonary responses associated with the intravenous administration of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)