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Biomedical subjects

W M Abraham

Publications and source records attributed to W M Abraham.

At least 91 records · Page 5Linked to original sources
PubMed1990

Increased leukotriene E4 excretion during antigen-induced bronchoconstriction in allergic sheep.

The metabolism of leukotrienes (LT) in the sheep was investigated to define markers of 5-lipoxygenase involvement in allergic responses, obtainable by noninvasive techniques. Intravenous administration of 14, 15-[3H]LTC4 (0.5 microCi/kg) revealed a rapid clearance from the circulation (half time = 90 s). Circulatory metabolism was apparent, with early formation (within 1 min) of LTD4 and LTE4 shown by reverse-phase high-pressure liquid chromatography (RP-HPLC). Urinary 3H excretion comprised 10% of the original dose. [3H]LTE4 (characterized by coelution with authentic standards during RP-HPLC analysis) was observed in early urine samples. By use of a sensitive and specific RP-HPLC radioimmunoassay analysis, immunoreactive material coeluting with LTE4 was detected in urine from allergic sheep. Excretion of this material was significantly increased during antigen-induced acute bronchoconstriction in eight conscious allergic sheep [preantigen, 65.70 +/- 24.27 (SE) pg; 0-1 h postantigen, 208.00 +/- 71.10 pg, P less than 0.05], but not during late responses. However, total postantigen LTE4 excretion (37.8 - 956.1 pg/8 h) was highly correlated (r = 0.976, P less than 0.001) with the severity of bronchoconstriction (445.3 - 2,409.1% specific pulmonary resistance per hour) assessed by measurement of the area under the curve of pulmonary function plotted against time. These findings represent an important demonstration of in vivo allergen-induced peptide LT generation in a physiologically characterized animal model of prolonged allergic bronchoconstriction and further substantiate an important role for LT in this model of allergic asthma.

Animals↗
PubMed1990

Effect of ozone on the postnatal development of lamb mucociliary apparatus.

We determined whether exposure to O3 early in the postnatal period impairs the normal development of the mucociliary apparatus in lambs and whether such changes lead to prolonged abnormalities in mucociliary function. Lambs were exposed to air (controls) or to 1 ppm O3 for 4 h/day for 5 days during the 1st wk of life. Tracheal mucus velocity (TMV), a marker of lung mucociliary clearance, was measured in vivo at birth (0 wk) and up to 24 wk later, and tracheal secretory function was measured (in vitro) and the morphology of the tracheal mucosa was determined at 0 and 2 wk in both groups. In the control group, TMV increased 94% from 0 to 2 wk (P less than 0.05), continued to increase until reaching a plateau at 8 wk, and then remained constant from 8 to 24 wk. In contrast, O3-exposed lambs showed a 24% decrease in TMV from 0 to 2 wk (P less than 0.05 vs. control), and throughout the remaining time TMV remained below (P less than 0.05) that observed in control lambs. O3 exposure partially prevented the age-dependent decrease in basal secretion of tracheal macromolecules normally observed between 0 and 2 wk. These changes in secretory function were associated with a significant increase in tissue conductance (37%, P less than 0.05 vs. 0 wk), predominantly the result of active chloride secretion. The functional changes induced by O3 were associated with a retardation of the normal morphological development of the tracheal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Late-phase bronchial vascular responses in allergic sheep.

Sheep were classified on the basis of their airway response to Ascaris suum antigen aerosols as allergic or nonsensitive. Allergic sheep were classed as acute or dual responders. Acute responders had only an immediate increase in mean airflow resistance after antigen, whereas dual responders had an immediate and late-phase (6-8 h after antigen challenge) increase in mean airflow resistance; nonsensitive sheep had minimal airway responses to antigen (less than 30% increase from base line). The sheep were anesthetized 2 wk later and, after a left thoracotomy, were challenged with antigen to determine bronchial vascular responses; bronchial artery blood flow was measured with an electromagnetic flow probe. Airway responses to antigen aerosol challenge were similar in the anesthetized and conscious animals. The mean fall in bronchial vascular resistance (BVR) immediately after antigen challenge was similar in acute and dual responders (41 +/- 7 and 47 +/- 9% of base line, respectively). In dual responders, late-phase airway responses were preceded by a significant increase from base line in Qbr and a fall in bronchovascular resistance (BVR). The mean fall in BVR 6-8 h after antigen challenge in documented dual responders was significantly different from bronchial vascular responses in acute responders (59 +/- 3 vs. 89 +/- 10%, respectively). Sheep without airway responses to A. suum had no significant changes in bronchial hemodynamics or airways mechanics. Late-phase-associated changes in BVR are a specific response to antigen challenge and may be a sensitive index of mediators being released.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1990

Vasomotion influences airflow in peripheral airways.

The purpose of this study was to test the hypothesis that blood flow, by its effect on blood volume, influences airflow resistance in peripheral airways. In conscious ewes, forced sinusoidal flow oscillations (5 Hz) were applied through a balloon-tipped, dual-channel fiberoptic bronchoscope placed in a segmental bronchus, and peripheral airflow resistance (Rp) was determined from flow and bronchial pressure. Drugs with predominant vascular or airway smooth muscle effects were administered locally through the bronchoscope. Nitroglycerin (NTG) produced a dose-dependent increase in mean Rp (+288% at 1,000 micrograms), which was blocked by methylene blue (p less than 0.05) and not reversed by atropine. Carbachol (CARB) also increased mean Rp in a dose-dependent manner (+605% at 400 micrograms); this effect was not blocked by methylene blue, but it was reversed by atropine (p less than 0.05). The increase in mean Rp after a single dose of NTG (250 micrograms) was sustained for at least 20 min and transiently reversed by vasopressin (0.2 units, p less than 0.05) but not by isoproterenol (100 micrograms). Conversely, the sustained increase in Rp after a single dose of CARB (50 micrograms) was transiently reversed by isoproterenol (p less than 0.05) but not by vasopressin. We conclude that NTG increased Rp by vasodilation and CARB by bronchoconstriction. This supports the hypothesis that vasodilation limits airflow in the lung periphery, presumably because of vascular congestion.

Airway Resistance↗
PubMed1989

YM461, a PAF antagonist, blocks antigen-induced late airway responses and airway hyperresponsiveness in allergic sheep.

We examined the effect of an orally active antagonist, YM461, of platelet activating factor (PAF) on antigen-induced early and late airway responses and on the development of airway hyperresponsiveness 24 h after challenge in allergic sheep. Early and late airway responses were determined by measuring specific lung resistance (SRL) before and periodically after challenge. Airway responsiveness was determined from the slopes of dose-response curves of SRL vs. increasing doses of carbachol aerosol. The sheep were challenged with Ascaris suum antigen once after vehicle treatment (control) and once 1 h after oral administration of 3 or 10 mg/kg YM461 (each trial was greater than or equal to 14 days apart). Airway responsiveness to carbachol was determined 1-3 days prior to and 24 h after antigen challenge. In control 1 and control 2 trials antigen challenge caused significant peak early (288 and 292%, respectively) and peak late (103 and 124%, respectively) increases over baseline in SRL. SRL returned to baseline 24 h after challenge but the sheep developed airway hyperresponsiveness as indicated by the 2.6-fold increases in the slopes of the carbachol dose-response curves in the control trials. YM461, 3 and 10 mg/kg p.o., significantly inhibited the late responses (66 and 82%, respectively) and blocked the development of airway hyperresponsiveness at 24 h. The early responses were not significantly reduced in either trial. These results suggest that PAF contributes to the antigen-induced late airway responses and associated airway hyperresponsiveness in allergic sheep.

Aerosols↗
PubMed1989

The effect of an orally active leukotriene (LT) antagonist YM-16638 on antigen-induced early and late airway responses in allergic sheep.

In this study we examined the effects of an orally active leukotriene (LT) antagonist YM-16638 [[5-[[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propyl]thio]-1,3,4- thiadiazol-2-yl]thio] acetic acid on antigen-induced early and late responses in allergic sheep. For all studies YM-16638 was administered via intragastric tube 1 h before airway challenge with Ascaris suum antigen. Six allergic sheep were challenged on four occasions (2 control and 2 drug trials) each greater than or equal to 14 days apart and the tests were conducted in the following order: control-1; YM-16638 30 mg/kg; control-2; YM-16638 10 mg/kg. Specific lung resistance (SRL) was used as an index of the airway response to antigen and was measured before and serially after antigen challenge. In both control trials antigen challenge resulted in significant early and late airway responses (i.e. increases in SRL); however, there was a significant difference between the peak late increases of SRL in control-1 (206%) and control-2 (115%) suggesting a carry-over effect of the 30 mg/kg dose of YM-16638. At both doses, YM-16638 reduced the early response and blocked the late response when compared to either control trial. These results suggest that sulfidopeptide LTs contribute to both antigen-induced early and late airway responses in allergic sheep.

Airway Resistance↗
PubMed1989

Pharmacology of allergen-induced early and late airway responses and antigen-induced airway hyperresponsiveness in allergic sheep.

The pharmacology of antigen-induced early and late phase airway responses and the associated antigen-induced airway hyperresponsiveness was studied in allergic sheep. Data from studies with anti-allergic agents and specific receptor antagonists, especially leukotriene antagonists and antagonists of platelet activating factor (PAF), have led to the hypothesis that allergen-induced late responses in allergic sheep are linked to a heightened metabolism of arachidonic acid via the 5-lipoxygenase pathway. This increases leukotriene production during the acute allergic reaction, which results in a more prolonged acute bronchoconstriction and subsequently a more severe airway inflammation. These recruited inflammatory cells can then release mediators and other cell products which contribute to the late response and airway hyperresponsiveness.

Allergens↗
PubMed1989

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)

Aerosols↗
PubMed1989

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.

Airway Resistance↗
PubMed1989

Developmental changes in the tracheal mucociliary system in neonatal sheep.

We studied the postnatal development of the tracheal epithelium and mucociliary system in neonatal sheep. Secretion of macromolecules (radiolabeled with 35SO4 and [3H]-threonine), unidirectional fluxes of Cl-, Na+, and water (measured with radioactive tracers), and ciliary beat frequency (CBF) were measured in tracheal tissues in vitro. Tracheal mucus transport velocity (TMV) was measured in vivo. Sheep were studied at 0, 2, 4, 8, and greater than 24 (adult) wk after birth. In newborn sheep trachea, secretion of macromolecules was significantly elevated (cf. adults), and there was basal net secretion of Cl- under short-circuit and open-circuit conditions. This induced open-circuit secretion of Na+. Secretion of macromolecules decreased rapidly by 2 wk (by 40-50%) and was not different from adult values by 4 wk. Active Na+ absorption developed rapidly, and from 2 wk onward it predominated under open-circuit conditions, inducing net Cl- absorption. These changes in secretory function were associated with an age-related increase in TMV, whereas inherent tracheal CBF was unchanged. In sheep, therefore, the newborn's trachea has elevated secretion of macromolecules and secretes Cl- and liquid under basal conditions. Normal secretory function (a reduction in secretion of macromolecules coupled with net absorption of ions and presumably of liquid also) approaches adult function by 2-4 wk of age.

Animals↗
PubMed1989

Role of arachidonic acid metabolites in allergen-induced late responses.

The sheep model of allergic airway disease shares many pathophysiological similarities with allergic airway disease in humans. Studies performed in this animal model present strong evidence that the release of arachidonic acid metabolites plays an important role in the development of late bronchial responses to antigen challenge. The release of leukotrienes through the lipoxygenase pathway during the acute bronchial obstruction after inhalation of Ascaris suum antigen represents the key factor for the initiation of the subsequent events, namely the late phase response and the bronchial hyperreactivity. If this hypothesis can be substantiated in patients with bronchial asthma then pharmacologic modification of the lipoxygenase pathway and/or products may be important in the treatment of asthma.

Animals↗
PubMed1989

Enhanced aerosol deposition in the lung with mild airways obstruction.

We investigated the sensitivity of aerosol deposition to airways obstruction by measuring total deposition fraction of inert aerosol in normal conscious sheep (n = 6) after challenging cholinergic agent, pilocarpine (PL) (0.5 mg/kg intravenously) with and without a prior challenge of beta 2-adrenergic agonist, terbutaline sulfate (TS) (0.025 mg/kg subcutaneously). Aerosol deposition was measured by a light-scattering aerosol photometer in situ while sheep rebreathed 1.0-micron-diameter inert oil droplets from a 0.2-L collapsible bag at a rate of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as a percentage of initial aerosol concentration was determined and compared with mean pulmonary airflow resistance (RL). After PL, both AD5 and RL increased significantly from baseline values by 51 +/- 9% and 597 +/- 118% (mean +/- SE), respectively, whereas AD5 and RL decreased significantly by 16 +/- 4% and 34 +/- 6%, respectively after TS (p less than 0.05). After PL subsequent to TS (TS-PL), AD5 increased in all six sheep by 33 +/- 7% from post-TS values (p less than 0.05). However, RL did not change from post-TS values. Greater changes in RL than in AD5 after PL (bronchoconstriction) or TS (bronchodilation) suggest a greater sensitivity of RL than AD5 to airway patency in the large airways. Lack of increase of RL after TS-PL indicates that bronchoconstrictive effect of PL was blocked by prior challenge with TS. Therefore, the increase in AD5 after TS-PL may be related to the peripheral airway obstructions which might have been caused by increased secretions induced by a potent secretagogue PL.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1989

Effect of calcium antagonist gallopamil on antigen-induced early and late bronchoconstrictor responses in allergic sheep.

Calcium channel blockers have been shown to modify acute antigen-induced bronchoconstriction in allergic animals and in some human subjects with bronchial asthma; however, the effects of calcium antagonists on late-phase bronchial responses are not known. In this investigation, we studied the effects of calcium antagonist gallopamil on antigen-induced early- and late-phase bronchial responses in sheep allergic to Ascaris suum antigen. In 11 unsedated sheep, specific lung resistance (SRL) was measured before, immediately after, and serially up to 8 h after inhalation challenge with A. suum antigen. On different experiment days, at least 3 wk apart, the sheep were pretreated with gallopamil, administered either as an aerosol (5 mg, n = 10; 10 mg, n = 9) or as an intravenous injection (20 micrograms/kg, n = 10), and the antigen challenge was repeated. For the control experiments (n = 11), mean +/- SE SRL increased immediately after antigen challenge (early response) to 533 +/- 72% of baseline and again 6 to 8 h after challenge (late response) to 304 +/- 31% of baseline (p less than 0.05). Neither intravenously administered nor aerosolized gallopamil had a significant effect on baseline SRL. Both aerosolized and intravenously administered gallopamil blunted the early response and completely blocked the late-phase bronchoconstrictor response (p less than 0.05). Mean SRL during early phase increased to 208 +/- 39% and 245 +/- 39% of baseline with 5 mg and 10 mg of aerosolized gallopamil and to 191 +/- 35% of baseline with intravenously administered gallopamil, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Platelet-activating factor (PAF)-dependent biochemical, morphologic, and physiologic responses of human platelets: demonstration of translocation of protein kinase C associated with protein phosphorylation.

Platelet-activating factor (PAF) is a potent stimulus for platelet aggregation and secretion. PAF has been shown to stimulate the phosphatidylinositol (PI) pathway in platelets, which implies that PAF should activate protein kinase C. In this study, measurements of PI metabolites, the elevation of intracellular free calcium concentration, (Ca2+)i, the activation of protein kinase C, and the phosphorylation of platelet proteins (using a two-dimensional gel electrophoretic technique) were performed before and after the addition of 10(-8) M PAF to human platelets. These findings were correlated with morphologic changes in the platelets as determined by immunoelectron microscopic studies on the cytoskeleton and by X-ray analysis of dense bodies. The results show that PAF stimulates the production of PI metabolites and causes an increase in the membrane-associated activity of protein kinase C. These changes are accompanied by a rise in the (Ca2+)i and protein phosphorylation. The increase in protein kinase C activity reaches a maximum at approximately 60 s, a time frame that is consistent with the protein phosphorylation and the subsequent morphologic and secretory events. X-ray analysis revealed two types of dense bodies containing various amounts of calcium which appeared to be released sequentially after PAF activation. These results suggest that the protein phosphorylation that controls the physiologic events resulting from PAF activation of human platelets is catalyzed by protein kinase C.

Actins↗