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Platelet-activating factor (PAF) has been implicated as a mediator of airway hyperresponsiveness. PAF, infused intra-arterially into the canine cervical trachea, causes adherence of neutrophils to vascular endothelium, increases vascular permeability, and increases the responsiveness of tracheal muscle to parasympathetic stimulation. We hypothesized that the increase in airway responsiveness induced by PAF in this model depends on the presence of neutrophils. To test this hypothesis, we perfused a cervical tracheal segment with autologous blood depleted of leukocytes or with similar leukocyte-depleted blood that had been repleted with its neutrophils. Fifteen minutes after the onset of perfusion with either leukocyte-depleted or neutrophil-repleted blood, PAF infusion was begun into the tracheal arterial vasculature. The contractile response of the tracheal muscle to parasympathetic stimulation was measured before and 15 and 30 min after the onset of PAF infusion. PAF did not significantly change the response of tracheal muscle during perfusion with neutrophil-depleted blood but increased the response of tracheal muscle during perfusion with neutrophil-repleted blood. We conclude that the increase in canine tracheal muscle response induced by intra-arterial PAF depends on neutrophils.

We investigated the role of platelet-activating factor (PAF) in ozone-induced airway responses by examining the effects of L659,989, a potent PAF antagonist, on bronchial hyperresponsiveness and airway inflammation. Twenty-four male guinea pigs were studied in four equal groups. Total lung resistance (RL) in intubated and spontaneously breathing animals was measured in a constant-volume body plethysmograph. Dose-response curves to methacholine were determined in all animals at the start of the experiment. These were repeated on a separate day after the following types of treatments: air exposure in Group 1, intraperitoneally administered alcohol and air exposure in Group 2; intraperitoneally administered alcohol and ozone exposure in Group 3, and intraperitoneally administered L659,989 (a specific PAF antagonist), 5 mg/kg dissolved in alcohol, and ozone exposure in Group 4. Bronchoalveolar lavage (BAL) was performed after the second methacholine challenge, and the bronchial mucosa was also examined for inflammatory cells. Exposure to 3 ppm ozone for 2 h resulted in a three-doubling concentration increase in bronchial responsiveness, which was not significantly inhibited by prior treatment with L659,989. Ozone induced a 1.8-fold increase in BAL total cell count, increased eosinophilic influx into the airways, and increased eosinophilic infiltration in the bronchial mucosa, which were all not inhibited by L659,989 pretreatment. The results suggest that PAF may not have an essential role in ozone-induced airway hyperresponsiveness and nonallergic airway inflammation.

To determine the relationship of inflammatory cells and eicosanoid mediators to the pathogenesis of the late asthmatic response (LAR) and increases in nonspecific airway responsiveness, we studied bronchoalveolar lavage (BAL) cells and fluid in 27 subjects 12 hours after inhaled antigen challenge. Methacholine challenge was performed before antigen challenge and 24 hours later (12 hours after BAL). Eight subjects had no LAR (-LAR, less than or equal to 10% fall in FEV1), nine subjects had an equivocal LAR (+/- LAR, 11% 25% fall in FEV1), and 10 subjects had a definite LAR (+LAR, greater than 25% fall in FEV1). Subjects developing +LAR had increased airway responsiveness at baseline compared with that of subjects developing an +/- LAR, but not with subjects having -LAR. If airway responsiveness was markedly increased at baseline, further increases after antigen challenge were often not observed. We found that both percent neutrophils and eosinophils increased in BAL as the severity of the LAR increased, but significant differences between the groups with -LAR and +LAR were only observed when both cell types were considered together. In addition, there was a significant correlation between the combined cell percentages and the severity of the LAR as determined by fall in FEV1. Likewise, increases in airway responsiveness were associated with significant increases in both neutrophil and eosinophil numbers, but only neutrophils correlated with the change in airway responsiveness after antigen challenge. However, despite the significant physiologic and cellular differences that we found between our groups, no significant differences could be found in BAL eicosanoid-mediator concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-activating factor (PAF) has potent effects on the respiratory airways that may be mediated through its ability to act as an inflammatory stimulant. To study its inflammatory properties in the airways, we infused PAF into the vasculature of the canine trachea and examined (1) the kinetics of neutrophil transit through the tracheal microcirculation, (2) accompanying changes in vascular permeability, and (3) the dependence of vascular permeability changes on neutrophil accumulation. Neutrophil kinetics were assessed by measuring the transit times of fluorescein isothiocyanate-labeled canine neutrophils by in vivo microscopy. Changes in vascular permeability were measured by the extravascular leakage of radiolabeled albumin and comparison of wet-to-dry weight ratios. The importance of neutrophils in increasing vascular permeability was assessed by perfusing the trachea with either autologous blood depleted of its leukocytes, or leukocyte-depleted blood replenished with neutrophils. Our data indicate that PAF causes rapid and prolonged neutrophil accumulation in the canine trachea and an increase in vascular permeability that is partially mediated by neutrophils.

Airway cooling causes bronchoconstriction in many persons who have asthma. To determine the direct effect of cooling on the response of tracheal muscle to parasympathetic and muscarinic stimuli in situ, the temperature of a segment of canine cervical trachea was adjusted to 37 degrees, 30 degrees, or 25 degrees C by superfusing temperature-controlled saline over its epithelial surface. The contractile response of the tracheal muscle to electrical stimulation of the vagus nerves and to intra-arterial acetylcholine was then determined. Cooling the segment to 25 degrees C decreased the contraction induced by parasympathetic stimulation. However, cooling did not alter the contraction induced by intra-arterial acetylcholine. Parallel studies were conducted in vitro using nine excised tracheal muscle strips taken from the same section of trachea in three additional dogs. Cooling the tracheal muscle to 25 degrees C in vitro increased the maximal contraction induced by both electrical field stimulation and by acetylcholine. Thus, cooling in situ does not alter the response of tracheal muscle to muscarinic stimuli and inhibits the response to parasympathetic stimuli. These data indicate that augmentation of the tracheal muscle response elicited by cooling in vitro does not reflect the response in situ. They suggest that a direct effect of cooling on airway smooth muscle response to parasympathetic and muscarinic stimuli does not account for cooling-induced bronchoconstriction in vivo.

To determine whether cyclooxygenase inhibitors alter parasympathetic control of airway smooth muscle in situ, we pretreated anesthetized dogs with intravenous indomethacin, meclofenamate, or normal saline and measured the isometric contraction of tracheal muscle in response to electrical stimulation of the vagus nerves. Indomethacin and meclofenamate increase the response of airway smooth muscle to parasympathetic stimulation. In subsequent experiments to determine the site of action of cyclooxygenase inhibitors, we found that indomethacin does not alter the response of tracheal muscle to intra-arterial acetylcholine (a muscarinic agonist) but does augment the response to intra-arterial dimethylpiperaziniumiodide (a nicotinic agonist). Moreover, the response to parasympathetic stimulation after pretreatment with a combination of indomethacin and BW755C (a combined cyclooxygenase-lipoxygenase inhibitor) does not differ significantly from the response after indomethacin or meclofenamate alone. We conclude that cyclooxygenase inhibitors increase the sensitivity of the contractile response of tracheal smooth muscle to parasympathetic stimulation, that they exert their effect on the postganglionic parasympathetic neuron, and that their effect is prejunctional. The effect appears secondary to a decrease in cyclooxygenase products rather than to an increase in lipoxygenase products. These findings suggest that endogenous cyclooxygenase products may modulate parasympathetic control of airway smooth muscle in vivo. They may relate to the mechanisms that underlie airway hyperresponsiveness, by which mediators of inflammation modulate airway responsiveness and by which nonsteroidal anti-inflammatory drugs induce severe bronchoconstrictor responses in some persons who have asthma.

We studied the relationship between cough and bronchoconstriction caused by inhaled distilled water aerosol in 8 subjects with asthma by measuring specific airways resistance (SRaw) and recording cough while subjects breathed serially increasing volumes of distilled water or normal saline aerosol produced by an ultrasonic nebulizer. We performed the distilled water dose-response curves after no treatment and after treatment with cromolyn aerosol, lidocaine aerosol, or atropine aerosol in doses of 0.2 mg and 2.0 mg on separate days. Without prior treatment, distilled water aerosol caused cough in 7 of 8 subjects and a marked increase in SRaw in every subject, whereas saline aerosol did not cause cough or a greater than 50% increase in SRaw in any subject. The 2 doses of atropine caused an equivalent reduction in baseline SRaw, but 2.0 mg caused greater inhibition of water-induced bronchoconstriction than did 0.2 mg. Neither dose of atropine inhibited cough. These data suggest that water-induced bronchoconstriction involves cholinergic nerves and that water-induced cough is not dependent on bronchoconstriction. Lidocaine inhibited cough but not bronchoconstriction, whereas cromolyn inhibited bronchoconstriction but not cough, suggesting that cromolyn does not inhibit bronchoconstriction by a generalized inhibition of airway afferent nerves.

To determine whether sulfur dioxide and airway cooling and drying interact in causing bronchoconstriction in persons who have asthma, we measured specific airway resistance in seven asthmatic subjects before and after they performed voluntary eucapnic hyperpnea for 3 min breathing four different gas mixtures. The mixtures, which the subjects breathed through a mouthpiece in random order on 4 different days, were 1) humidified room-temperature air, 2) humidified room-temperature air containing 0.5 ppm SO2, 3) cold dry air, and 4) cold dry air containing 0.5 ppm SO2. Each subject breathed at a rate and depth known from preliminary studies to cause little or no bronchoconstriction when that subject inhaled 0.5 ppm SO2 in humidified room-temperature air or cold dry air. When given independently in the blinded study, 0.5 ppm SO2 or cold dry air again caused insignificant bronchoconstriction, but when given together the two stimuli caused significant bronchoconstriction, as indicated by an increase in specific airway resistance from 6.94 +/- 2.85 to 22.35 +/- 10.28 l X cmH2O X l-1 X s (mean +/- SD) (P less than 0.001). thus airway cooling and/or drying increases the bronchoconstriction induced by inhaled SO2 in persons who have asthma. This increase suggests that persons who have asthma may be more sensitive to the bronchoconstrictor effects of ambient SO2 in cold dry environments than in warm moist environments.

We studied the effect of leukotriene B4 aerosols on airway responsiveness to inhaled acetylcholine aerosols and on the cellular components and cyclooxygenase metabolites in bronchoalveolar lavage fluid in dogs. Inhalation of leukotriene B4 aerosols had no effect on resting total pulmonary resistance but increased airway responsiveness, an effect that was maximum in 3 h and that returned to control levels within 1 wk. Three hours after leukotriene B4, the number of neutrophils and the concentration of thromboxane B2 recovered in lavage fluid increased markedly. Pretreatment with the thromboxane synthase inhibitor OKY-046 prevented the increases in airway responsiveness and in thromboxane B2 but did not alter neutrophil chemotaxis. Thus we speculate that leukotriene B4 causes neutrophil chemotaxis and release of thromboxane B2, which increases airway responsiveness.

Six children aged 12-15 yr, deficient in endogenous growth hormone, were each treated, after a 7-day control period, for 7 days with 0.0168, 0.052, and 0.168 U/kg body wt3/4 human growth (hGH) (doses A, B, and C, respectively) in separate metabolic balance studies. Doses B and C caused a dose-related retention of N, P, K, Na, and Cl in ratios of 1/0.069/4.5/7.5/5.6. These ratios indicate increments in masses of protoplasm/extracellular fluid (ECF)/bone in ratios of 1/2.0/ less than 0.001. Three of the children were also treated with doses A, B, and C of reduced and carbamidomethylated hGH (RCAM-hGH). Doses B and C caused 1.2-2.8 times as much retention of N, P, and K, and 0.3-0.5 times as much retention of Na and Cl, as did the corresponding doses of hGH. The plasmin digest of RCAM-hGH gave results generally similar to RCAM-hGH. For RCAM-hGH and its plasmin digest, N, P, K, Na, and Cl were retained in ratios of about 1/0.14/5.4/2.2/2.1, indicating increments of protoplasm/ECF/bone of about 1/0.8/0.05. These findings indicate that reduction and carbamidomethylation alter the anabolic actions of hGH in man in both quantitative and qualitative manner. RCAM-hGH is more potent in stimulating enlargement of protoplasm and bone, and less potent in stimulating expansion of ECF, than is the native hormone. The profile of anabolic actions of RCAM-hGH in man does not appear to be further altered by digestion with plasmin.

Platelet-activating factor (PAF) increases the bronchoconstrictor response of mammalian airways to cholinergic agonists and is thus implicated as a potential mediator of airway hyperreactivity. This study further defines the nature of the increase in airway responsiveness induced by PAF. We employed an in situ canine tracheal preparation, which allows differentiation of the effects PAF has on airway smooth muscle contraction from confounding effects it has on inducing airway edema and secretions. We found that PAF, infused regionally into tracheal arteries, increases the responsiveness of the trachealis muscle to parasympathetic stimuli in a dose-dependent manner. This effect occurred within 15 min. To determine whether the increase in trachealis muscle responsiveness resulted from effects localized to the trachea, we compared the effect of PAF on the tracheal segment with effects of the lower airways of the lung. Delivered to the arteries perfusing the tracheal segment, PAF did not increase lung resistance during vagus nerve stimulation. These data indicate that airway hyperresponsiveness elicited by PAF results from regional stimulation and/or release of mediators that augment tracheal contractility and that this effect is distinct from systemic effects elicited by PAF.

To determine whether morphine sulfate alters the bronchoconstrictive response to inhalation of distilled water, we gave 13 subjects with mild asthma 0.15 mg/kg morphine sulfate or normal saline intravenously, after which they inhaled increasing volumes of nebulized distilled water from an ultrasonic nebulizer. We constructed stimulus-response curves, and by interpolation determined the provocative output of the nebulizer that resulted in a 50% increase in SRaw from baseline (PO50). On a separate day the subjects inhaled 2.0 mg of atropine sulfate 30 min before they inhaled distilled water. We compared the bronchoconstrictive response after morphine and after atropine with the bronchoconstrictive response after saline by determining the ratio of the PO50 values. Atropine was considered effective in inhibiting bronchoconstriction in 7 of the 13 subjects in whom the ratio of PO50 after atropine to the PO50 after saline was greater than 2.0. By similar criteria, morphine was also considered effective in 5 of these 7 subjects. Neither atropine nor morphine was effective in the remaining 6 subjects. By chi-square analysis, we found a positive correlation between the inhibitory effects of morphine and those of atropine (p less than 0.05). In the 5 subjects in whom morphine was effective, naloxone reversed the inhibitory effect of morphine. Atropine caused significant baseline bronchodilation when compared with placebo (normal saline), whereas morphine did not. We conclude that opiate receptor stimulation by morphine causes inhibition of the vagally mediated component of water-induced bronchoconstriction.

Severe protein-energy undernutrition is a frequent finding among chronically ill patients. Its causes are anorexia, hypermetabolism, and malabsorption. Adverse consequences include impaired cell-mediated immunity increased susceptibility to infection, poor wound healing, weakness, and death. Spontaneous oral intake is inadequate in patients with this disorder, and therapeutic maintenance or repletion alimentation is needed. Enteral hyperalimentation is the method of choice, if tolerated. A successful treatment program usually requires a small-bore, flexible nasoenteral tube, appropriate feeding solution, and constant flow delivery of nutrient. If only partial dietary requirements are tolerated enterally, peripheral intravenous nutrient solutions can often supply the deficit. Although not suitable for all patients, enteral hyperalimentation is more physiologic, safer, easier, and more economical than central venous hyperalimentation. It would be well tolerated by many patients who now receive nutritional repletion by the latter method.

We studied the effect of prostaglandin F2 alpha (PGF2 alpha) on the responsiveness of pulmonary airways in dogs. Airway responsiveness was assessed by determining the bronchoconstrictor response to increasing concentrations of acetylcholine aerosol delivered to the airways. In each of five dogs, we determined responsiveness during treatment with physiologic saline, histamine, or PGF2 alpha aerosols. The doses of histamine and PGF2 alpha were determined by establishing the largest dose of each which could be given to the dog without causing bronchoconstriction (subthreshold doses). We found that airway responsiveness was not significantly different during histamine treatment than after saline, however, responsiveness increased during treatment with PGF2 alpha. In addition, the hyperresponsiveness induced by PGF2 alpha was prevented by pretreatment with the ganglion blocking drug hexamethonium (5 mg/kg given intravenously). The results show that PGF2 alpha specifically increases the responsiveness of pulmonary airways in doses that do not cause bronchoconstriction, and suggest that the hyperresponsiveness involves a neural mechanism such as increased responsiveness of airway sensory nerves.

The effect of chemotherapy on the urinary excretion of a cancer-related glycoprotein labeled EDCl, recently isolated from the urine of a patient with acute myelocytic leukemia, has been studied by radioimmunoassay in eight cancer patients who were excreting 200 to 500 mg/day before treatment. In five patients, chemotherapy caused marked clinical improvement, and the glycoprotein disappeared from the urine within 10 days after chemotherapy began. In the two patients with solid tumor who responded to chemotherapy, disappearance of glycoprotein EDCl from the urine preceded clinical improvement by 1 to 2 months. Four of the five responsive patients relapsed within 6 months; in each instance, the glycoprotein reappeared in the urine (greater than 100 mg/day) 2 to 5 weeks before clinical relapse. Three patients were resistant to chemotherapy, and their urinary glycoprotein did not decline during chemotherapy. Measurement of urinary glycoprotein EDCl will be useful in rapidly ascertaining which drug will be effective in a cancer patient and in predicting relapse.

Two hundred children 7 to 14 years of age with isolated cleft defects of the lip, palate, or both were surveyed for stature. Twelve percent were less than the third percentile in height and were designated "short." All of the short children received an endocrine evaluation. Endogenous growth hormone was examined after two days' pretreatment with stilbesteral. Four of the 25 short children with CLP had total, and four had partial, GH deficiency. Three of the GH-deficient patients were also deficient in ACTH or TSH. In contrast, in a series of 75 short (less than third percentile) children 7 to 14 years of age without cleft defect or other apparent congenital abnormality, only two had total and two had partial GH deficiency. The data suggest that children with isolated CLP have short stature about four times more often, and GH-deficiency about 40 times more often, than children without CLP. The increased prevalence of GH-deficiency may stem from the embryologic relation of adenohypophysis and oral ectoderm.

We studied the interaction between airway drying (cooling) and inhalation of sulfur dioxide (SO2) causing bronchoconstriction in 8 subjects with mild asthma. On 3 separate days, we measured specific airway resistance (SRaw) before and after the subject performed voluntary eucapnic hyperpnea at a constant minute ventilation (30 to 40 L/min) for successive 3-min periods with doubling concentrations of SO2 in dry cold air (-20 degrees C, 0% relative humidity), in dry warm air (22 degrees C, 0% relative humidity), and in partially humidified warm air (22 degrees C, 70% relative humidity). On another day, we measured SRaw before and after the subject performed each of 6 successive 3-min periods of voluntary eucapnic hyperpnea at the same minute ventilation breathing dry cold air without SO2. The concentration of SO2 that caused a 100% increase in SRaw was significantly lower in dry cold air and in dry warm air than it was in humidified warm air. Repeated hyperpnea with dry cold air without SO2 at the same ventilation had no effect on SRaw. We then had the same subjects perform voluntary eucapnic hyperpnea at successively increasing levels of ventilation on 3 different days with dry air alone, dry air with 0.1 ppm SO2, or dry air with 0.25 ppm SO2. The minute ventilation that caused an 80% increase in SRaw was significantly lower for hyperpnea with 0.1 and with 0.25 ppm SO2 than for dry air without SO2, but these differences were small.(ABSTRACT TRUNCATED AT 250 WORDS)

To follow up our previous observation that airway hyperresponsiveness induced by ozone is linked to airway inflammation, we investigated the effect of BW755C, an anti-inflammatory drug, on ozone-induced hyperresponsiveness in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in two sets of experiments. In one set (placebo treatment), five dogs were given only saline solution treatment and were studied before treatment or ozone exposure and then after treatment both before and after ozone (3.0 ppm, 2 hours); in another set (BW755C treatment), the same dogs were studied before BW755C treatment or ozone and then after treatment (10 mg/kg intravenously) both before and after ozone. When the dogs were given no BW755C treatment, ozone induced a marked increase in airway responsiveness to acetylcholine. When the dogs were given BW755C, responsiveness was no different during treatment than before treatment but, more importantly, responsiveness did not increase significantly after ozone. We conclude that BW755C markedly inhibits ozone-induced airway hyperresponsiveness in dogs, probably by inhibiting the formation of oxygenation products of arachidonic acid.

Nine asthmatic subjects exercised at low, moderate, and high work rates on a cycle ergometer while breathing filtered, humidified air with or without 0.5 ppm of sulfur dioxide (SO2) in a double-blind study. Subjects first performed these experiments breathing through a mouthpiece while wearing a noseclip (oral breathing) and then repeated the experiments breathing through a facemask that separated and permitted independent measurement of oral and nasal air flow (oronasal breathing). We determined specific airway resistance before and after exercise by body plethysmography. Inhaled by mouthpiece, 0.5 ppm So2 caused bronchoconstriction at moderate and high but not at low work rates. There was a dose-response relationship between the work rate performed and the degree of bronchoconstriction induced. Inhaled oronasally, 0.5 ppm SO2 caused bronchoconstriction only at the high work rate. These findings demonstrate that So2-induced bronchoconstriction is dependent on the work rate of exercise during exposure, that oronasal breathing is only partially effective in preventing the bronchoconstriction observed with oral breathing, and that oronasal breathing is less effective in preventing bronchoconstriction with high than with moderate exercise at this concentration of SO2.

To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.

The purpose of this study was to determine whether 0.50 ppm sulfur dioxide (SO2) in filtered air causes bronchoconstriction in freely breathing asthmatic subjects exercising at a moderately heavy work rate. Ten volunteers who had mild asthma breathed air containing no SO2 or containing 0.50 ppm SO2 In an exposure chamber as they exercised for 5 min on a cycle ergometer at a work rate of 750 kilopond meters/min (about 125 watts). We determined their specific airway resistance by body plethysmography before and after exercise. Specific airway resistance increased by 13.55 +/- 9.18 cm H2O X s (mean +/- SD) when subjects exercised and breathed 0.50 ppm SO2 but only by 2.24 +/- 2.34 when they exercised and breathed air without SO2 (p less than 0.005). Thus, 0.50 ppm SO2 causes significant bronchoconstriction in freely breathing asthmatics during moderately heavy exercise.

A study to determine whether the bronchoconstriction induced by low concentration of sulfur dioxide in subjects with asthma decreases with repeated exposure was undertaken. Eight subjects with asthma performed 3 min of voluntary eucapnic hyperpnea with 0.5 ppm of SO2 in humidified filtered air three times at 30-min intervals and we measured specific airway resistance (SRaw) before and after each period of hyperpnea. Specific airway resistance increased significantly more after the first exposure to SO2 [(from 7.6 +/- 1.7 to 15.5 +/- 2.0 L x cm H2O/liter/sec (mean +/- SEM)] than after the second (from 8.1 +/- 1.3 to 10.8 +/- 1.6) or third (from 7.6 +/- 1.6 to 10.1 +/- 1.9) exposures (P less than 0.025). When seven subjects repeated hyperpnea with SO2 24 hr and 7 days later, SRaw increased as much as it had after the first exposure (from 8.2 +/- 2.5 to 15.5 +/- 4.5 at 24 hr and from 6.6 +/- 1.4 to 15.4 +/- 2.1 at 7 days). In four subjects repeated exposure to SO2 caused short-term inhibition of the bronchomotor response to SO2 but did not inhibit the bronchomotor response to histamine aerosol. It was concluded that repeated exposures to a low concentration of SO2 over a short period (on 1 day) can induce tolerance to the bronchomotor effects of SO2 in subjects with asthma. Tolerance to the bronchomotor effects of SO2 is not caused by decreased responsiveness of airway smooth muscle or a generalized decrease in the responsiveness of vagal reflex pathways since the bronchomotor response to histamine is preserved.

To determine whether treatment with atropine causes dose-dependent inhibition of histamine-induced bronchoconstriction, we constructed dose-response curves to inhaled histamine after inhalation of placebo and 0.26 and 2.08 mg of atropine in eight subjects with mild asthma. Both doses of atropine significantly inhibited histamine-induced bronchoconstriction, and 2.08 mg caused significantly greater inhibition than 0.26 mg. Baseline specific airway resistance was significantly reduced by both doses of atropine but was no different after 2.08 mg than after 0.26 mg. There were considerable differences in the efficacy of atropine among individuals. We conclude that atropine causes dose-dependent inhibition of histamine-induced bronchoconstriction and that this effect is not merely a function of the atropine-induced in baseline airway caliber. The large magnitude of the atropine effect in some subjects and the small magnitude of the effect in others suggest that there is variability in the degree of involvement of muscarinic mechanisms in the exaggerated bronchomotor response to histamine in asthmatic subjects.

We sought to determine whether 0.25 ppm sulfur dioxide in filtered air causes bronchoconstriction when inhaled by freely breathing, heavily exercising, asthmatic subjects. Nineteen asthmatic volunteers exercised at 750 kilogram meters/min for 5 min in an exposure chamber that contained filtered air at ambient temperature and humidity or, on another day, filtered air plus 0.25 ppm sulfur dioxide. The order of exposure to sulfur dioxide and to filtered air alone was randomized, and the experiments were double-blinded. Specific airway resistance, measured by constant-volume, whole-body plethysmography, increased from 6.38 +/- 2.07 cm H2O X s (mean +/- SD) before exercise to 11.32 +/- 8.97 after exercise on days when subjects breathed filtered air alone and from 5.70 +/- 1.93 to 13.33 +/- 7.54 on days when subjects breathed 0.25 ppm sulfur dioxide in filtered air. The increase in specific airway resistance on days when subjects breathed 0.25 ppm sulfur dioxide was only slightly greater than on days when they breathed filtered air, but the difference was significant. To determine whether 0.25 ppm sulfur dioxide causes greater bronchoconstriction in asthmatic subjects exercising more vigorously, 9 subjects then repeated the experiment exercising at 1,000 instead of 750 kilogram meters/min. Specific airway resistance increased from 6.71 +/- 2.25 to 13.59 +/- 7.57 on days when subjects breathed filtered air alone and from 5.23 +/- 1.23 to 12.54 +/- 6.17 on days they breathed 0.25 ppm sulfur dioxide in filtered air. The increase in specific airway resistance on the 2 days was not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

An intravascular injection of substance P is known to increase vascular permeability in the rat trachea. Electrical stimulation of the cervical vagus nerve produces a similar response, presumably by releasing substance P or other tachykinins from sensory nerve endings. In the present study, we sought to determine whether the increase in vascular permeability induced by intravascular substance P or by vagal stimulation requires the presence of neutrophils or other components of circulating blood. To eliminate circulating blood, we perfused into the aorta of anesthetized rats an oxygenated Krebs-Henseleit solution containing albumin and monastral blue, a colloidal pigment that does not cross normal tracheal blood vessels. We then injected substance P intravascularly or electrically stimulated the right cervical vagus nerve. Increases in vascular permeability were quantified by using a microspectophotometer to measure the amount of extravasated monastral blue in tracheal whole-mounts. We found that the elimination of neutrophils and other components of circulating blood did not prevent the increase in tracheal vascular permeability induced by intravascular substance P or by vagal stimulation.