Involvement of IL-5 in a murine model of allergic pulmonary inflammation: prophylactic and therapeutic effect of an anti-IL-5 antibody.

Interleukin-5 (IL-5) is important in the control of differentiation, migration, and activation of eosinophils. In order to study the role of IL-5 in the development of eosinophilic inflammation of the airways, we have used a monoclonal antibody to murine IL-5 (TRFK-5) in a murine model of allergic pulmonary inflammation. B6D2F1 mice were sensitized with alum-precipitated ovalbumin and were challenged with aerosolized ovalbumin on day 12 after sensitization. Samples of bronchoalveolar lavage (BAL) fluid, lung tissue, blood, and bone marrow aspirate were collected at different times after ovalbumin challenge. Twenty-four hours after challenge there were significant increases in the number of eosinophils in the BAL fluid, lung tissue, and blood while bone marrow eosinophils were decreased. Treatment of sensitized mice with TRFK-5 (0.01-1 mg/kg, i.p.) 2 h before ovalbumin challenge reduced the numbers of eosinophils in the BAL fluid and lung tissue and prevented the decrease in bone marrow eosinophils in a dose-dependent fashion. The number of eosinophils in the BAL fluid, peribronchial and alveolar regions of the lung was also reduced when TRFK-5 (2 mg/kg, i.p.) was given up to 5 d after ovalbumin challenge. Furthermore, there was no evidence of increased epithelial damage, edema, or the presence of mucus that could have resulted from eosinophil apoptosis and release of toxic proteins after neutralization of IL-5. These results demonstrate an important role for IL-5 in the development of eosinophilic inflammation of the airways and for the migration of eosinophils from the bone marrow into blood in response to antigen challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of an antibody to interleukin-5 in a monkey model of asthma.

To investigate the role of interleukin-5 (IL-5) on airway hyperreactivity and pulmonary inflammation in nonhuman primate airways, the effect of a neutralizing monoclonal antibody to murine IL-5 (TRFK-5) was investigated in a cynomolgus monkey model of allergic asthma. Anesthetized Ascaris-sensitive monkeys underwent bronchoalveolar lavage (BAL) to assess the granulocyte content of this fluid before and 24 h after aerosolized Ascaris suum extract inhalation. Airway reactivity was assessed by the concentration of inhaled histamine required to produce a 40% reduction in dynamic lung compliance (Cdyn40). Exposure to A. suum extract produced an increase in airway reactivity (Cdyn40 = 0.065 +/- 0.024% before Ascaris; Cdyn40 = 0.014 +/- 0.004% after Ascaris) and an inflammatory reaction in the airways characterized by an increase in BAL eosinophils (0.05 +/- 0.03 x 10(3) cells/ml before Ascaris; 176 +/- 76 x 10(3) cells/ml after Ascaris) and neutrophils (3 +/- 1 x 10(3) cells/ml before Ascaris; 406 +/- 211 x 10(3) cells/ml after Ascaris). In contrast, only small nonsignificant changes in airway reactivity and granulocyte influx into the BAL occurred after aerosolized saline as a sham challenge. When the monkeys were treated 1 h before Ascaris challenge with the TRFK-5 antibody (0.3 mg/kg, intravenously), there was no increase in airway reactivity after Ascaris challenge (Cdyn40 = 0.032 +/- 0.016% before Ascaris; Cdyn40 = 0.217 +/- 0.196% after Ascaris) and there were only small increases in the number of eosinophils and neutrophils in the BAL after Ascaris challenge. The inhibition of this pulmonary eosinophilia and bronchial hyperresponsiveness by TRFK-5 was seen for up to 3 mo after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of a murine model of allergic pulmonary inflammation.

Pulmonary inflammation with eosinophil (EOs) infiltration is a prominent feature of allergic respiratory diseases such as asthma. In order to study the cellular response during the disease development, an animal model of IgE-mediated pulmonary inflammation with characteristic eosinophilia is needed. We developed a method for inducing severe pulmonary eosinophilia in the mouse and also studied the numbers of EOs in blood and bone marrow and the response to corticosteroid treatment. Animals were sensitized with alum-precipitated ovalbumin (OVA) and challenged with aerosolized OVA 12 days later when serum IgE levels were significantly elevated. Four to eight hours after challenge there were moderate increases in the number of EOs in the bone marrow and peripheral blood, but only a few EOs were observed in the lung tissue and in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, there was a marked reduction of EOs in bone marrow, while the number of EOs peaked in the perivascular and peribronchial regions of the lung. Forty-eight hours after challenge, the highest number of EOs was found in the BAL fluid, making up > 80% of all cells in that compartment. The high levels of EOs in the lung tissue and BAL fluid lasted for 2-3 days and was followed by a more moderate but persistent eosinophilia for another 10 days. Nonsensitized animals showed no significant changes in the number of EOs in BAL fluid, lungs, blood or bone marrow. Histopathological evaluation also revealed epithelial damage, excessive mucus in the lumen and edema in the submucosa of the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous vasodilators modulate pulmonary vascular anaphylaxis.

We examined the role of endothelium-derived nitric oxide during antigen-induced contraction in pulmonary arteries isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml)-induced contraction was not sustained, and tension returned to baseline within 15 min. Pretreatment with methylene blue (10(-5) M) increased both the amplitude and the duration of the contractile response in these tissues. At 15 min, tension remained elevated and was > 70% of the peak amplitude. Removal of the endothelium with saponin (200 micrograms/ml) increased the magnitude of the contraction by > 125%; however, the duration of the response was unaffected. After pretreatment with saponin, methylene blue no longer increased the amplitude of antigen-induced contraction but its effect on the duration was unchanged. Pretreatment with nitro-L-arginine methyl ester significantly increased the magnitude of the contraction in each of the tissues. These results suggest that the response of guinea pig pulmonary arteries to antigen is modulated by two types of endogenous vasodilators, endothelium-derived nitric oxide that inhibits the initial phase of the response and an endothelium-independent relaxing factor that is guanosine 3',5'-cyclic monophosphate dependent and attenuates the duration of anaphylactic contraction.

Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients.

OBJECTIVE: To maximize deposition of an aerosolized dose of insulin (mean +/- SD = 0.99 +/- 0.06 U/kg of body weight) in the lungs of subjects with non-insulin-dependent diabetes mellitus (NIDDM), and investigate its efficacy in normalizing plasma glucose levels during the fasting state. DESIGN: Nonrandomized, placebo-controlled trial. SETTING: A primary care facility. PATIENTS OR OTHER PARTICIPANTS: Six nonobese, nonsmoking volunteers with NIDDM. No subjects withdrew from the study. INTERVENTION: Aerosolized insulin was administered by oral inhalation after a 12-hour period of fasting. Aerosol was generated by a raindrop nebulizer from regular 500 U/mL pork insulin. During inhalation, inspiratory flow was regulated at 17 L/min. Plasma samples were collected after inhalation and analyzed for insulin and glucose levels. MAIN OUTCOME MEASURES: Plasma insulin and glucose levels. RESULTS: Deposition of the aerosol was maximized within the lungs, with 79% +/- 17% of the inhaled dose depositing below the larynx. Geometric mean fasting plasma insulin level was 71 pmol/L (11.8 microU/mL), rising to 269 pmol/L (44.8 microU/mL) after insulin inhalation. Average time to peak insulin level was 40 +/- 34 minutes. The mean fasting plasma glucose level (12.63 +/- 2.59 mmol/L [225.5 +/- 46.3 mg/dL]) was reduced to within the normal range in five subjects and was almost normal in the sixth subject (5.52 +/- 0.89 mmol/L [98.6 +/- 15.9 mg/dL]). Average maximum decrease in plasma glucose from baseline was 55% +/- 10% (n = 6) vs 13% +/- 9% after placebo aerosol inhalation (n = 3). No side effects were reported following insulin or placebo aerosol inhalation. CONCLUSIONS: These preliminary results indicate that a dose of approximately 1.0 U of aerosolized insulin per kilogram of body weight, delivered by oral inhalation and deposited predominantly within the lungs, is well tolerated and can effectively normalize plasma glucose levels in patients with NIDDM.

Antigen-induced contraction of guinea pig isolated pulmonary arteries and lung parenchyma.

We characterized the kinetics of and determined the mediators involved in antigen-induced contraction of pulmonary arteries (PA) and lung parenchyma isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml) induced contractions of PA rings, which reached maximum amplitude by 2 min and decayed to 50% of maximum by 4-6 min. Pyrilamine (10(-6) M) delayed the onset of contraction and decreased the peak of the response by > 50%. Metiamide (10(-4) M) partially reversed this effect. The addition of indomethacin (10(-6) M) to the combination of pyrilamine and metiamide had no significant effect. The further addition of the leukotriene (LT) D4/LTE4 receptor antagonist SKF 104353 (10(-5) M) reduced the contraction by > 80%. The maximum amplitude of antigen-induced contraction of parenchymal strips was reached by 15 min and was sustained for > 60 min. In these tissues, SKF 104353 inhibited the contraction by approximately 35%, but the histamine receptor antagonists and indomethacin had no significant effect. These results suggest that both histamine and sulfidopeptide LTs mediate antigen-induced contraction of PA, whereas sulfidopeptide LTs, but not histamine, are involved in the parenchymal response.

Nonpharmacologic aids in the treatment of depression.

While pharmacotherapy is often necessary to effectively treat depression, many depressed patients do not fully respond to, or will not cooperate with, medication trials. Nonpharmacologic interventions such as patient and family education, self-help efforts, cognitive therapy, family involvement and behavioral scheduling may, in various combinations, provide either primary or adjunctive treatment for mild to moderate depression. Family physicians can adapt these techniques to the primary care setting. Recent changes in the economic climate as it affects the availability of psychiatric care have magnified the role of primary care physicians in the treatment of depression.

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hypoxia on leukotriene activity and vasomotor tone in isolated sheep lungs.

To determine whether hypoxic pulmonary vasoconstriction was associated with release of sulfidopeptide leukotrienes (SPLTs) from the lung, we measured SPLT activity by bioassay (guinea pig ileum) and radioimmunoassay in lymph, perfusate, and bronchoalveolar lavage (BAL) fluid from sheep lungs (n = 20) isolated and perfused in situ with a constant flow of autologous blood (100 ml.kg-1.min-1) containing indomethacin (60 micrograms/ml). The protocol consisted of three periods, each at least 1 h in duration. In experimental lungs, inspired O2 concentration (FIO2) was 28.2% in periods 1 and 3 and 4.2% in period 2. In control lungs, FIO2 was 28.2% throughout. Hypoxia increased pulmonary arterial pressure but did not alter peak tracheal pressure, lung lymph flow, or weight gain measured during the last 30 min of each period. SPLT activity was greatest in lung lymph and least in BAL fluid. Hypoxia did not alter SPLT activity in any fluid. Similar results were obtained in lungs not treated with indomethacin (n = 15). These data do not support the hypothesis that hypoxic pulmonary vasoconstriction is mediated by SPLTs.

Influence of electrical field stimulation on antigen-induced contraction and mediator release in the guinea pig isolated superfused trachea and bronchus.

These studies examined the ability of electrical field stimulation (EFS) to influence antigen-induced responses in the guinea pig isolated trachea and main-stem bronchi. Airways isolated from guinea pigs actively sensitized to ovalbumin were superfused and stimulated transmurally with square pulses of 1 msec duration at a frequency of 16 pulses per sec. In the trachea, EFS caused an atropine-sensitive contraction followed by a maintained relaxation. The relaxation consisted of adrenergic and nonadrenergic components. In the bronchus, EFS caused a maintained contraction. This contraction was due to a combination of cholinergic (atropine-sensitive) and noncholinergic (capsaicin-sensitive) mechanisms. Histamine could not be detected in superfusate samples during electrical stimulation alone of either the trachea or bronchus. EFS significantly inhibited ovalbumin-induced tracheal contractions by about 30% without altering ovalbumin-induced histamine or immunoreactive peptido-leukotriene release from the tissues. EFS had a similar inhibitory effect on the contraction induced by application of exogenous histamine (10(-5) M). The electrical stimulus-induced inhibition of the antigen-induced contraction was abolished by tetrodotoxin and propranolol and reduced by a combination of atropine, propranolol and phentolamine. Norepinephrine (5 x 10(-6) M) inhibited ovalbumin-induced histamine release by about 30% without altering the contraction. Carbamylcholine had no effect on ovalbumin-induced histamine release. In the guinea pig bronchus, EFS stimulation had no effect on either histamine release or contraction induced by ovalbumin. These results demonstrate that in the guinea pig trachea nerve stimulation can significantly antagonize antigen-induced contractions and suggest that this is due to a functional antagonism by adrenergic and nonadrenergic relaxant neurotransmitters at the level of the airway smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

An analysis of the functional interactions of selected contractile agonists in the guinea pig isolated trachea.

Functional interactions between several contractile agonists were examined in the guinea pig isolated trachea. Cumulative concentration-response effects of agonist A were obtained in the absence and presence of steady-state contractions induced by agonist B. The agonists examined included histamine, prostaglandin D2, platelet activating factor, leukotrienes E4 and D4 and carbamylcholine. We found that none of the agonists studied caused a leftward shift in the concentration-response curve of a second agonist, nor did any agonist decrease the concentration of a second agonist required to evoke a maximum response. In general the functional interactions fit the predictions based on the early models of functional additivity. However, the interactions deviated categorically from this model in that there was less than predicted additivity at concentrations of the interactants that alone induced greater than a 50% response. The degree to which this deviation occurred was agonist dependent. The results suggest that in the guinea pig trachea a contractile agonist does not uncover or increase a reserve in the receptor-subeffect-response chain of a second contractile agonist. The findings that the quantitative nature of the interactions were somewhat agonist dependent supports the hypothesis that more than one biochemical mechanism is involved in the receptor-mediated contraction of airway smooth muscle.

Simplified assessment of fine aerosol distribution in human airways.

We characterized homogeneity of bronchopulmonary distribution of a 0.9% saline aerosol with a mass median aerodynamic diameter (MMAD) of 1.12 micron (sigma g = 2.04) labeled with [99mTc]sulfur colloid in nine normal subjects and nine patients with asthma. Aerosol distribution was quantified from frequency distribution histograms generated from Anger camera scans. Skew (a measure of histogram asymmetry) and kurtosis (a measure of histogram range) were significantly elevated (p less than 0.05) in the asthma patients with 0.68 +/- 0.30 and 2.62 +/- 0.81, respectively, compared with 0.39 +/- 0.12 and 1.89 +/- 0.18, respectively, in the normal subjects. Skew and kurtosis were significantly correlated with baseline forced expiratory volume in 1 sec (FEV1, an index of airway obstruction) with rs = -0.4799 (p less than 0.05) and -0.5929 (p less than 0.01), respectively. Skew and kurtosis were also significantly correlated with mucociliary clearance after approximately 90 min (an index of large, central airway deposition) with rs = 0.6801 and 0.6373, respectively (p less than 0.01). This simplified method of analysis does not require additional study days or procedures and facilitates the detection of airflow obstruction in asthma.

The osmolality of nasal secretions increases when inflammatory mediators are released in response to inhalation of cold, dry air.

Inhaling cold, dry air nasally induces in some persons symptoms of rhinitis that are associated with an increase in the level of mast-cell-associated mediators in nasal lavages. The present study, directed at understanding the mechanism of this reaction, showed that 9 subjects who displayed symptoms and inflammatory mediator release had significant (p less than 0.01) increments in nasal fluid osmolality, whereas the osmolality of the fluids of 6 subjects unaffected by cold, dry air challenge did not differ from baseline. Significant correlations were found between the mediator concentration and the osmolality of recovered nasal lavages (rs = 0.617, p less than 0.02; rs = 0.679, p less than 0.01 for histamine and TAME-esterase(s), respectively). No changes in the osmolality of nasal secretions were found in atopic subjects undergoing nasal challenge with antigen, despite the generation of symptoms and significant elevations in the levels of inflammatory mediators in their nasal lavages. Because increasing the osmolality of the medium surrounding isolated mast cells in vitro triggers mediator secretion, these observations support the concept that the response to cold, dry air nasal inhalation is caused by the release of mediators secondary to an increase in the osmolality of the mucosal secretions.

Effect of removal of epithelium on antigen-induced smooth muscle contraction and mediator release from guinea pig isolated trachea.

We examined the effect of removal of the epithelium on antigen-induced smooth muscle contraction and the release of mediators of inflammation from superfused, sensitized guinea-pig tracheal spirals in vitro. The epithelium was stripped from one-half of each trachea by mechanical means, and immunologic responses were evaluated by paired analysis. Removing the epithelium potentiated antigen-induced contraction, as reflected by a 5-fold leftward shift in the antigen dose-response curve, but the maximum response to antigen was not altered. This potentiation was not inhibited by pretreating the tissues with indomethacin (5 X 10(-6) M). At maximum concentrations of antigen removing the epithelium had no effect on the magnitude or kinetics of release of immunoreactive sulfidopeptide leukotrienes, prostaglandin (PG) D2, PGF2 alpha or thromboxane B2. Removing the epithelium did, however, significantly decrease the release of PGE and 6-keto-PGF1 alpha, a prostacyclin metabolite. Antigen-induced histamine release was enhanced by removing the epithelium; this effect varied inversely with antigen concentration. Selectively exposing either the luminal or serosal surface of an intact, superfused trachea to antigen resulted in the release of less than 5% of the total tissue histamine. Removing the epithelium from the intact trachea increased histamine release to approximately 25% following luminal but not serosal exposure to antigen. These studies demonstrate that the tracheal epithelium can act to inhibit antigen-induced airway contraction in vitro. This may in part reflect the role of the intact epithelium as a diffusion barrier which can limit the rate of influx of antigen molecules and thereby influence tissue mast cell activation.

The effect of indomethacin on immunologic release of histamine and sulfidopeptide leukotrienes from human bronchus and lung parenchyma.

We studied the effect of indomethacin on immunologic mediator release from human bronchial tissue (n = 6) and lung parenchyma (n = 7). Tissues were obtained from surgical specimens, minced, passively sensitized, and challenged with antigen E or anti-IgE in the presence or absence of indomethacin. At maximal levels of immunologic stimulation with either antigen or anti-IgE, the bronchial and parenchymal tissues released approximately 5 and 20% of total histamine (net), respectively, and approximately 3.5 and 45 ng/g of immunoreactive sulfidopeptide leukotriene, respectively. Analysis by high performance liquid chromatography followed by radioimmunoassay revealed that the airway supernatants contained LTD4 and LTE4, whereas the lung parenchymal samples contained predominantly LTE4. Little or no LTC4 was detected in either airway or parenchymal samples. Incubation with indomethacin (5 x 10(-6) M) resulted in approximately a 3-fold increase in antigen or anti-IgE-induced release of leukotrienes from the bronchial tissue. Indomethacin also enhanced antigen-induced histamine release approximately 2-fold but had no effect on anti-IgE-induced histamine release from this tissue. In contrast, indomethacin had no effect on antigen or anti-IgE-induced histamine or leukotriene release from the lung parenchymal tissue at any level of immunologic stimulation. These results support the hypothesis that indomethacin enhances human anaphylactic bronchospasm in vitro through an increase in mediator release from bronchial mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-induced sulfidopeptide leukotriene release from the guinea pig superfused trachea.

The effect of antigen (ovalbumin) challenge on smooth muscle contraction and release of sulfidopeptide leukotrienes and histamine from superfused, actively sensitized guinea pig trachea was examined. Maximum concentrations of ovalbumin caused the release of 16 +/- 4 ng/g immunoreactive sulfidopeptide leukotriene (i-LT) and 27 +/- 3% of the endogenous histamine (x +/- S.E.M., n = 19). High performance liquid chromatography combined with a sulfidopeptide leukotriene radioimmunoassay was used to demonstrate that on a molar basis, approximately 10% of the leukotriene immunoreactivity recovered was LTC4, 45% LTD4 and 45% LTE4. Indomethacin slightly increased ovalbumin-induced histamine release and substantially enhanced (3-fold) i-LT release from the trachea. Neither the profile nor rate of sulfidopeptide leukotriene release was altered by indomethacin. Indomethacin had no effect on the maximum amplitude of the antigen-induced contraction but significantly enhanced the magnitude of contraction observed after 10 min of antigen exposure. These results demonstrate that actively sensitized airways synthesize and release sulfidopeptide leukotrienes upon challenge with specific antigen and that endogenously formed LTC4 is efficiently metabolized to LTD4 and LTE4. The results with indomethacin support the hypothesis that indomethacin potentiates antigen-induced airway contraction in vitro by enhancing the release of mast cell associated mediators.

Antigen- and histamine H1 receptor-mediated relaxation of guinea pig isolated trachea.

We have investigated the effect of challenge in vitro with specific antigen (ovalbumin) on actively sensitized guinea pig tracheal rings maximally precontracted with methacholine. Ovalbumin relaxed the trachea in a concentration-dependent fashion with a negative log ED50 value (g/ml) of 7.0 +/- 0.3. In 16 experiments, the maximum antigen-induced relaxation was 26 +/- 3% of complete relaxation induced by 10(-3) M papaverine (mean +/- S.E.M.). Antigen-induced relaxations were selectively antagonized by diphenhydramine. Similarly, histamine relaxed the precontracted tracheal smooth muscle with a negative log molar ED50 of about 4.5 and a maximum effect of 28 +/- 3% (mean +/- S.E.M., n = 20). Histamine-induced relaxations were antagonized by diphenhydramine and mepyramine but were unaffected by cimetidine, metiamide or burimamide. Dimaprit (10(-5)-10(-3) M) did not relax the precontracted trachea. Indomethacin significantly inhibited relaxation induced by both antigen and histamine. In contrast, phenidone or 5,8,11,14-eicosa-tetraynoic acid had no effect on relaxation but reversed the inhibition by indomethacin. Neither propranolol (10(-6) M) nor removing the tracheal epithelium inhibited histamine-induced relaxation. These results suggest that antigen-induced relaxation of guinea pig tracheal smooth muscle involves activation of histamine H1 receptors and can occur independently of arachidonic acid metabolism, beta-adrenoceptor activation or airway epithelium.

Dexamethasone inhibits the antigen-induced contractile activity and release of inflammatory mediators in isolated guinea pig lung tissue.

Treatment for 24 h in vitro with dexamethasone inhibited the antigen-induced contractile response in guinea pig tracheal rings and parenchymal strips without inhibiting the contractile response of the tissues to either methacholine or histamine, respectively. Antigen-induced histamine release was inhibited by approximately 50% in both tissues by prior treatment with dexamethasone. Dexamethasone treatment also inhibited the release of immunoreactive sulfidopeptide leukotriene from parenchymal strips. In tracheal rings, dexamethasone treatment reduced spontaneous release of all cyclooxygenase metabolites (PGE2, PGF2 alpha, TXB2, PGD2, and 6-k-PGF1 alpha were tested), with the exception of PGD2, and also inhibited the antigen-induced release of all cyclooxygenase metabolites studied. Dexamethasone-treatment did not inhibit the spontaneous release of cyclooxygenase metabolites in the guinea pig lung strips, and only modestly inhibited the antigen-induced release of PGE2, PGF2 alpha, and PGD2. The results suggest that the inhibition of contractile response of guinea pig lung strips and airway tissue to antigen by dexamethasone is the result of a reduced release of inflammatory mediators. The inhibition by dexamethasone of antigen-induced release of mast cell mediators from guinea pig lung parenchyma contrasts with results previously obtained with human parenchymal lung tissue.

The effect of bronchial obstruction on central airway deposition of a saline aerosol in patients with asthma.

We studied the effect of bronchial obstruction on central airway deposition of a 0.9% saline aerosol (MMAD = 1.12 micron; sigma g = 2.04) labeled with 99mTc sulfur colloid. Radioaerosol was inhaled on 2 occasions by 8 patients with asthma. The degree of bronchial obstruction at the time of radioaerosol inhalation was measured by the FEV1. Mucociliary clearance of the radioaerosol was used as an index of regional aerosol distribution, because clearance from the densely ciliated central airways occurs more rapidly than from the peripheral, nonciliated regions of the lung. Using the Weibel lung model and an average mucociliary clearance rate of 1 mm/min, we determined that clearance of the radioaerosol from lung generations 1 to 5 (central airways) would be complete within approximately 90 min. Central airway deposition was therefore quantified as radioaerosol clearance in 97 min using a gamma camera. On Days 1 and 2, clearance ranged from 0 to 45% and from 0 to 17%, respectively; FEV1 as a percent of predicted FEV1 ranged from 36 to 88 on Day 1, and on Day 2 from 54 to 92. Radioaerosol clearance was inversely correlated with the baseline FEV1, with r = -0.7673 (linear regression analysis; p less than 0.05). These data suggest that the magnitude of bronchial obstruction is a determinant of aerosol distribution within the lung of patients with asthma and that increased bronchial obstruction enhances central airway deposition of inhaled particles.

Increased in vitro airway responsiveness in sheep following repeated exposure to antigen in vivo.

We have studied the effect of repeated in vivo antigen exposure on in vitro airway responsiveness in sensitized sheep. Fourteen sheep underwent five biweekly exposures to aerosolized Ascaris suum antigen or saline. Following this exposure regimen, the animals were killed and tracheal smooth muscle and lung parenchymal strips were prepared for in vitro studies of isometric contraction in response to histamine, methacholine, prostaglandin F2 alpha, and a thromboxane A2 analogue. No alteration in tracheal smooth muscle responsiveness was observed between saline- and antigen-exposed tissue. In contrast, by use of lung parenchymal strips as an index of peripheral airway responsiveness, significant increases in responsiveness to histamine and a thromboxane A2 analogue (10(-6) and 10(-5) M) were observed in antigen-exposed tissue compared with saline controls. These results demonstrate that repeated antigen exposure in vivo selectively increase the responsiveness of peripheral lung smooth muscle to certain chemical mediators of anaphylaxis.