Effect of nintedanib on airway inflammation in a mouse model of acute asthma.

Objective: New treatments are needed for cases of asthma that are refractory to traditional therapies. In this study, we examined the effect of oral nintedanib, an intracellular inhibitor of tyrosine kinases, on airway hyper-responsiveness (AHR) and airway smooth muscle cells, using a mouse model of experimental asthma. Methods: Asthma was experimentally induced in mice via subcutaneous injection of ovalbumin (OVA). A group of saline-injected mice served as a control group. The OVA mice were then divided into four treatment groups according to the dose of nintedanib. AHR was examined via exposure to vaporized methacholine. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cell counts and Th2 cytokine concentrations. Results: Baseline levels of AHR and airway inflammation were higher in OVA mice than in the control group. Treatment with nintedanib lowered AHR, BALF cell counts and BALF cytokine levels in a dose-dependent fashion. The effect of nintedanib was comparable to that of dexamethasone. In particular, treatment with nintedanib lowered the expression of transforming growth factor-ß1 and inhibited the expression and phosphorylation of platelet-derived growth factor receptor-ß, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, fibroblast growth factor receptor 2 (FGFR2), FGFR3, and extracellular signal-regulated kinase. Conclusions: Nintedanib lowered AHR and the expression of factors associated with airway inflammation and remodeling in a mouse model of experimental asthma. Our results suggest that nintedanib may be useful in the treatment of asthma.

Diagnosis of asthma in children: the contribution of a detailed history and test results.

INTRODUCTION: There are few data on the usefulness of different tests to diagnose asthma in children. AIM: We assessed the contribution of a detailed history and a variety of diagnostic tests for diagnosing asthma in children. METHODS: We studied children aged 6-16 years referred consecutively for evaluation of suspected asthma to two pulmonary outpatient clinics. Symptoms were assessed by parental questionnaire. The clinical evaluation included skin-prick tests, measurement of exhaled nitric oxide fraction (F eNO), spirometry, bronchodilator reversibility and bronchial provocation tests (BPT) by exercise, methacholine and mannitol. Asthma was diagnosed by the physicians at the end of the visit. We assessed diagnostic accuracy of symptoms and tests by calculating sensitivity, specificity, positive and negative predictive values and area under the curve (AUC). RESULTS: Of the 111 participants, 80 (72%) were diagnosed with asthma. The combined sensitivity and specificity was highest for reported frequent wheeze (more than three attacks per year) (sensitivity 0.44, specificity 0.90), awakening due to wheeze (0.41, 0.90) and wheeze triggered by pollen (0.46, 0.83) or by pets (0.29, 0.99). Of the diagnostic tests, the AUC was highest for F eNO measurement (0.80) and BPT by methacholine (0.81) or exercise (0.74), and lowest for forced expiratory volume in 1 s (FEV1) (0.62) and FEV1/forced vital capacity ratio (0.66), assessed by spirometry. CONCLUSION: This study suggests that specific questions about triggers and severity of wheeze, measurement of F eNO and BPT by methacholine or exercise contribute more to the diagnosis of asthma in school-aged children than spirometry, bronchodilator reversibility and skin-prick tests.

Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats.

Naturally occurring asbestos (NOA) fibers are found in geologic deposits that may be disturbed by mining, earthworks, or natural processes, resulting in adverse health risks to exposed individuals. The toxicities of Libby amphibole and NOA samples including Sumas Mountain chrysotile (SM), El Dorado tremolite (ED), and Ontario ferroactinolite cleavage fragments (ON) were compared in male Fischer 344 (F344) rats 15 mo after exposure. Rat-respirable fractions of LA and SM displayed greater mean lengths and aspect ratios than ED and ON. After a single intratracheal (IT) instillation (0.5 or 1.5 mg/rat), persistent changes in ventilatory parameters and a significant increase in lung resistance at baseline and after methacholine aerosol dosing were found only in rats exposed to 1.5 mg SM. High-dose ED significantly elevated bronchoalveolar lavage lactate dehydrogenase (LDH) activity and protein levels, while high-dose SM increased γ-glutamyl transferase and LDH activities. A moderate degree of lung interstitial fibrosis after exposure to 1.5 mg SM persisted 15 mo after exposure, unchanged from previous findings at 3 mo. LA induced mild fibrosis, while ED and ON produced minimal and no apparent fibrosis, respectively. Bronchioloalveolar carcinoma was observed 15 mo after exposure to LA or ED. Data demonstrated that SM, given by bolus IT dosing on an equivalent mass basis, induced greater pulmonary function deficits, airway hyperresponsiveness, and interstitial fibrosis than other NOA, although unlike LA and ED, no apparent evidence for carcinogenicity was found. All NOA samples except ON cleavage fragments produced some degree of long-term toxicity.

The protective effect of α-hederin, the active constituent of Nigella sativa, on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs.

Many investigations have demonstrated the prophylactic effect of Nigella sativa on asthma disease. One of its active constituents is α-hederin. In the present study, the preventive effect of two different concentrations of α-hederin on tracheal responsiveness and lung inflammation in ovalbumin-sensitized guinea pigs was examined. Forty male adult Dunkin-Hartley guinea pigs were randomly divided into the control (C), sensitized (S) and sensitized pretreated groups with thymoquinone (3 mg/kg i.p., S + TQ), low-dose α-hederin (0.3 mg/kg i.p., S + LAH) and high-dose α-hederin (3 mg/kg i.p., S + HAH). The responsiveness of tracheal smooth muscle (TR) to methacholine, histamine and ovalbumin was assessed. Moreover, total and differential white blood cell counts in lung lavage fluid were examined. Compared with the S group, the mean EC50 value in the S + LAH group increased significantly (p < 0.05). The mean EC50 value of histamine contraction in the S + LAH and S + HAH groups was significantly higher than in the S group (p < 0.05). In all pretreated groups, the TR to ovalbumin decreased in comparison to the S group (p < 0.001). Both the S + HAH and S + LAH groups showed significantly decreased TR compared to the S + TQ group (p < 0.01-p < 0.01). Total WBC and eosinophil counts in all pretreated groups decreased significantly in comparison with the S group (0.001-0.01). There was a significant increase in neutrophil, lymphocyte and monocyte counts in the pretreated groups compared to the S group (p < 0.001-p < 0.05). The basophil count in the S + TQ and S + HAH groups was significantly lower than in the S group (p < 0.01-p < 0.05). This study suggested that α-hederin has anti-inflammatory and bronchodilatory effects like thymoquinone.

Efficacy and safety of sublingual immunotherapy with grass monomeric allergoid: comparison between two different treatment regimens.

BACKGROUND: Sublingual immunotherapy (SLIT) with monomeric carbamylated allergoid proved to be well tolerated, safe and effective in patients with respiratory allergy. Standard administration regimens are expected to require a long time before clinical benefit can be appreciated. We investigated whether pre-seasonal and perennial regimens differently affect the clinical efficacy of grass pollen SLIT. METHODS: Adult patients with allergic rhino-conjunctivitis with/without mild intermittent asthma due to grass pollen were included into this open prospective study and randomised to receive SLIT with a continuous regimen (Group 1: 1,000 AU/week for the entire study period) or a pre-seasonal regimen (Group 2: 5,000 AU/week for 10 weeks/year for 2 years), or on demand drug therapy alone (Group 3) for two years. At entry (November 2005), at the end of the first and second pollen season, a Visual Analogue Scale (VAS) was used to assess patients' well-being. Symptom score and drug consumption were evaluated during the seasons. Methacholine challenge was performed at study entry and conclusion. Adverse events were recorded along the whole study duration. RESULTS: Thirty-two patients were divided into Group 1 (n = 10), Group 2 (n = 11) and Group 3 (n = 11). A significant VAS improvement was observed in both SLIT groups, after the first and second pollen season, compared to baseline and to Group 3 (p < 0.05). Less symptoms and need for medications resulted during the second season (p < 0.05). No relevant variations in bronchial hyper-reactivity have been observed between the three groups. Only 2 patients experienced local or mild reactions in SLIT groups. CONCLUSION: Both pre-seasonal and continuous regimen of SLIT with monomeric allergoid turned out effective and safe, suggesting that a pre-seasonal course with 5,000 AU/week for 10 weeks may represent a convenient option in patients with grass pollen allergic rhinitis with/without mild intermittent asthma. Further research is urgently needed to consolidate these preliminary evidences.

Vitamin D levels, lung function, and steroid response in adult asthma.

RATIONALE: Patients with asthma exhibit variable response to inhaled corticosteroids (ICS). Vitamin D is hypothesized to exert effects on phenotype and glucocorticoid (GC) response in asthma. OBJECTIVES: To determine the effect of vitamin D levels on phenotype and GC response in asthma. METHODS: Nonsmoking adults with asthma were enrolled in a study assessing the relationship between serum 25(OH)D (vitamin D) concentrations and lung function, airway hyperresponsiveness (AHR), and GC response, as measured by dexamethasone-induced expression of mitogen-activated protein kinase phosphatase (MKP)-1 by peripheral blood mononuclear cells. MEASUREMENTS AND MAIN RESULTS: A total of 54 adults with asthma (FEV(1), 82.9 +/- 15.7% predicted [mean +/- SD], serum vitamin D levels of 28.1 +/- 10.2 ng/ml) were enrolled. Higher vitamin D levels were associated with greater lung function, with a 22.7 (+/-9.3) ml (mean +/- SE) increase in FEV(1) for each nanogram per milliliter increase in vitamin D (P = 0.02). Participants with vitamin D insufficiency (<30 ng/ml) demonstrated increased AHR, with a provocative concentration of methacholine inducing a 20% fall in FEV(1) of 1.03 (+/-0.2) mg/ml versus 1.92 (+/-0.2) mg/ml in those with vitamin D of 30 ng/ml or higher (P = 0.01). In ICS-untreated participants, dexamethasone-induced MKP-1 expression increased with higher vitamin D levels, with a 0.05 (+/-0.02)-fold increase (P = 0.02) in MKP-1 expression observed for each nanogram per milliliter increase in vitamin D, a finding that occurred in the absence of a significant increase in IL-10 expression. CONCLUSIONS: In asthma, reduced vitamin D levels are associated with impaired lung function, increased AHR, and reduced GC response, suggesting that supplementation of vitamin D levels in patients with asthma may improve multiple parameters of asthma severity and treatment response. Clinical trials registered with www.clinicaltrials.gov (NCT00495157, NCT00565266, and NCT00557180).

The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions.

BACKGROUND: Petasin (Ze 339) was recently introduced on the market as a potent herbal antiallergic drug for treatment of respiratory allergies such as hay fever. Few clinical studies have been performed so far addressing the clinical effectiveness of Ze 339. OBJECTIVE: To evaluate the antiallergic properties of Ze 339 using skin prick tests with different stimuli, such as codeine, histamine, methacholine, and a relevant inhalant allergen. METHODS: A randomized, double-blind, placebo-controlled study was performed in which Ze 339 was compared to acrivastine, a short-acting antihistamine, in 8 patients with respiratory allergy and in 10 nonatopic, healthy volunteers. Antiallergic activity of Ze 339 was determined by analyzing inhibitory potency in skin prick tests with codeine, histamine, methacholine, and an inhalant allergen. Wheal-and-flare reactions were assessed 90 minutes after a double dose of Ze 339, acrivastine, or placebo. An interval of at least 3 days was left between the skin tests. RESULTS: Acrivastine was identified as the only substance that significantly inhibited skin test reactivity to all solutions analyzed in all study subjects. In contrast, no significant inhibition could be demonstrated for Ze 339 with any test solution. Moreover, the results of Ze 339 did not differ significantly from placebo. CONCLUSIONS: In this study we found no antiallergic, particularly antihistaminic, effect of Ze 339 in skin tests using a variety of stimuli often used to evaluate immediate skin test reactivity. The mechanism by which Ze 339 is effective in the treatment of seasonal allergic rhinitis still needs to be elucidated.

Esmodil: an acetylcholine mimetic resurfaces in a Southern Australian marine sponge Raspailia (Raspailia) sp.

Bioassay directed fractionation of a Raspailia (Raspailia) sp. (Order Poecilosclerida; Family Raspailiidae) collected during scientific trawling operations off the Northern Rottnest Shelf yielded as nematocidal agents the known metabolites, phorboxazoles A (1) and B (2). Further examination revealed the new natural product but known synthetic compound, esmodil (3). The structure for 3 was confirmed by spectroscopic analysis and total synthesis.

Activation sequences following failed atrial defibrillation.

OBJECTIVES: The purposes of this study were to examine the first activations following atrial defibrillation shocks to help understand how and where atrial fibrillation (AF) relapsed following failed shocks and to assess the difference in postshock activation between failed and successful shocks. BACKGROUND: While many studies have investigated the mechanism of ventricular defibrillation, much less is known about the mechanisms of AF. METHODS: Sustained AF was induced electrically after pericardial infusion of methylcholine in 10 sheep. Biphasic subthreshold shocks were delivered to three configurations: right atrium to distal coronary sinus (RA-CS), sequential shocks with RA-CS as the first pathway followed by proximal CS to superior vena cava as the second pathway (Sequential), and right ventricle to superior vena cava plus can (V-triad). In eight sheep, global atrial mapping was performed with 504 electrodes spaced 3 to 4 mm apart. RESULTS: Earliest postshock activations mostly arose from the left atrium for V-triad but arose from either atrium for RA-CS and Sequential. Preshock AF cycle lengths were significantly shorter at the earliest activation sites than at seven of eight other sites globally distributed over both atria. In all type B successful episodes in which one or more rapid activations occurred after the shock and in 50 of the 72 failed episodes analyzed, activation fronts spread away from the earliest site in a focal pattern, and discrete nonfragmented activation complexes were present in the first derivatives of the electrograms. In the other 22 failed episodes, earliest activation fronts spread in a nonfocal pattern, and earliest postshock electrogram derivatives were fractionated. To better interpret the activation pattern in the fragmented regions, a 504 electrode plaque with 1.5-mm electrode spacing was placed on the right atrial appendage in two additional sheep. In 11 of 108 failed episodes, earliest postshock activation appeared inside the plaque and spread in a focal pattern with nonfragmented electrogram derivatives in 10 episodes and in a reentrant pattern with fragmented electrogram derivatives in the other. CONCLUSIONS: (1) The electrode configuration influenced the location of earliest postshock activation. (2) Earliest postshock activation occurred where the preshock AF cycle length was short. (3) Earliest activations following all type B successful and most failed episodes were not fragmented and spread in a focal pattern. (4) The region of earliest postshock activation in the failed episodes without a focal postshock activation pattern exhibited regions of fragmented electrogram derivatives that may represent conduction block and possibly reentry.

Magnesium infusion improves endothelium-dependent vasodilation in the human forearm.

The effect of intra-arterial magnesium infusion on endothelium-dependent vasodilation (EDV) in the forearm was studied in nine young healthy students (four men and five women). The EDV was assessed as forearm blood flow (FBF), measured by venous occlusion plethysmography, during infusion of methacholine (MCh). Endothelium-independent vasodilation (EIDV) was defined as FBF during infusion of sodium nitroprusside (SNP). During magnesium infusion in the brachial artery, 0.066 mmol/min, the concentration of ionized magnesium in venous plasma in the infused arm increased by 114%, from 0.59 (SD 0.04) to 1.26 (0.34) mmol/L (P = .0002). The FBF at baseline (ie, before administration of MCh or SNP) increased from 3.5 (1.1) to 7.3 (3.4) mL/min/100 mL tissue during magnesium infusion (P = .002). During low-dose MCh administration (2 microg/min), FBF increased by 24%, from 15.4 (5.5) to 19.1 (6.8) mL/min/100 mL tissue (P = .04), and during high-dose MCh administration (4 microg/min) FBF increased by 18%, from 20.3 (6.4) to 24.0 (7.2) mL/min/100 mL tissue (P = .04). The EIDV did not change significantly. Systemic blood pressure was not significantly altered by magnesium infusion. No change in FBF either at rest or during infusion of MCh or SNP was observed during the time-control protocol. In conclusion, this in vivo study showed that intraarterial magnesium infusion increased EDV in the infused human forearm, which is in accordance with findings in previous in vitro and animal experiments.

Effect of apocynin on ozone-induced airway hyperresponsiveness to methacholine in asthmatics.

Apocynin is an inhibitor of NADPH oxidase present in inflammatory cells such as eosinophils and neutrophils. We investigated the effect of inhaled apocynin on ozone-induced bronchial hyperresponsiveness in vivo. Seven mild atopic asthmatics participated in a placebo-controlled, cross-over study with two exposures to O(3) at 2-week intervals. Apocynin (3 ml of 0.5 mg/ml) was inhaled 2 times before and 6 times after O(3) exposure at hourly intervals. At 36 h before and 16 h after O(3) exposure, methacholine inhalation challenge tests (Mch) were performed, and PC(20) and maximal % fall from baseline (MFEV(1)) were calculated from dose-response curves. O(3)-induced change in PC(20) (Delta PC(20)) after placebo treatment was -1.94 +/- 0.39 DD (mean +/- SEM doubling dose Mch) (p =.001) and apocynin was -0.6 +/- 0.33 DD (p =.17). The difference between apocynin and placebo treatment was 1.3 DD +/- 0.42 (p =.02). O(3)-induced Delta MFEV(1) was 11.9 +/- 1.5% (p =.008) during placebo inhalation and 3.85 +/- 1.8% during apocynin (p =.47). Apocynin reduced the Delta MFEV(1) by 8.05% compared to placebo (p =.025). We conclude that apocynin markedly reduced O(3)-induced hyperreactivity for Mch as well as maximal airway narrowing. The results suggest that apocynin may have a role in preventing ozone-induced exacerbations of asthma.

Atrial defibrillation thresholds of electrode configurations available to an atrioventricular defibrillator.

INTRODUCTION: Little investigation has been conducted to assess the atrial defibrillation thresholds of electrode configurations using electrodes designed for internal ventricular defibrillation (right ventricle [RV], superior vena cava [SVC], and pulse generator housing [Can]) combined with coronary sinus (CS) electrodes. We hypothesized that a CS-->SVC+Can electrode configuration would have a lower atrial defibrillation threshold than a standard configuration for defibrillation, RV-->SVC+Can. We also tested the atrial defibrillation thresholds of five other configurations. METHODS AND RESULTS: In 12 closed chest sheep, we situated a two-coil (RV, SVC) defibrillation catheter, a left-pectoral subcutaneous Can, and a CS lead. Atrial fibrillation was burst induced and maintained with continuous infusion of intrapericardial acetyl-beta-methylcholine chloride. Using fixed-tilt biphasic shocks, we determined the atrial defibrillation thresholds of seven test configurations in random order according to a multiple-reversal protocol. The peak voltage and delivered energy atrial defibrillation thresholds of CS-->SVC+Can (168+/-67 V, 2.68+/-2.40 J) were significantly lower than those of RV-->SVC+Can (215+/-88 V, 4.46+/-3.40 J). The atrial defibrillation thresholds of the other test configurations were RV+CS-->SVC+Can: 146+/-59 V, 1.92+/-1.45 J; RV-->CS+SVC+Can: 191+/-89 V, 3.53+/-3.19 J; CS-->SVC: 188+/-98 V, 3.77+/-4.14 J; SVC-->CS+ Can: 265+/-145 V, 7.37+/-9.12 J; and SVC-->Can: 516+/-209 V, 24.5+/-15.0 J. CONCLUSIONS: The atrial defibrillation threshold of CS-->SVC+Can is significantly lower than that of RV-->SVC+Can. In addition, the low atrial defibrillation threshold of RV+CS-->SVC+Can merits further investigation. Based on corroboration of low atrial defibrillation thresholds of CS-based configurations in humans, physicians might consider using CS leads with atrioventricular defibrillators.

Histamine and tryptase in nasal lavage fluid following challenge with methacholine and allergen.

BACKGROUND: The level of histamine in nasal lavage fluid has been used as an index of mast cell/basophil activation in a number of studies. Obviously, such an index can only be valid if changes in the secretory activity of nasal glands do not affect the level of histamine in lavage fluid (i.e. hypersecretion, without a simultaneous activation of mast cells/basophils in the nasal mucosa, must not increase the level of histamine). OBJECTIVES: To asses the effect of nasal hypersecretion on histamine levels in lavage fluid. METHODS: Nasal challenges were performed with methacholine and allergen in grass pollen-allergic patients and non-allergic controls. Nasal lavage fluid was collected before and repeatedly for nine hours after nasal challenge, and the level of histamine was compared with that of a specific mast cell-derived enzyme, tryptase. In addition, the effect of methacholine on basophils was examined in vitro. RESULTS: Allergen challenge of allergic patients produced sneezing and a significant increase in histamine and tryptase levels, whereas challenge of non-allergic subjects produced no such response. Interestingly, challenge with methacholine also induced a significant increase in histamine levels. This increase was seen in both allergic and non-allergic subjects and it was not associated with any sneezing or increase in tryptase levels, indicating that mast cells were not activated. Furthermore, stimulation of basophils with methacholine did not induce any histamine release in vitro. CONCLUSIONS: Apparently, there exists a pool of histamine in the human nose that can be transferred to lavage fluid during glandular hypersecretion. The source of this histamine is yet to be identified. As the level of histamine seems to be affected by the secretory activity of nasal glands, we question the use of this single mediator as an index of mast cell/basophil activation in nasal lavage studies.

Once daily intranasal fluticasone propionate (200 micrograms) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis.

BACKGROUND: Fluticasone propionate aqueous nasal spray, a new topical corticosteroid, has been proved to be an effective treatment for seasonal allergic rhinitis. OBJECTIVES: We studied the effect of fluticasone propionate on nasal symptoms, circulating eosinophils, and nasal inflammation in patients with seasonal allergic rhinitis after high-load pollen exposure. Moreover, we examined its efficacy in preventing the increase in bronchial responsiveness to methacholine (PD20) during the pollen season. METHODS: We conducted a double-blind, placebo-controlled, parallel-group study in patients who had a history of allergic rhinitis in response to pollens of grass and Parietaria species and were living in northern Italy. After a run-in period of 2 weeks, 24 patients were treated with fluticasone propionate (200 micrograms, once daily), and 26 patients received matched placebo for 6 weeks, starting from the beginning of the pollen season. Assessment of efficacy was based on scores of daily nasal symptoms. Nasal lavage was performed at the end of the season, and differential cell count was expressed as percent of total cells. PD20 methacholine was measured at the beginning and end of the season and after the season had ended. RESULTS: Fluticasone propionate significantly reduced nasal obstruction, itching, and rhinorrhea. Eosinophils in blood (p < 0.01) and nasal lavage (p < 0.001) were also reduced. Moreover, fluticasone significantly attenuated the decrease in mean PD20 methacholine (from 1.95 to 0.89 mg) compared with placebo (from 1.38 to 0.37 mg: p < 0.01). After the season, no difference in PD20 methacholine was found between treatment groups. CONCLUSIONS: The results of this study indicate that fluticasone propionate is effective in decreasing nasal symptoms and eosinophil inflammation in patients with seasonal allergic rhinitis after high-load pollen exposure. Our results also demonstrate that treatment with fluticasone propionate partially prevents the increase in bronchial responsiveness provoked by the inhalation of seasonal pollens in allergic rhinitis.

Comparison of early and late asthmatic responses between patients with allergic rhinitis and mild asthma.

Allergic rhinitic subjects without symptoms of asthma show airway hyperresponsiveness, but to a lesser degree than asthmatics. As airway responsiveness is a determinant of the bronchial response to allergen, rhinitic subjects should also respond to allergen challenge, but to a lesser extent than asthmatics. However, studies have so far failed to show quantitative differences in allergen responses between patients with rhinitis and patients with asthma. We studied 123 allergic subjects classified, on the basis of a scored symptom questionnaire, as follows: pure rhinitics without any symptom of asthma (Group 1, n = 39), true asthmatics with or without rhinitis (Group 2, n = 41), and subjects with borderline symptoms of asthma (Group 3, n = 43). All subjects underwent both methacholine and allergen inhalation challenges, with pollen challenges performed out of season. When the three groups were pooled, the asthma symptom score was directly correlated with the sensitivities both to methacholine and allergen, whilst both the sensitivity to allergen and the severity of late-phase response were correlated with the sensitivity to methacholine. The percentage of subjects with a positive early-phase asthmatic response to allergen was similar in Groups 1 and 2. Group 2 had higher sensitivities both to methacholine and to allergen than Group 1. A late-phase asthmatic response occurred more frequently in Group 2 than in Group 1, and this difference was due to a higher occurrence of late-phase response in subjects allergic to house dust mite in Group 2. This study confirms that the bronchial response to allergen can be predicted, in rhinitic as well as in asthmatic allergic subjects, on the basis of airway responsiveness to methacholine. We conclude that the presence or the absence of asthma symptoms in allergic subjects may be related to a quantitatively different airway responsiveness to allergen.

Neonatal capsaicin treatment alters basal pulmonary mechanics and response to methacholine in F344 rats.

Full methacholine dose-response curves were performed on anesthetized tracheostomized Fischer 344 adult rats treated neonatally with capsaicin (50 mg/kg) or with vehicle alone. Capsaicin, the hot extract of pepper, releases substance P (SP) from nonmyelinated sensory nerve endings and causes acute bronchoconstriction and airway microvascular leakiness. Chronic treatment with capsaicin leads to depletion of SP and other tachykinins from afferent C-fibers and can therefore be used as a tool to investigate the contribution of SP innervation to airway responses. The rats (9 controls and 6 treated with capsaicin) were paralyzed with succinylcholine and mechanically ventilated at a constant tidal volume and frequency. Airway resistance (RL) and dynamic compliance (Cdyn) were determined at each dose of methacholine from measurements of volume, flow, and transpulmonary pressure. Capsaicin-treated rats were found to have a significantly reduced baseline RL [0.150 +/- 0.039 (SD) vs. 0.225 +/- 0.050 cmH2O.ml-1.s, P = 0.009] and a correspondingly significantly elevated Cdyn (0.371 +/- 0.084 vs. 0.268 +/- 0.053 ml/cmH2O, P = 0.012). There was no significant difference in sensitivity to methacholine, but the maximal response to methacholine was significantly greater in the capsaicin-treated rats. In terms of RL, the maximal response for capsaicin-treated rats was 6.03 x baseline +/- 0.98 vs. 4.30 x baseline +/- 1.80 (P = 0.05) for controls, and for Cdyn changes the maximal decrease was 5.75 x baseline +/- 1.22 vs. 3.83 +/- 0.69 (P = 0.002). The observed differences in RL and Cdyn coupled with the differences in maximal responses can be attributed to the selective destruction of a subpopulation of pulmonary afferent C-fibers.(ABSTRACT TRUNCATED AT 250 WORDS)