Inhibition of allergen-induced basophil activation by ASM-024, a nicotinic receptor ligand.

BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet. OBJECTIVE: We investigated surface receptor expression of nAChR α4, α7 and α1/α3/α5 subunits on basophils. Furthermore, we examined the effects of ASM-024, a synthetic nicotinic ligand, on in vitro anti-IgE and in vivo allergen-induced basophil activation. METHODS: Basophils were enriched from the peripheral blood of allergic donors and the expression of nAChR subunits and muscarinic receptors was determined. Purified basophils were stimulated with anti-IgE in the presence of ASM-024 with or without muscarinic or nicotinic antagonists for the measurement of CD203c expression and histamine release. The effect of 9 days of treatment with 50 and 200 mg ASM-024 on basophil CD203c expression was examined in the blood of mild allergic asthmatics before and after allergen inhalation challenge. RESULTS: nAChR α4, α7 and α1/α3/α5 receptor subunit expression was detected on basophils. Stimulation of basophils with anti-IgE increased CD203c expression and histamine release, which was inhibited by ASM-024 (10(-5) to 10(-)(3) M, p < 0.05). The effect of ASM-024 was reversed in the presence of muscarinic and nicotinic antagonists. In subjects with mild asthma, ASM-024 inhalation significantly inhibited basophil CD203c expression measured 24 h after allergen challenge (p = 0.03). CONCLUSION: This study shows that ASM-024 inhibits IgE- and allergen-induced basophil activation through both nicotinic and muscarinic receptors, and suggests that ASM-024 may be an efficacious agent for modulating allergic asthma responses.

CD34 is required for dendritic cell trafficking and pathology in murine hypersensitivity pneumonitis.

RATIONALE: Although recent work has shown that CD34 plays an important role in the trafficking of inflammatory cells during Th2-biased inflammatory responses, its role in Th1/Th17-biased disease as well as dendritic cell (DC) trafficking is unknown. OBJECTIVES: We used CD34-deficient mice (Cd34(-/-)) to investigate the role of CD34 in the Th1/Th17-biased lung inflammatory disease, hypersensitivity pneumonitis (HP). METHODS: HP was induced in wild-type (wt) and Cd34(-/-) mice by repeated intranasal administration of Saccharopolyspora rectivirgula antigen. Lung inflammation was assessed by histology and analysis of bronchoalveolar lavage cells. Primary and secondary immune responses were evaluated by cytokine recall responses of pulmonary inflammatory cells as well as draining lymph node cells. MEASUREMENTS AND MAIN RESULTS: Cd34(-/-) mice were highly resistant to the development of HP and exhibited an inflammatory pattern more reflective of a primary response to S. rectivirgula rather than the chronic lymphocytosis that is typical of this disease. Cytokine recall responses from Cd34(-/-) lymph node cells were dampened and consistent with a failure of antigen-loaded Cd34(-/-) DCs to deliver antigen and prime T cells in the draining lymph nodes. In agreement with this interpretation, adoptive transfer of wt DCs into Cd34(-/-) mice was sufficient to restore normal sensitivity to HP. CD34 was found to be expressed by wt DCs, and Cd34(-/-) DCs exhibited an impaired ability to chemotax toward a subset of chemokines in vitro. Finally, expression of human CD34 in Cd34(-/-) mice restored normal susceptibility to HP. CONCLUSIONS: We conclude that CD34 is expressed by mucosal DCs and plays an important role in their trafficking through the lung and to the lymph nodes. Our data also suggest that CD34 may play a selective role in the efficient migration of these cells to a subset of chemokines.

Farmer's lung-induced hypersensitivity pneumonitis complicated by shock.

Hypersensitivity pneumonitis is an immunologic reaction to an inhaled antigen, with a wide spectrum of clinical presentations. The most common manifestations are fever, cough, and dyspnea. We describe a case of hypersensitivity pneumonitis with marked alveolar lymphocytosis; the patient presented with respiratory failure and shock requiring mechanical ventilation and vasopressive agents. We hypothesized that immune mediators implicated in the pathogenesis of hypersensitivity pneumonitis were responsible for the transient shock observed in this patient.

Association between obesity and atopy in adults.

BACKGROUND/AIM: Previous literature on the association between obesity and atopy has been inconsistent. The aim of the study was to determine the relationship between obesity and atopic sensitization in adults. METHODS: The study included a total of 1,997 residents aged 18-79 years and was conducted in the town of Humboldt, Sask., Canada in 2003. Body mass index (BMI) and waist circumference (WC) were objectively measured. Allergy skin tests were conducted to determine atopic sensitization. RESULTS: Overall, the prevalence of one or more positive skin tests for atopy was 33.3% among those with a BMI of at least 30.0, 28.2% among those with a BMI of 25.0-29.9 and 27.3% among those with a BMI of less than 25 (p = 0.003). The odds ratio for atopy among those with a BMI of at least 30.0 versus those with a BMI of less than 25.0 was 1.51 (95% confidence interval, CI: 1.17, 1.95) after adjustment for sex, age, and other covariates. Stratified by sex, the adjusted odds ratios for obesity versus normal weight were 1.27 (95% CI: 0.73, 1.93) for men and 1.63 (95% CI: 1.18, 2.26) for women. WC was also significantly associated with the prevalence of atopy in both sexes after controlling for covariates. CONCLUSION: The data demonstrated a significant association between obesity, defined either by BMI or by WC, and atopy.

Toll-like receptor 4 variants reduce airway response in human subjects at high endotoxin levels in a swine facility.

BACKGROUND: Toll-like receptor 4 (TLR4) variants have been shown to reduce the respiratory responses to inhaled LPS in controlled experiments among healthy volunteers. OBJECTIVE: We sought to investigate whether naive subjects with TLR4 variants showed reduced respiratory response to a complex aerosol including endotoxin as a major constituent. METHODS: Twenty-nine nonsmoking, nonatopic healthy subjects with TLR4 299/399 polymorphisms and 29 age- and sex-matched, wild-type TLR4 control subjects were exposed for 5 hours each in a noncontaminated environment (baseline day) and in a swine confinement facility (exposure day). There were 16 men and 13 women in each of the 2 age- and sex-matched groups. RESULTS: TLR4 polymorphic subjects who were exposed to high endotoxin levels (>or=1550 EU/m(3)) had less reduction in the percentage across-shift change in FEV(1) from baseline than did wild-type subjects exposed to similar endotoxin levels. Among subjects exposed to higher endotoxin levels, the mean differences in the percentage across-shift changes between baseline and exposure days were significantly less in TLR4 polymorphic subjects compared with those seen in wild-type subjects in FEV(1) (-8.48% +/- 1.52% [mean +/- SE] vs -11.46% +/- 1.79%, P = .001), forced expiratory flow between 25% and 75% of forced vital capacity (-18.30% +/- 1.99% vs -24.14% +/- 3.28%, P = .009), and FEV(1)/forced vital capacity ratio (-5.40% +/- 0.56% vs -8.53% +/- 1.51%, P = .04). These patterns were not observed in IL-6 levels from serum and nasal lavage fluid, IL-8 levels from nasal lavage fluid, white blood cell counts, or blood differential counts. CONCLUSION: The association between TLR4 variants and reduced airway responsiveness to inhaled particulate was observed at high endotoxin concentrations, creating the possibility of certain threshold phenomena for the apparent protective effect of TLR4 variants.

Metalworking fluid-related aerosols in machining plants.

Respiratory problems are observed in machinists using soluble metalworking fluid (MWF). Evidences suggest that these problems could be related to the aerosolized microorganisms and their byproducts from MWF. To establish MWF aerosol exposure thresholds and to better understand their effect on human health, these aerosols must be fully characterized. This article evaluates airborne microorganisms and aerosols from soluble MWF in the working environment. Air quality parameters (endotoxin levels, culturable airborne microorganisms, fluid mist, inhalable dust and air exchange rates) were evaluated at 44 sites, in 25 shops in Quebec, Canada. Microorganism concentrations were also measured in MWF. Culturable airborne bacteria concentrations were low, ranging from 1.2 x 10(1) to 1.5 x 10(3) CFU (colony forming units) m(-3), even for metalworking fluid highly contaminated by bacteria (up to 2.4 x 10(9) CFU mL(-1)). Inhalable dust varied between < 0.1 to 2.6 mg m(-3), while air exchange rates were mostly below the standard (4 h(-1)) for this type of workplace, between 0.6 to 14.2 h(-1). Only nine of 44 sites respected the suggested minimum value for air exchange rates. Fluid mist ranged from 0.02 to 0.89 mg m(-3), which is below the threshold limit value (TLV) (ACGIH) of 5 mg m(-3). Airborne endotoxin concentrations ranged from undetectable to 183 EU m(-3) (endotoxin units), showing no correlation with airborne microorganisms or inhalable dust. Most workstations respected the suggested minimum values for fluid mist and showed low concentrations of airborne endotoxin, culturable microorganisms and inhalable dust despite fluid contamination, even when air exchange rates were below the recommendations. Airborne Pseudomonas pseudoalcaligenes was recovered from many sites at significant concentrations. Health-associated risks following exposure to this microorganism should be further investigated.

Classification of hypersensitivity pneumonitis: a hypothesis.

BACKGROUND: Regardless of the causative antigen, hypersensitivity pneumonitis (HP) is usually classified as 'acute', 'subacute' or 'chronic'. Considerable confusion still surrounds this classification because there are no widely accepted criteria to distinguish the various stages. The objective of this study was to determine whether the current classification of HP truly reflects categories of patients with distinct clinical features. METHODS: Data obtained from a large prospective multicenter cohort study (the HP Study) were used to divide a cohort of patients with HP into a limited number of categories (clusters) with maximally differing clinical patterns, without prejudgment. The results of this cluster analysis were compared with the current classification of HP (acute, subacute or chronic). RESULTS: 168 patients were included in the analysis. A 2-cluster solution best fitted the data. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills and body aches) and normal chest radiographs than those in cluster 2 (127 patients) who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests and fibrosis on high-resolution computed tomography (HRCT). All p values were <0.0001, using Fisher's exact test. Nodular opacities were seen on HRCT as often in cluster 1 as in cluster 2. There was considerable disagreement between the current classification of HP and the results of our analysis. CONCLUSION: The current classification of acute, subacute and chronic HP is not supported by our analysis. Subacute HP is particularly difficult to define.

Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer.

BACKGROUND: We undertook to determine whether adjuvant vinorelbine plus cisplatin prolongs overall survival among patients with completely resected early-stage non-small-cell lung cancer. METHODS: We randomly assigned patients with completely resected stage IB or stage II non-small-cell lung cancer to vinorelbine plus cisplatin or to observation. The primary end point was overall survival; principal secondary end points were recurrence-free survival and the toxicity and safety of the regimen. RESULTS: A total of 482 patients underwent randomization to vinorelbine plus cisplatin (242 patients) or observation (240); 45 percent of the patients had pathological stage IB disease and 55 percent had stage II, and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. In both groups, the median age was 61 years, 65 percent were men, and 53 percent had adenocarcinomas. Chemotherapy caused neutropenia in 88 percent of patients (including grade 3 febrile neutropenia in 7 percent) and death from toxic effects in two patients (0.8 percent). Nonhematologic toxic effects of chemotherapy were fatigue (81 percent of patients), nausea (80 percent), anorexia (55 percent), vomiting (48 percent), neuropathy (48 percent), and constipation (47 percent), but severe (grade 3 or greater) toxic effects were uncommon (<10 percent). Overall survival was significantly prolonged in the chemotherapy group as compared with the observation group (94 vs. 73 months; hazard ratio for death, 0.69; P=0.04), as was relapse-free survival (not reached vs. 46.7 months; hazard ratio for recurrence, 0.60; P<0.001). Five-year survival rates were 69 percent and 54 percent, respectively (P=0.03). CONCLUSIONS: Adjuvant vinorelbine plus cisplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected early-stage non-small-cell lung cancer.

Obesity and asthma: a specific phenotype?

BACKGROUND: Obesity is associated with an increased prevalence of asthma, especially in women, and appears to be more severe in the obese. This study aimed to determine if obese subjects have a specific asthma phenotype. METHODS: Forty-four consecutive obese subjects (body mass index [BMI] > or = 30 kg/m(2)) and 44 consecutive nonobese subjects (BMI < 25 kg/m(2)), all with asthma, completed an asthma control questionnaire, and underwent methacholine challenge with symptom perception scores, and sputum induction for differential cell count. BMI, waist circumference, and waist-to-hip ratio also were measured. RESULTS: Despite similar expiratory flows, bronchodilator response, airway responsiveness to methacholine, and symptom perception scores, asthma control was poorer in obese subjects than in nonobese subjects (p = 0.005). Total lung capacity (p = 0.01), expiratory reserve volume (p < 0.0001), functional residual capacity (p < 0.0001), and residual volume (p = 0.006) were lower in obese subjects than in nonobese subjects. Induced-sputum eosinophil and neutrophil counts were similar in both groups, although there was an inverse correlation between sputum eosinophils and waist circumference and a trend for a similar relationship for BMI. Blood serum C-reactive protein (p = 0.009) and fibrinogen (p = 0.0004) levels were higher in obese subjects than in nonobese subjects. CONCLUSION: Obese people with asthma had poorer asthma control than nonobese asthmatics despite similar symptoms perception. Bronchial and systemic inflammatory characteristics and the specific pattern of pulmonary function changes suggest a different phenotype of asthma in these subjects. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00532363 and NCT00532831.

Myths and controversies in hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is a pulmonary disease with symptoms of dyspnea and cough resulting from the inhalation of an antigen to which the patient has been previously sensitized. HP is an orphan disease, and current concepts on its diagnosis and management are often outdated. The objectives of this review are to summarize the modern evidence regarding the diagnostic criteria of HP, its pathophysiology, the procedures involved in the management of the disease, and its treatment strategies. Several areas for further research are identified, with priority given to (1) the establishment of a multicenter collaborative network to enhance the recognition, diagnosis, and management of the disease; (2) the development and support of population-based studies to provide additional insights into environmental and clinical characterization of HP; and (3) the exploration of the use and validity of biomarkers of both exposure and disease.

Modulation of eosinophil activation in vitro by a nicotinic receptor agonist.

Nicotinic receptor agonists decreased the infiltration of eosinophils into the lung and airways in a mouse model of asthma. To better understand the mechanisms implicated in this anti-inflammatory phenomenon, the expression of nicotinic acetylcholine receptors (nAChRs) and the effect of dimethylphenylpiperazinium (DMPP), a nonselective nAChR agonist, on human blood eosinophils were studied. The expression of alpha-3, -4, and -7 nAChR subunits on human blood eosinophils was measured by cell ELISA and immunocytochemistry. mRNA expression for all three subunits was evaluated by quantitative RT-PCR. The effect of DMPP on leukotriene C4 (LTC4) and matrix metalloproteinase-9 (MMP-9) production, eosinophil migration, and intracellular calcium mobilization was measured. The results show that the alpha-3, -4, and -7 nAChR subunits and mRNAs are expressed by blood eosinophils. In vitro treatment of these cells with various concentrations of DMPP reduced platelet-activating factor (PAF)-induced LTC4 production significantly. DMPP (160 microM) decreased eotaxin, and 5-oxo-6,8,11,14-eicosatetranoic acid induced eosinophil migration through Matrigel by 40.9% and 55.5%, respectively. This effect was reversed by the nAChR antagonist mecamylamine. In addition, DMPP reduced MMP-9 release and the inositol 1,4,5-triphosphate-dependent intracellular calcium increase provoked by PAF. Taken together, these results indicate that functional nAChRs are expressed on eosinophils and that nAChR agonists down-regulate eosinophil function in vitro. These anti-inflammatory effects could be of interest in the treatment of allergic asthma.

Waist circumference is associated with pulmonary function in normal-weight, overweight, and obese subjects.

BACKGROUND: Obesity is becoming a serious public health issue and is related to lung dysfunction. Because both weight and height are indicators of body size, body mass index (BMI) may not be an ideal index of obesity in prediction of pulmonary dysfunction. OBJECTIVE: The objective of the study was to determine the predictability of waist circumference (WC) and BMI for pulmonary function in adults with and without excess body weight. DESIGN: A cross-sectional study of 1674 adults aged > or = 18 y was conducted in a rural community. Height, weight, WC, and pulmonary function were measured. Multivariate analysis was conducted. RESULTS: WC was negatively associated with forced vital capacity and forced expiratory volume in 1 s, and the associations were consistent across sex, age, and BMI categories. On average, a 1-cm increase in WC was associated with a 13-mL reduction in forced vital capacity and an 11-mL reduction in forced expiratory volume in 1 s. The association between WC and pulmonary function was consistent in subjects with normal weight, overweight, and obesity. In subjects with normal weight, BMI was positively associated with forced vital capacity and forced expiratory volume in 1 s. CONCLUSION: WC, but not BMI, is negatively and consistently associated with pulmonary function in normal-weight, overweight, and obese subjects.

Reduced risk of atopic sensitization among farmers: the Humboldt study.

BACKGROUND: It needs to be clarified whether farming is associated with a reduced risk of atopy or allergic condition. There is a lack of consistent evidence for prevalences of atopy, respiratory allergy and asthma in adult farmers. METHODS: A cross-sectional study of adults (n = 2,081) was conducted in the town of Humboldt, Sask. Allergy skin prick tests were conducted to determine atopic sensitization. Respiratory allergy and physician-diagnosed asthma were based on self-reporting. Logistic regression was used to assess the associations of atopy, respiratory allergy and asthma with farming practices, adjusting for other important variables. RESULTS: Of 2,081 participants, 27.8% were farmers. Reduced risks of atopic sensitization, respiratory allergy and asthma were observed among farmers compared to non-farmers. After adjustment for sex and age, which are major confounders, the odds ratio for atopic sensitization was 0.79 (95% confidence interval: 0.65, 0.97) for farmers versus non-farmers. Asthma showed a similar trend; however, there was no statistically significant difference in either respiratory allergy or asthma rates observed between farmers and non-farmers. CONCLUSIONS: The prevalence of atopy was lower in adult farmers than in non-farmers.

Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.

PURPOSE: To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS: Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS: The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION: L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

Sex specificity of asthma associated with objectively measured body mass index and waist circumference: the Humboldt study.

STUDY OBJECTIVE: To investigate the possibility of sex specificity for the association of obesity and asthma using objective measures of body mass index (BMI) and waist circumference (WC). DESIGN: Cross-sectional study of adults (n = 2,057) living in Humboldt, SK, Canada in 2003. SETTING: A rural community. MEASUREMENTS: Ever-asthma was defined as lifetime physician-diagnosed asthma, and recent asthma was defined as asthma diagnosed by a physician during the past 12 months. BMI and WC were objectively measured. RESULTS: Among the participants, 5.6% of men and 10.0% of women reported having ever-asthma, and 2.7% and 6.0% had recent asthma, respectively. Higher levels of both BMI and WC were significantly associated with asthma in women but not in men. The adjusted odds ratios for women with a BMI of at least 30.0 kg/m2 relative to women with a BMI of < 25.0 kg/m2 were 2.06 (95% confidence interval [CI], 1.42 to 4.05) for ever-asthma and 3.47 (95% CI, 1.64 to 7.32) for recent asthma. CONCLUSIONS: Our study demonstrated that the increased risk of asthma associated with obesity was only significant in women but not in men even when BMI was objectively measured, and this association was robust to the anthropometric measures.

ASM-024, a piperazinium compound, promotes the in vitro relaxation of ß2-adrenoreceptor desensitized tracheas.

Inhaled ß2-adrenoreceptor agonists are widely used in asthma and chronic obstructive pulmonary disease (COPD) for bronchoconstriction relief. ß2-Adrenoreceptor agonists relax airway smooth muscle cells via cyclic adenosine monophosphate (cAMP) mediated pathways. However, prolonged stimulation induces functional desensitization of the ß2-adrenoreceptors (ß2-AR), potentially leading to reduced clinical efficacy with chronic or prolonged administration. ASM-024, a small synthetic molecule in clinical stage development, has shown activity at the level of nicotinic receptors and possibly at the muscarinic level and presents anti-inflammatory and bronchodilator properties. Aerosolized ASM-024 reduces airway resistance in mice and promotes in-vitro relaxation of tracheal and bronchial preparations from animal and human tissues. ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog and human bronchi. Although the precise mechanisms by which ASM-024 promotes airway smooth muscle (ASM) relaxation remain unclear, we hypothesized that ASM-024 will attenuate and/or abrogate agonist-induced contraction and remain effective despite ß2-AR tachyphylaxis. ß2-AR tachyphylaxis was induced with salbutamol, salmeterol and formoterol on guinea pig tracheas. The addition of ASM-024 relaxed concentration-dependently intact or ß2-AR desensitized tracheal rings precontracted with methacholine. ASM-024 did not induce any elevation of intracellular cAMP in isolated smooth muscle cells; moreover, blockade of the cAMP pathway with an adenylate cyclase inhibitor had no significant effect on ASM-024-induced guinea pig trachea relaxation. Collectively, these findings show that ASM-024 elicits relaxation of ß2-AR desensitized tracheal preparations and suggest that ASM-024 mediates smooth muscle relaxation through a different target and signaling pathway than ß2-adrenergic receptor agonists. These findings suggest ASM-024 could potentially provide clinical benefit when used adjunctively with inhaled ß2-adrenoreceptor agonists in those patients exhibiting a reduced response to their chronic use.

Effects of ASM-024, a modulator of acetylcholine receptor function, on airway responsiveness and allergen-induced responses in patients with mild asthma.

OBJECTIVES: To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma. METHODS: The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured. RESULTS: Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo -1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo. CONCLUSIONS: ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.

Pathogenesis of hypersensitivity pneumonitis.

PURPOSE OF REVIEW: Hypersensitivity pneumonitis is a group of immunologically mediated diseases caused by an abnormal response to a wide variety of inhaled antigens. Its pathogenesis is complex and involves many immunological concepts. This review discusses recent advances in our understanding of the pathogenesis of hypersensitivity pneumonitis. RECENT FINDINGS: Over the last 3 years, several studies on the pathogenesis of hypersensitivity pneumonitis have been published. New antigens have been identified. We now have a better understanding of the role of inflammatory cells and mediators, and promoting and protective factors have been suggested. SUMMARY: Most of the mechanisms involved in the pathogenesis of hypersensitivity pneumonitis remain incompletely understood. Current and future findings will not only help our understanding of the disease and its prevention, but also improve its treatment.

Saccharopolyspora rectivirgula from Quebec dairy barns: application of simplified criteria for the identification of an agent responsible for farmer's lung disease.

Saccharopolyspora rectivirgula (Micropolyspora faeni) is one of the major agents responsible for farmer's lung disease, a form of hypersensitivity pneumonitis. It is frequently isolated from the air of contaminated barns. The identification of this actinomycete is difficult because most of its phenotypic characteristics are variable and classical tests are not easy to perform on actinomycetes. Fatty acid analysis is very useful for the identification of these strains, but is not available except in some research or reference laboratories. Morphological (microscopic and macroscopic observations), physiological and biochemical tests (growth properties; macromolecules degraded; citrate utilisation and acid production from carbohydrates; resistance to antibiotics, lysozyme and heat), cell wall and fatty acid analyses and IgG analyses with serum from patients with farmer's lung were performed on 12 environmental isolates presumed to be S. rectivirgula and two control strains of S. rectivirgula. From this, a simple and rapid scheme for the identification of this actinomycete is proposed: optimal growth temperature (55 degrees C); colony appearance based on morphology (filamentous) and colour (beige to orange-brown); microscopic morphology (chains of spores on both aerial and substrate mycelium); growth on NaCl 10%; cell-wall analysis (type IV); and the verification of antibody response with serum from a patient with farmer's lung. This last criterion is important to confirm the immunogenicity of the strains identified as S. rectivirgula. This scheme provides an accurate and efficient way of identifying S. rectivirgula strains and evaluating exposure to this bacterium. The study shows the limited value and the lack of reproducibility of some classical biochemical tests.

Chronic inflammation induced by organic dust and related metabolic cardiovascular disease risk factors.

OBJECTIVE: Chronic inflammation is now considered a risk factor for cardiovascular diseases. Exposure to organic dust induces an inflammatory response. This study was done to verify whether inflammation caused by exposure to organic dust increases the metabolic risk factors for cardiovascular diseases. METHODS: Thirty-six nonsmoking men who worked in a swine confinement building and 35 unexposed matched controls were studied. Each person was evaluated for inflammatory markers, including white blood cell counts, cell-bound (CD11b, CD18, CD31, CD62L) and circulating soluble adhesion molecule levels (sICAM-1, sPECAM-1, sL, sE, and sP selectins), serum CRP (C-reactive protein), fibrinogen, and interleukin-6 (IL-6). Cardiovascular risk factors [the serum lipid profile, apoprotein B (Apo B)] and insulin levels were also assessed. RESULTS: The groups were similar with respect to age, physical characteristics, and blood cell counts. The expression of adhesion molecules (P-values <0.01) and serum levels of sL-selectin (P<0.0001) were higher for the workers than for the controls, while neutrophils and interleukin-6 were slightly higher for the workers (P=0.05). No differences in CRP, fibrinogen, lipid profile, Apo B, or insulin levels were observed. CONCLUSIONS: Exposure to contaminated organic dust induces a chronic inflammation that is not associated with increased metabolic or acute-phase cardiovascular risk factors; this finding suggests that chronic inflammation per se may not be a cardiovascular risk factor in this group of pig farmers.