HMGB1 inhibition reduces TDI-induced occupational asthma through ROS/AMPK/autophagy pathway.

Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells. We found that suppression of HMGB1 obviously alleviated airway inflammation, airway hyperresponsiveness, and airway remodeling in the lung tissue of the asthma mice. The in vitro results showed that inhibition of HMGB1 ameliorated TDI-induced reactive oxygen species (ROS) release, inflammatory response, and activation of autophagy in HBE cells. At the molecular level, inhibition of HMGB1 decreased the expressions of HMGB1, Toll-like receptor 4, Vimentin and matrix metalloproteinase-9 proteins, activated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome, and increased E-cadherin expression. Importantly, activation of autophagy could lead to the overactivation of NLRP3 inflammasome in TDI-induced asthma. These results suggest that inhibition of HMGB1 can alleviate TDI-induced asthma through ROS/AMPK/autophagy pathways, which may provide valuable evidence for the pathogenesis and therapeutic targets of TDI-induced asthma.

Long-Term Follow-Up of Cluster-Based Diisocyanate Asthma Phenotypes.

BACKGROUND: Data on the outcome of occupational asthma (OA) are heterogeneous. OBJECTIVE: To assess the impact of being part of a specific cluster at diagnosis on the long-term outcome of diisocyanate-induced OA. METHODS: We collected data from 56 patients who had a diagnosis of OA confirmed by a positive specific inhalation challenge. Patients sensitized to toluene diisocyanate were allocated to cluster 1 or 2 based on a tree analysis, using the 3 variables relevant for cluster segregation identified in a previous study: age, body mass index, and forced expiratory volume in 1 second/forced vital capacity at diagnosis. Patients sensitized to methylene diisocyanate were allocated to cluster 3, as in previous study. We defined OA remission when a patient had met a total of 3 criteria: no asthma symptoms and no antiasthma therapy for the last year, as well as having normal lung function. RESULTS: At follow-up, 16 patients showed OA remission. They exhibited better lung function, less bronchial hyperreactivity, as well as younger age at diagnosis. Twenty-eight patients were allocated to cluster 1, 10 to cluster 2, and 18 to cluster 3. The percentage of patients with OA remission was higher in cluster 2 (50% vs 25% in cluster 1 and 22.5% in cluster 3), although the difference was not statistically significant (P = .2789). CONCLUSIONS: Age at diagnosis was a strong predictor of OA remission. The outcome of diisocyanate OA tended to be more favorable for patients with toluene diisocyanate OA allocated in cluster 2, but this finding needs to be validated by further data.

Prevalence of COPD among workers with work-related asthma.

Objective: Concurrent asthma and chronic obstructive pulmonary disease (COPD) diagnoses occur in 15%-20% of patients, and have been associated with worse health outcomes than asthma or COPD alone. Work-related asthma (WRA), asthma that is caused or made worse by exposures in the workplace, is characterized by poorly controlled asthma. The objective of this study was to assess the proportion of ever-employed adults (≥18 years) with current asthma who have been diagnosed with COPD, by WRA status.Methods: Data from 23 137 respondents to the 2012-2014 Behavioral Risk Factor Surveillance System Asthma Call-back Survey from 31 states and the District of Columbia were examined. Logistic regression was used to calculate adjusted prevalence ratios (PRs), examining six disjoint categories of WRA-COPD overlap with non-WRA/no COPD as the referent category.Results: An estimated 51.9% of adults with WRA and 25.6% of adults with non-WRA had ever been diagnosed with COPD. Adults with WRA/COPD were more likely than those with non-WRA/no COPD to have an asthma attack (PR = 1.77), urgent treatment for worsening asthma (PR = 2.85), an asthma-related emergency room visit (PR = 4.21), overnight stay in a hospital because of asthma (PR = 6.57), an activity limitation on 1-13 days (PR = 2.01) or ≥14 days (PR = 5.02), and very poorly controlled asthma (PR = 3.22).Conclusions: COPD was more frequently diagnosed among adults with WRA than those with non-WRA, and adults diagnosed with both WRA and COPD appear to have more severe adverse asthma outcomes than those with non-WRA and no COPD.

Severe Occupational Asthma: Insights From a Multicenter European Cohort.

BACKGROUND: Although sensitizer-induced occupational asthma (OA) accounts for an appreciable fraction of adult asthma, the severity of OA has received little attention. OBJECTIVE: The aim of this study was to characterize the burden and determinants of severe OA in a large multicenter cohort of subjects with OA. METHODS: This retrospective study included 997 subjects with OA ascertained by a positive specific inhalation challenge completed in 20 tertiary centers in 11 European countries during the period 2006 to 2015. Severe asthma was defined by a high level of treatment and any 1 of the following criteria: (1) daily need for a reliever medication, (2) 2 or more severe exacerbations in the previous year, or (3) airflow obstruction. RESULTS: Overall, 162 (16.2%; 95% CI, 14.0%-18.7%) subjects were classified as having severe OA. Multivariable logistic regression analysis revealed that severe OA was associated with persistent (vs reduced) exposure to the causal agent at work (odds ratio [OR], 2.78; 95% CI, 1.50-5.60); a longer duration of the disease (OR, 1.04; 95% CI, 1.00-1.07); a low level of education (OR, 2.69; 95% CI, 1.73-4.18); childhood asthma (OR, 2.92; 95% CI, 1.13-7.36); and sputum production (OR, 2.86; 95% CI, 1.87-4.38). In subjects removed from exposure, severe OA was associated only with sputum production (OR, 3.68; 95% CI, 1.87-7.40); a low education level (OR, 3.41; 95% CI, 1.72-6.80); and obesity (OR, 1.98; 95% CI, 0.97-3.97). CONCLUSIONS: This study indicates that a substantial proportion of subjects with OA experience severe asthma and identifies potentially modifiable risk factors for severe OA that should be targeted to reduce the adverse impacts of the disease.

Effect of anti-IgE in occupational asthma caused by exposure to low molecular weight agents.

BACKGROUND: The role of immunoglobulin (Ig)-E in occupational asthma (OA) due to low molecular weight (LMW) agents is not well established compared to classical atopic asthma. In this study, we evaluate whether anti-IgE monoclonal antibody (mAb) has an effect in a mouse model of OA, using persulfate salts. METHODS: On days 1 and 8, BALB/C mice were dermally sensitized with 5% ammonium persulfate (AP) or dimethyl sulfoxide (DMSO). On days 15, 18, and 21, animals were injected intraperitoneally with anti-IgE mAb or PBS 6 hours before challenge with AP or saline. Airway hyper-responsiveness (AHR) using a methacholine test, airway inflammation in bronchoalveolar lavage (BAL) and lung tissue, and total free IgE in serum samples were analyzed 24, 48, and 96 hours after the last challenge. RESULTS: Anti-IgE mAb treatment almost completely neutralized free serum IgE. In AP-sensitized and challenged mice, anti-IgE mAb treatment abolished AHR 24 hour and 48 hour after the last challenge and significantly reduced the total number of eosinophils and neutrophils 48 hour and 96 hour after the last AP challenge compared with nontreated mice. Levels of interleukin (IL)-13 in BAL were also significantly decreased after anti-IgE administration 24 hour and 48 hour after the last AP challenge. Histological analysis of the lung sections from anti-IgE-treated mice revealed normal inflammatory patterns similar to control groups 48 hour after the last challenge. CONCLUSIONS: Anti-IgE-treated mice showed a significant improvement in asthma features related to the AHR and airway inflammation. Anti-IgE mAb has positive effects in OA induced by persulfate salts.

The role of allergen components for the diagnosis of latex-induced occupational asthma.

BACKGROUND: Recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergen components have been developed to assess the patients' allergen sensitization profile and to improve the diagnosis of NRL allergy. OBJECTIVE: To examine whether the determination of specific IgE (sIgE) reactivity to a panel of recombinant allergen components would be helpful for diagnosing NRL-induced occupational asthma (OA) in predicting the outcome of a specific inhalation test. METHODS: sIgE levels to NRL extract and 12 recombinant NRL allergen components were assessed in 82 subjects with OA ascertained by a positive specific inhalation challenge (SIC) with NRL gloves and in 25 symptomatic subjects with a negative challenge. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of a NRL-sIgE level ≥0.35 kUA /l as compared to the result of SICs were 94%, 48%, 86%, and 71%, respectively. The positive predictive value increased above 95% when increasing the cutoff value to 5.41 kUA /l. Subjects with a positive SIC showed a significantly higher rate of sIgE reactivity to rHev b 5, 6.01, 6.02, and 11 than those with a negative SIC. A sIgE sum score against rHev b 5 plus 6.01/6.02 ≥ 1.46 kUA /l provided a positive predictive value >95% with a higher sensitivity (79%) and diagnostic efficiency (Youden index: 0.67) as compared with a NRL-sIgE ≥5.41 kUA /l (49% and 0.41, respectively). CONCLUSION: In suspected OA, high levels of sIgE against rHev b 5 combined with rHev b 6.01 or 6.02 are the most efficient predictors of a bronchial response to NRL.

[Effect of Wenyang Decoction on the Differentiation of CD34+ Progenitor Cells in Occupational Asthma Model Rats].

OBJECTIVE: To study the effect of Wenyang Decoction (WD) on the differentiation of CD34+ progenitor cells of occupational asthma (OA) model rats. METHODS: Fifty healthy male SD rats were randomly divided into five groups, i.e., the model group, the blank control group,the WD group,the Western medicine group,the combined group, 10 in each group. Prednisone suspension (10 mg/kg) was administered to rats in the Western medicine group by gastrogavage. WD (20 g/kg) was administered to rats in the WD group by gastrogavage. Prednisone suspension plus WD was administered to rats in the combined group by gastrogavage. Normal saline was administered to rats in the model group and the blank control group by gastrogavage. The general condition of rats was observed. Expression levels of peripheral blood IL-5 and eotaxin, eosinophils (EOS), CD34+, CC chemokine receptor 3 (CCR3+) in bone marrow suspension were detected by ELISA, Wirght-Giemsa, and flow cytometry, respectively. RESULTS: Compared with the blank control group,expression levels of IL-5 and eotaxin in peripheral blood were significantly higher (P < 0.01), and the count of EOS and CD34+ cells, as well as CD34+ /CCR3+ significantly increased (P < 0.01) in the model group. Compared with the model group, expression levels of IL-5 and eotaxin, the count of EOS, CD34+ cells, CD34+ / CCR3+ were lowered in three treated groups (P < 0.01). Compared with the Western medicine group, the count of EOS and CD34+ / CCR3+ decreased in the combined group (P < 0.01). The count of EOS was significantly lower in the combined group than in the WD group (P < 0.01). CONCLUSION: WD could reduce levels of in vivo inflammatory factors, and restrain the differentiation and recruitment of EOS,thereby alleviating the differentiation of CD34 progenitor cells to EOS.

Persistent and Unusual Respiratory Findings after Prolonged Glutaraldehyde Exposure.

Glutaraldehyde is commonly used in endoscopy labs to clean and disinfect instruments. It can cause direct irritation of the skin and the upper and lower airways. Health care workers are also at risk for the development of irritant-induced or sensitizer-induced occupational asthma when exposed to this chemical. Herein, we report on a patient who had frequent exposures to glutaraldehyde over one year while working in an endoscopy lab and developed chronic upper and lower respiratory tract symptoms. Multiple spirometric tests during her evaluation revealed variable results including restrictive pattern with a response to bronchodilators, obstructive pattern with a paradoxic bronchoconstrictive response to bronchodilators, and obstructive pattern with a partial response to bronchodilators. These results indicate that the distribution of inflammation and bronchial responsiveness can vary in a single patient with glutaraldehyde-induced occupational asthma. Therefore, the evaluation may be more difficult than might be expected in patients with occupational asthma, and some patients will need multiple pulmonary function tests to characterize their airway disease.

An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma.

The fifth Jack Pepys Workshop on Asthma in the Workplace focused on the similarities and differences of work-related asthma (WRA) and non-work-related asthma (non-WRA). WRA includes occupational asthma (OA) and work-exacerbated asthma (WEA). There are few biological differences in the mechanisms of sensitization to environmental and occupational allergens. Non-WRA and OA, when due to high-molecular-weight agents, are both IgE mediated; it is uncertain whether OA due to low-molecular-weight agents is also IgE mediated. Risk factors for OA include female sex, a history of upper airway symptoms, and a history of bronchial hyperresponsiveness. Atopy is a risk factor for OA due to high-molecular-weight agents, and exposure to cleaning agents is a risk factor for both OA and non-WRA. WEA is important among workers with preexisting asthma and may overlap with irritant-induced asthma, a type of OA. Induced sputum cytology can confirm airway inflammation, but specific inhalation challenge is the reference standard diagnostic test. Inhalation challenges are relatively safe, with the most severe reactions occurring with low-molecular-weight agents. Indirect health care costs account for about 50% of total asthma costs. Workers with poor asthma control (WRA or non-WRA) are less likely to be employed. Income loss is a major contributor to the indirect costs of WRA. Overall, asthma outcomes probably are worse for adult-onset than for childhood-onset asthma but better for OA than adult-onset non-WRA. Important aspects of management of OA are rapid and proper confirmation of the diagnosis and reduction of exposure to sensitizers or irritants at work and home.

Sputum eosinophilia is a determinant of FEV1 decline in occupational asthma: results of an observational study.

OBJECTIVE: To evaluate the potential determinants of forced expiratory volume in 1 s (FEV1) decline in workers with occupational asthma (OA) still exposed to the causative agent. We hypothesised that sputum eosinophilia might be a predictor of poor asthma outcome after diagnosis. SETTING, DESIGN AND PARTICIPANTS: In a specialistic clinical centre of the University Hospital of Pisa, we studied 39 participants (28 M, 11 F) diagnosed as having OA, routinely followed up between 1990 and 2009. They were a subgroup of 94 participants diagnosed as affected by OA in that period: 9 had been removed from work at the diagnosis, 21 were excluded for having ceased occupational exposure after few months from diagnosis, and 25 were lost at the follow-up or had no acceptable sputum measurements at the diagnosis. Estimates of the decline in FEV1 were obtained by means of simple regression analysis during the period of occupational exposure after diagnosis. Logistic regression was used to analyse the effects of factors (baseline FEV1 and sputum inflammatory cells, duration and type of exposure) that may potentially influence FEV1 decline. RESULTS: At follow-up (5.7+3.7 years), most participants were still symptomatic despite inhaled corticosteroids (ICS) treatment and had their occupational exposure reduced. Participants with higher sputum eosinophils (>3%) at baseline had a significantly greater decline of FEV1 (-52.5 vs -18.6 mL/year, p=0.012). Logistic regression showed that persistent exposure and sputum eosinophilia were significantly associated with a greater decline in FEV1 (OR 11.5, 95% CI 1.8 to 71.4, p=0.009 and OR 6.7, 95% CI 1.1 to 41.7, p= 0.042, respectively). CONCLUSIONS: Sputum eosinophilia at diagnosis, together with the persistence of occupational exposure during follow-up, may contribute to a greater decline in FEV1 in patients with OA still at work. Further long-term studies are required as to whether intensive ICS treatment may be beneficial for patients with OA and increase ad eosinophilic inflammation.

Redemption of asthma pharmaceuticals among stainless steel and mild steel welders: a nationwide follow-up study.

PURPOSE: The purpose was to examine bronchial asthma according to cumulative exposure to fume particulates conferred by stainless steel and mild steel welding through a proxy of redeemed prescribed asthma pharmaceuticals. METHODS: A Danish national company-based historical cohort of 5,303 male ever-welders was followed from 1995 to 2011 in the Danish Medicinal Product Registry to identify the first-time redemption of asthma pharmaceuticals including beta-2-adrenoreceptor agonists, adrenergic drugs for obstructive airway diseases and inhalable glucocorticoids. Lifetime exposure to welding fume particulates was estimated by combining questionnaire data on welding work with a welding exposure matrix. The estimated exposure accounted for calendar time, welding intermittence, type of steel, welding methods, local exhaustion and welding in confined spaces. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model adjusting for potential confounders and taking modifying effects of smoking into account. RESULTS: The average incidence of redemption of asthma pharmaceuticals in the cohort was 16 per 1,000 person year (95% CI 10-23 per 1,000 person year). A moderate nonsignificant increased rate of redemption of asthma medicine was observed among high-level exposed stainless steel welders in comparison with low-level exposed welders (HR 1.54, 95% CI 0.76-3.13). This risk increase was driven by an increase risk among non-smoking stainless steel welders (HR 1.46, 95% CI 1.06-2.02). Mild steel welding was not associated with increased risk of use asthma pharmaceuticals. CONCLUSION: The present study indicates that long-term exposure to stainless steel welding is related to increased risk of asthma in non-smokers.

[Occupational asthma caused by maleic anhydride].

Organic acid anhydrides (OAA) are widely used in the chemical industry. They are irritants and can cause sensitization and asthma. We describe the first documented case of occupational asthma caused by the OAA maleic anhydride (MA) in the production of insecticides. A 60-year-old man developed work-related respiratory symptoms after eight years of intermittent exposure to MA. Peak expiratory flow measurements showed greater variance on work days than on days off. Both a basophilic activation test and determination of the MA-specific IgE level in serum showed sensitization to MA.

[Asthma among mink workers].

We report two cases of asthma among mink workers. The first case is about a mink farmer who had asthma that was difficult to treat. In the medical history there was no clear relation to work, and no conclusive work relation with peak flow monitoring. He had a positive histamine release test to mink urine. The second case is about a mink farm worker, who had an asthma attack when handling mink furs. Peak flow monitoring showed a clear relation to this work, but there were no signs of allergy. We conclude that these two cases suggest an increased risk of asthma among mink workers.

Shiitake mushroom (Lentinus edodes): a poorly known allergen in Western countries responsible for severe work-related asthma.

OBJECTIVES: The aim of this study was to investigate the IgE-mediated pathogenesis of severe asthma presented by a patient only after handling shiitake (Lentinus edodes) mushrooms (SM). MATERIAL AND METHODS: Skin tests were performed using in-house extracts from mushrooms that the patient usually handled, i.e., shiitake, porcini, oyster and black fungus mushroom varieties. Specific IgE to champignons and various molds were determined. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) immunoblotting was performed to detect IgE-binding components. Four negative controls were included in the study. RESULTS: Skin prick tests performed with in-house mushroom extracts from varieties other than shiitake were completely negative, in contrast to the positive test obtained for shiitake mushrooms. Serum specific IgE levels for common molds and champignons were all negative. SDS-PAGE revealed many protein bands in the four mushroom extracts. Immunoblotting using the patient's serum showed allergenic bands at about 15 and 24 kDa exclusively for SM that were not shared with negative controls. Another faint band was detectable at approximately 37 kDa for SM and porcini varieties. CONCLUSIONS: Here, we present the first European case of SM-induced occupational asthma, a disease more frequently occurring in Asia. Asthma attacks stopped when the patient avoided contact with shiitake mushrooms. No skin reactions and no IgE-binding proteins by immunoblotting were detectable with the other mushrooms tested. The positive skin test with shiitake mushrooms and IgE-binding components in the shiitake extract confirmed the IgE-mediated etiology of the reaction.

Usefulness of omalizumab in ten patients with severe occupational asthma.

BACKGROUND: The management of severe occupational asthma (OA) remains problematic and new alternative treatments providing better disease control are required, ideally enabling affected individuals to remain in their job. METHODS: Ten patients with severe uncontrolled OA were treated with the monoclonal anti-IgE antibody omalizumab. In six cases the causative agent was a high molecular weight (HMW) compound and in four cases it was a low molecular weight (LMW) chemical. All of the patients had well documented OA despite workplace adjustments. RESULTS: During treatment, nine patients exhibited a lower rate of asthma exacerbations and used less oral or inhaled corticosteroids. Seven patients were able to continue working at the same workplace as before treatment. CONCLUSION: We have demonstrated that omalizumab is a potential treatment for severe uncontrolled OA and enabled seven of the ten patients in the study to remain in their job.