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.

Potential classification of chemical immunologic response based on gene expression profiles.

Occupational immune diseases are a serious public health burden and are often a result of exposure to low molecular weight (LMW) chemicals. The complete immunological mechanisms driving these responses are not fully understood which has made the classification of chemical allergens difficult. Antimicrobials are a large group of immunologically-diverse LMW agents. In these studies, mice were dermally exposed to representative antimicrobial chemicals (sensitizers: didecyldimethylammonium chloride (DDAC), ortho-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals Tslp (skin), and S100a8 (skin, blood, lung). Expression of the TH2 cytokine Il4 peaked at different timepoints for the chemicals based on exposure duration. Unique expression profiles were identified for OPA (Il10 in lymph node, Il4 and Il13 in lung) and TCS (Tlr4 in skin). Additionally, all chemicals except OPA induced decreased expression of the cellular adhesion molecule Ecad. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for additional studies. In order to advance the development of preventative and therapeutic strategies to combat immunological disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chemical toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases.

Assessment of eosinophilic airway inflammation as a contribution to the diagnosis of occupational asthma.

BACKGROUND: Ascertaining the presence of asthma through the assessment of nonspecific bronchial hyperresponsiveness (NSBH) is a key step in the diagnosis of occupational asthma (OA). We aimed at investigating whether indices of airway inflammation including fractional exhaled nitric oxide (FeNO) and sputum eosinophils would be useful adjuncts to the measurement of NSBH in diagnosing OA defined as a positive specific inhalation challenge (SIC). METHODS: The study included 240 consecutive subjects with a suspicion of OA who completed a SIC, of whom 133 showed a positive response. The sensitivity, specificity, and predictive values of NSBH, and FeNO, as well as sputum eosinophil counts assessed at baseline of the SIC were determined. RESULTS: A concentration of histamine inducing a 20% decline in FEV1 (PC20 ) ≤16 mg/mL showed a sensitivity of 87% and a specificity of 36%. A FeNO level ≥25 ppb and a sputum eosinophil count ≥2% provided lower sensitivity rates (47% and 39%, respectively) than the PC20 value. Eight of the 17 subjects without baseline NSBH despite a positive SIC showed a sputum eosinophil count ≥2%, a FeNO level ≥25 ppb, or both outcomes. Combining either a PC20 value ≤16 mg/mL or a FeNO ≥25 ppb increased the sensitivity to 91%. Using either a PC20 ≤16 mg/mL or a sputum eosinophil count ≥1% increased the sensitivity to 94%. CONCLUSION: Adding the assessment of FeNO level and sputum eosinophils to NSBH improves the identification of subjects who may have OA and require further objective testing before excluding the possibility of OA.

Occupational Asthma Due to Inhalation of Aerosolized Lipophilic Coating Materials.

We present a case of onset of severe asthma in a 59-year-old patient who worked in an aerospace plant. He was noted to have wheezing on exam and obstruction on PFTs. Review of his occupational history revealed exposure to lipophilic industrial compounds. We outline the radiographic and histologic findings that were found in the patient, and discuss occupational asthma due to inhalation of lipophilic compounds.

Do Low Molecular Weight Agents Cause More Severe Asthma than High Molecular Weight Agents?

INTRODUCTION: The aim of this study was to analyse whether patients with occupational asthma (OA) caused by low molecular weight (LMW) agents differed from patients with OA caused by high molecular weight (HMW) with regard to risk factors, asthma presentation and severity, and response to various diagnostic tests. METHODS: Seventy-eight patients with OA diagnosed by positive specific inhalation challenge (SIC) were included. Anthropometric characteristics, atopic status, occupation, latency periods, asthma severity according to the Global Initiative for Asthma (GINA) control classification, lung function tests and SIC results were analysed. RESULTS: OA was induced by an HMW agent in 23 patients (29%) and by an LMW agent in 55 (71%). A logistic regression analysis confirmed that patients with OA caused by LMW agents had a significantly higher risk of severity according to the GINA classification after adjusting for potential confounders (OR = 3.579, 95% CI 1.136-11.280; p = 0.029). During the SIC, most patients with OA caused by HMW agents presented an early reaction (82%), while in patients with OA caused by LMW agents the response was mainly late (73%) (p = 0.0001). Similarly, patients with OA caused by LMW agents experienced a greater degree of bronchial hyperresponsiveness, measured as the difference in the methacholine dose-response ratio (DRR) before and after SIC (1.77, range 0-16), compared with patients with OA caused by HMW agents (0.87, range 0-72), (p = 0.024). CONCLUSIONS: OA caused by LMW agents may be more severe than that caused by HMW agents. The severity of the condition may be determined by the different mechanisms of action of these agents.

IgE Reactivity, Work Related Allergic Symptoms, Asthma Severity, and Quality of Life in Bakers with Occupational Asthma.

In Germany, bakers with occupational asthma willing to stay in their job are included in an interdisciplinary program of the Social Accident Insurance for Foodstuff and Catering Industry (BGN). The primary aim is to reduce flour dust exposure, and to provide adequate medical treatment. Our aim was to evaluate the program's effect on the disease's course using routinely collected data. Forty three bakers with allergic occupational asthma and with the available baseline level of IgE (f4, f5) were investigated. Changes in IgE related to wheat and rye flour exposure were measured by ImmunoCAP test during follow-up visits. A questionnaire on work-related allergic complaints (WRAC), the Asthma Control Test (ACT), a 10-point scale of asthma severity grade, and quality of life instruments (EQ-5D-5L, Mini-AQLQ) were administered. We found an improvement of asthma severity in 88.4 % of the bakers. WRAC were reported by 65 %; 77 % had good asthma control (ACT ≥ 20); and 81 % had regular asthma medication. A relevant reduction of ≥2 CAP-classes for both allergens was seen in 12 % of the subjects. Health-related and asthma-specific quality of life was high. We conclude that satisfactory asthma control is probably the result of adequate medical management. In a subgroup of bakers with decreased specific IgE, it may also be attributed to reduced allergen exposure.

Occupational rhinitis affects occupational asthma severity.

BACKGROUND: The strong interactions between asthma and rhinitis, and the influence of rhinitis in the severity and/or control of asthma, have clearly been demonstrated. Nevertheless, no specific study has been conducted in the occupational setting. OBJECTIVE: The aim of the study was to assess the severity of occupational asthma and rhinitis and evaluate whether rhinitis is a predictor for increased asthma severity. METHODS: We retrospectively reviewed the clinical charts of 72 patients who received a diagnosis of allergic occupational asthma, with or without associated occupational rhinitis. RESULTS: Our findings suggested that persistent asthma tended to be more common in subjects with associated occupational asthma and rhinitis, and occupational asthma severity was associated with occupational rhinitis severity. Moderate-severe persistent occupational rhinitis is a risk factor for persistent occupational asthma. CONCLUSIONS: We demonstrated, for the first time in the occupational setting, a significant association between occupational rhinitis and asthma severity.

Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation.

BACKGROUND: The natural history of asthma includes in some patients periods of disease remission, but the underlying mechanisms are unknown. OBJECTIVES: We explored whether type 1 myeloid dendritic cell (mDC) dysfunction could be involved in the persistence of asthma, studying the controlled setting of occupational asthma after allergen avoidance. METHODS: We recruited 32 patients with occupational asthma to flour or latex ascertained by specific inhalation challenge and who were no longer exposed to the causal allergen. Leukapheresis was performed in each patient to isolate and characterise blood type 1 mDCs, and their functionality was studied in coculture with allogeneic CD4(+) T cells from controls. RESULTS: At follow-up, 11/32 patients (34%) were characterised by the absence of symptoms and non-specific bronchial hyper-responsiveness to histamine and were considered to be cured. When compared with cured patients, mDCs from patients with persistent disease increased the production of interleukin (IL) 5 and IL-13 by CD4(+) T cells, and upregulated programmed death ligand 2 (PD-L2) upon allergen pulsing. In addition, IL-5 and IL-13 responses could be reversed by exogenous IL-12, as well as by PD-L2 blockade. CONCLUSIONS: This study indicates that pro-Th2 features of mDCs correlate with disease activity in asthma after cessation of exposure to the causal allergen. The findings also highlight that the Th2 programming by dendritic cells is flexible and partly mediated by PD-L2.

Persistence of asthmatic response after ammonium persulfate-induced occupational asthma in mice.

INTRODUCTION: Since persulfate salts are an important cause of occupational asthma (OA), we aimed to study the persistence of respiratory symptoms after a single exposure to ammonium persulfate (AP) in AP-sensitized mice. MATERIAL AND METHODS: BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO) on days 1 and 8. On day 15, they received a single nasal instillation of AP or saline. Airway hyperresponsiveness (AHR) was assessed using methacholine provocation, while pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL), and total serum immunoglobulin E (IgE), IgG1 and IgG2a were measured in blood at 1, 4, 8, 24 hours and 4, 8, 15 days after the single exposure to the causal agent. Histological studies of lungs were assessed. RESULTS: AP-treated mice showed a sustained increase in AHR, lasting up to 4 days after the challenge. There was a significant increase in the percentage of neutrophils 8 hours after the challenge, which persisted for 24 hours in AP-treated mice. The extent of airway inflammation was also seen in the histological analysis of the lungs from challenged mice. Slight increases in total serum IgE 4 days after the challenge were found, while IgG gradually increased further 4 to 15 days after the AP challenge in AP-sensitized mice. CONCLUSIONS: In AP-sensitized mice, an Ig-independent response is induced after AP challenge. AHR appears immediately, but airway neutrophil inflammation appears later. This response decreases in time; at early stages only respiratory and inflammatory responses decrease, but later on immunological response decreases as well.

Human mesenchymal stem cells resolve airway inflammation, hyperreactivity, and histopathology in a mouse model of occupational asthma.

Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 × 10(6) cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.

Definitions and classification of work-related asthma.

The workplace can trigger or induce asthma and cause the onset of different types of work-related asthma (WRA). Based on current knowledge of clinical features, pathophysiologic mechanisms, and evidence supporting a causal relationship, the following conditions should be distinguished in the spectrum of WRA: (1) immunologic occupational asthma (OA), (2) nonimmunologic OA, (3) work-exacerbated asthma, and (4) variant syndromes, including eosinophilic bronchitis, potroom asthma, and asthmalike disorders caused by organic dusts. The rationale, issues, and controversies relating to this approach are critically reviewed to stimulate the development of a consensus on operational definitions of the various phenotypes of WRA.

Pathogenesis and disease mechanisms of occupational asthma.

Occupational asthma (OA) is one of the most common forms of work-related lung disease in all industrialized nations. The clinical management of patients with OA depends on an understanding of the multifactorial pathogenetic mechanisms that can contribute to this disease. This article discusses the various immunologic and nonimmunologic mechanisms and genetic susceptibility factors that drive the inflammatory processes of OA.

Irritant-induced airway disorders.

Thousands of persons experience accidental high-level irritant exposures each year but most recover and few die. Irritants function differently than allergens because their actions proceed nonspecifically and by nonimmunologic mechanisms. For some individuals, the consequence of a single massive exposure to an irritant, gas, vapor or fume is persistent airway hyperresponsiveness and the clinical picture of asthma, referred to as reactive airways dysfunction syndrome (RADS). Repeated irritant exposures may lead to chronic cough and continual airway hyperresponsiveness. Cases of asthma attributed to repeated irritant-exposures may be the result of genetic and/or host factors.

Recaídas por enfermedades profesionales en un registro poblacional de declaración de casos (1989-1998) / Occupational disease relapses in apopulation register (1989-1998)

Objetivos: Analizar las principales características y determinantes de las recaídas de enfermedad profesional en un registro poblacional. Material y métodos: Los datos se obtuvieron del Registro de enfermedades profesionales del Instituto Navarro de Salud Laboral en el período 1989-1998. En el análisis se han empleado pruebas estadísticas no paramétricas y regresión logística no condicional para identificar los factores de riesgo de presentación de recaídas. Resultados: En el período de estudio, un 22% de las 4.547 enfermedades profesionales declaradas fueron recaídas de un proceso previo. Asma y enfermedades cutáneas presentaron el mayor porcentaje de recaídas, si bien las enfermedades musculoesqueléticas registraron el mayor número absoluto. La mayor incidencia se ha registrado en la fabricación de vehículos de motor (siete recaídas anuales por cada mil trabajadores) y la principal entidad nosológica ha sido la fatiga de vainas tendinosas. La media de edad en las recaídas ha sido de 40,3 años. En el 75% de casos la recaída se produce en los nueve meses siguientes al proceso inicial, si bien el intervalo de tiempo entre recaídas ha sido menor en el asma profesional, inferior a dos meses en el 75% de casos (p = 0,005). Se asociaron a un mayor riesgo de recaída las edades intermedias, las empresas de más de 25 trabajadores, la fabricación de vehículos de motor, un tiempo de exposición al riesgo superior a dos años y el presentar patología cutánea o respiratoria. Conclusiones: Las recaídas de enfermedades profesionales suponen un problema emergente de salud laboral, que sugieren una insuficiente modificación de las condiciones de trabajo tras constatar el daño. Se producen principalmente en adultos jóvenes en un breve período de tiempo tras el proceso inicial, con patologías que disponen de medidas eficaces de prevención, como el diagnóstico precoz y cese de exposición al agente nocivo (AU)

Objectives: To analyze the principal characteristics and determinants of occupational disease relapses in a population register. Material and methods: The study material is the data base of the Register of Occupational Diseases of the Navarre Institute of Occupational Health in the period 1989-1998. Non parametric statistics tests and unconditional logistic regression were performed to model the relationship between socioprofessional factors and risk of occupational disease recurrence. Results: During the study period, 22% of the 4,547 cases of reported occupational diseases were relapses of previous cases. The highest percentage of relapses included asthma and skin diseases, but the musculo-skeletal diseases represented the highest overall figure. The highest incidence occurred in the manufacturing of motor vehicles (7 relapses per 1000 workers yearly) and the principal nosologic entity has been the fatigue of tendinous pods. The average age among relapse cases was 40.3 years. In 75% of cases the relapse is produced within 9 months following the initial process, even though the time interval between relapses was smaller for occupational asthma, under 2 months in 75% of cases (p = 0,005). Middle age, long exposure time, motor vehicle manufacture, greater companies as well as skin and respiratory diseases were found to increase relapse risk in the first year after initial diagnosis, after adjustment for the confounding factors. Conclusion: The professional disease relapses indicate an emerging problem of occupational health, suggesting an insufficient modification of work conditions after the verification of the damage. They are produced largely in young adults in a short period of time after the initial case, with pathologies for which effective risk prevention measures are available, including early diagnosis and early removal from exposure to offending agents (AU)