Mechanisms of occupational asthma.

Inhalation of agents in the workplace can induce asthma in a relatively small proportion of exposed workers. Like nonoccupational asthma, occupational asthma is probably the result of multiple genetic, environmental, and behavioral influences. It is important that occupational asthma be recognized clinically because it has serious medical and socioeconomic consequences. Environmental factors that can affect the initiation of occupational asthma include the intrinsic characteristics of causative agents as well as the influence of the level and route of exposure at the workplace. The identification of host factors, polymorphisms, and candidate genes associated with occupational asthma may improve our understanding of mechanisms involved in asthma. High-molecular-weight compounds from biological sources and low-molecular-weight chemicals cause occupational asthma after a latent period of exposure. Although the clinical, functional, and pathologic features of occupational asthma caused by low-molecular-weight agents resemble those of allergic asthma, the failure to detect specific IgE antibodies against most low-molecular-weight agents has resulted in a search for alternative or complementary physiopathologic mechanisms leading to airway sensitization. Recent advances have been made in the characterization of the immune response to low-molecular-weight agents. In contrast, the mechanism of the type of occupational asthma that occurs without latency after high-level exposure to irritants remains undetermined.

Decreased heme-oxygenase (HO)-1 in the macrophages of non-small cell lung cancer.

Reactive oxygen species (ROS) are important in the initiation and promotion of cells to neoplastic growth. Heme-oxygenase (HO)-1, the inducible form of heme-oxygenase, is a cytoprotective enzyme that plays a central role in the defence against oxidative stress and is implicated in the protection of lung tissue against exogenous oxidant exposure. We investigated whether the expression of HO-1 would be decreased in lung tumour as compared with tumour-free adjacent lung tissues. HO-1 expression was quantified by immunohistochemistry in tumour macrophages, in macrophages of tumour-free lung and in tumour cells of surgical specimens collected from 53 individuals with surgically resectable non-small cell lung cancer (NSCLC). The expression of HO-1 was decreased in tumour as compared with tumour-free lung macrophages. No correlations were observed between the expression of HO-1 and both the clinicopathological characteristics and the overall survival of the examined subjects. In conclusion, our data show that macrophages of non-small cell lung cancer exhibit impaired anti-oxidant defence mechanisms, likely mediated by HO-1. Conversely, HO-1 expression does not seem to be associated with lung tumour progression and prognosis.

Occupational asthma.

Occupational asthma (OA) is one of the most common forms of occupational lung disease in many industrialized countries, having been implicated in 9 to 15% of adult-onset asthma. Work-related asthma includes: 1. immunologic OA, characterized by a latency period before the onset of symptoms; 2. nonimmunologic OA, which occurs after single or multiple exposures to high concentrations of irritants; 3. work-aggravated asthma, which is pre-existing or concurrent asthma exacerbated by workplace exposures; and 4. variant syndromes. OA is important to recognize clinically, because it has serious medical and socioeconomic consequences. Diagnosis of OA should be confirmed by objective testing early after its onset. Removal of the worker from exposure to the causal agent and early treatment with anti-inflammatory drugs lead to a better outcome. Assessment of the work environment and identification of host factors may provide us with useful information about the mechanisms involved in OA. Another issue concerns strategies for preventing OA which should be implemented.

Genetics and the occupational environment.

PURPOSE OF REVIEW: This article will focus on the role of risk factors including genetic factors in the development of sensitization and occupational asthma. RECENT FINDINGS: We will review the recent literature published on the genetics of occupational asthma, especially on genes coding for class II human leukocyte antigen and on respiratory antioxidant mechanisms. We will also discuss published work on non-occupational asthma and on allergic rhinitis because this information may contribute to a better understanding of the mechanisms involved in occupational asthma and serve to confirm data obtained on the disease. To date, although some progress has been made in the field of occupational asthma genetics, most studies were based on small sample sizes, findings were not replicated, and gene-environment interactions have not yet been established. SUMMARY: Occupational asthma is a widespread and frequent condition and has relevant long-term adverse health and economic consequences. The search for risk factors including genetic factors in the development of the disease and an understanding of the mechanisms of interaction between genes and environment are important because the identification of individuals who are susceptible to occupational asthma together with an effective control of exposure to respiratory sensitizers in the workplace may be helpful in preventing the disease.

Asthma induced by isocyanates: a model of IgE-independent asthma.

Developments in the understanding of causes and natural history of asthma induced by isocyanates may allow improved preventive strategies for occupational asthma (OA), and may also lead to improved understanding of mechanisms involved in IgE-independent nonoccupational asthma. Studies of genetic markers in OA induced by isocyanates suggest that HLA class II genes, glutathione S-transferase and NAT1 genotypes may predispose to development of this type of OA. Specific IgE antibodies against isocyanates are not always found in subjects with OA caused by isocyanates, leading most researchers to consider this type of OA, as a model of IgE-independent asthma. Evidence for cell-mediated immunity in OA induced by isocyanates has been provided by bronchoalveolar lavage, bronchial biopsy and induced sputum studies. The pathology of this type of asthma is similar to that of nonoccupational asthma, with cells such as eosinophils and T lymphocytes that exhibit signs of activation, and with thickening of the reticular layer of the basement membrane. Animal studies have shown that isocyanate asthma is driven primarily by CD4+ T cells and is dependent upon the expression of Th2 cytokines. However, animal models are not always reflective of human responses. OA induced by isocyanates similarly to nonoccupational asthma, is a multifactorial condition, and it is likely that complex gene-environment interactions play a role. Better understanding of these interactions is important for affected workers, and also has potential relevance for nonoccupational asthma.

Chronic obstructive pulmonary disease (COPD) and occupational exposures.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in both industrialized and developing countries. Cigarette smoking is the major risk factor for COPD. However, relevant information from the literature published within the last years, either on general population samples or on workplaces, indicate that about 15% of all cases of COPD is work-related. Specific settings and agents are quoted which have been indicated or confirmed as linked to COPD. Coal miners, hard-rock miners, tunnel workers, concrete-manufacturing workers, nonmining industrial workers have been shown to be at highest risk for developing COPD. Further evidence that occupational agents are capable of inducing COPD comes from experimental studies, particularly in animal models. In conclusion, occupational exposure to dusts, chemicals, gases should be considered an established, or supported by good evidence, risk factor for developing COPD. The implications of this substantial occupational contribution to COPD must be considered in research planning, in public policy decision-making, and in clinical practice.

Occupational asthma.

Substantial epidemiologic and clinical evidence indicates that agents inhaled at work can induce asthma. In industrialized countries, occupational factors have been implicated in 9 to 15% of all cases of adult asthma. Work-related asthma includes (1) immunologic occupational asthma (OA), characterized by a latency period before the onset of symptoms; (2) nonimmunologic OA, which occurs after single or multiple exposures to high concentrations of irritant materials; (3) work-aggravated asthma, which is preexisting or concurrent asthma exacerbated by workplace exposures; and (4) variant syndromes. Assessment of the work environment has improved, making it possible to measure concentrations of several high- and low-molecular-weight agents in the workplace. The identification of host factors, polymorphisms, and candidate genes associated with OA is in progress and may improve our understanding of mechanisms involved in OA. A reliable diagnosis of OA should be confirmed by objective testing early after its onset. Removal of the worker from exposure to the causal agent and treatment with inhaled glucocorticoids lead to a better outcome. Finally, strategies for preventing OA should be implemented and their cost-effectiveness examined.

Sputum substance P and neurokinin A are reduced during exacerbations of chronic obstructive pulmonary disease.

Involvement of tachykinins in airway inflammation has been demonstrated in animal models, but evidence in humans is sparse. The aim of this study was to quantify the levels of substance P and neurokinin A in induced sputum of patients with chronic obstructive pulmonary disease (COPD) and to compare them with the levels in smokers with normal lung function and healthy nonsmokers. Content of tackykinins was measured in 12 sputum samples collected during stable condition and nine sputum samples collected during exacerbations from 13 COPD patients, in eight sputum samples from smokers with normal lung function and in nine from healthy nonsmokers. Patients with COPD exacerbations had a lower sputum content of substance P compared with the other 3 groups (p<0.05). No differences were found between patients with stable COPD, smokers with normal lung function, and nonsmokers. Sputum levels of neurokinin A were trending in the same direction of substance P, but the significant difference was reached for the paired sputum samples collected from the same COPD patients (n=8) during exacerbation and in stable condition. COPD exacerbations are associated with a reduced sputum content of substance P and neurokinin A. These tackykinins might be involved in COPD exacerbations.

Defective production of soluble HLA-G molecules by peripheral blood monocytes in patients with asthma.

BACKGROUND: HLA-G, a human nonclassic MHC class I molecule, is responsible for complex immunoinhibitory functions. HLA-G is expressed as membrane-bound and is secreted as soluble molecules by the peripheral blood CD14+ monocytes activated by IL-10. OBJECTIVE: It has been reported that LPS stimulation induces IL-10 production by PBMCs and that IL-10 levels are reduced in patients with severe asthma compared with patients with mild asthma and healthy subjects. The study was designed to investigate whether this impaired IL-10 production can affect the expression and the secretion of soluble HLA-G (sHLA-G)-1/HLA-G5 molecules. METHODS: We investigated the production of sHLA-G1/HLA-G5 and IL-10 by specific ELISAs in the culture supernatants of LPS-activated PBMCs from 24 healthy subjects and 20 patients with moderate to severe persistent asthma. RESULTS: LPS stimulation induced the secretion of IL-10 and sHLA-G1/HLA-G5 molecules in all healthy subjects, whereas in patients with asthma, the levels of IL-10 were significantly lower (P < .001) and the number of cultures exhibiting detectable sHLA-G1/HLA-G5 was reduced (7/20; P < .001). The addition of exogenous IL-10 to LPS-stimulated PBMCs from patients with asthma restored normal sHLA-G1/HLA-G5 production. CONCLUSION: Our data suggest that a specific deficit of IL-10 secretion in patients with asthma could prevent the normal production of sHLA-G1/HLA-G5 molecules. The reduction of immunosuppressive activity mediated by HLA-G could in turn contribute to the persistence of chronic airway inflammation in asthma.

Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates.

BACKGROUND: Polymorphism at the pi class glutathione-S-transferase locus (GSTP1) is associated with allergen-induced asthma and related phenotypes. OBJECTIVE: We sought to determine whether GSTP1 polymorphism influences susceptibility to asthma induced by toluene diisocyanate (TDI). METHODS: The role of GSTP1 was assessed in 131 workers exposed to TDI, 92 with TDI-induced asthma and 39 asymptomatic subjects. The phenotype of the disease was characterized by using detailed clinical history, lung volumes, airway responsiveness to methacholine, and airway responsiveness to TDI. GST genotypes were determined by using PCR-based assays. RESULTS: In patients exposed to TDI for 10 or more years, the frequency of the GSTP1 Val/Val genotype was lower in subjects who had asthma (odds ratio, 0.23; 95% confidence interval, 0.05-1.13; P =.074). Similarly, the frequency of this genotype was significantly lower in subjects with evidence of moderate-to-severe airway hyperresponsiveness to methacholine compared with the frequency in subjects with normal or mild hyperresponsiveness (P =.033). CONCLUSION: These data suggest that homozygosity for the GSTP1*Val allele confers protection against TDI-induced asthma and airway hyperresponsiveness. This view is supported by the finding that the protective effect increases in proportion to the duration of exposure to TDI.