Immunoglobulin responses to experimental silicosis.

Silicosis is a crippling fibrotic lung disease induced by inhalation of crystalline silica. One feature of silicosis is systemic and pulmonary immune dysfunction characterized in part by elevations in serum and bronchoalveolar lavage (BAL) immunoglobulins. A major specific aim of the current report was to demonstrate that an experimental model of silicosis previously well characterized for the development of pulmonary inflammation and fibrosis would also exhibit increased levels of serum and BAL IgG and IgM similar to those of human silicosis. We also sought to document the anatomic compartments responsible for these immunoglobulin responses. To address these specific aims, we compared levels of IgG and IgM in serum and BAL from rats with experimental silicosis induced by inhalation of silica with levels of these immunoglobulins in titanium dioxide (TiO(2))- and sham (air)-exposed controls. The ability of mononuclear cell populations from lung, lung-associated lymph node, and spleen to produce IgG and IgM ex vivo were also compared. We found that experimental silicosis was associated with elevated IgG and IgM levels in blood and BAL relative to the control groups. Our findings also suggested that draining lung-associated lymph nodes (LALN) were the most important sites for increased IgG and IgM production in experimental silicosis, with lungs contributing to a lesser degree. Increased production in the LALN appeared related to marked expansion in total numbers, but not relative proportion, of B lymphocytes.

Workplace irritant exposures: do they produce true occupational asthma?

The recognition that irritant exposures can cause asthma is not new. Many investigators turn towards the gassings of soldiers in World War I as the first examples of this, while Brooks, in 1985, reported this in detail in workers and called it 'Reactive Airways Dysfunction Syndrome (RADS)'. There is considerable overlap with RADS and occupational asthma as both share respiratory symptoms which can be described as 'asthmatic', yet RADS is the result of an acute excessive exposure, while occupational asthma occurs due to a series of sensitizing exposures. Yet, a clear understanding of RADS has been limited by the lack of epidemiologic studies; rather the disease has been described by case series. This report contrasts RADS and occupational asthma and finds that although there may be some difference in lung pathology, reports for the past years since Brooks' initial reports have shown that the line separating occupational asthma and RADS has become increasingly blurred, rather than increasingly distinct, with considerable overlap in the clinical symptoms with the perspective that these described entities are a part of a continuum. Perhaps the development of animal models for RADS may hasten further understanding.

Occupational asthma: "the big picture".

With more than 200 agents inducing occupational asthma, an organized approach to identify the impact of both low- and high-molecular-weight agents is important. In this report, our goal is to explain the general categories of the sensitizing agents, present guidelines regarding what might be expected when exposures and sensitization occur, and present a number of references that can be explored to find information regarding the outcome of those with these illnesses.

Can We protect workers from developing the adverse respiratory effects of isocyanate exposure?

In this review, the authors have attempted to present the difficulty in defining a permissible exposure limit (PEL) to agents that act as sensitizers and may induce asthma-even at exposure levels less than the PEL. One approach to this relatively unaddressed problem may be to define the separate aspects of exposure to the specific sensitizing agent. The first effect is an accelerated rate of decline in lung function in nonsensitized individuals who are exposed to the agent (in this case the model used is isocyanates). The second effect is sensitization. Rules for developing a PEL might take this sensitizing effect into account, and this group of agents with such dual effects may be defined as "sensitizers." Exposure to agents with this designation would require special educational and surveillance initiatives to facilitate early detection. The elimination of sensitization may be a greater challenge. An important form of prevention is medical screening of exposed workers, yet it is unclear which screening approach best identifies workers with early isocyanate asthma.

Important issues in occupational asthma.

Although there has been a dramatic increase in awareness about the contributions of the work environment to asthma, many aspects of this illness remain to be explored in further detail. This article focuses on issues that need to be better understood. Data are reported that describe newly recognized agents in the workplace that have been shown in a sophisticated manner to induce asthma. In addition, data that further describe the mechanisms of occupational asthma and information regarding the management of occupational asthma are given. Important problems yet to be resolved include whether those who develop occupational asthma from different agents are likely to have different outcomes, whether screening is likely to have a significant effect on the outcome (and, if so, what is the best approach to screening), and identification of a clear definition of the role of immunologic-mediated parameters as they relate to the initiation of asthma attributable to low molecular weight agents and patient outcome. There is little information about "safe" levels of exposure that protect all workers. Data (such as underlying specific immunologic or genetic markers) are lacking that might aid in predicting which workers are likely to be sensitized by low molecular weight agents. This abbreviated list of unresolved issues makes the study of occupational asthma a fertile field for research.

Chest illnesses and the decline of FEV1 in steelworkers.

This study relates the impact of various medical conditions to clinically important forced expiratory volume in 1 second (FEV1) declines in a cohort of steelworkers evaluated cross-sectionally and longitudinally. Medical records of 1171 randomly chosen steelworkers were obtained from the medical department of a steel company. We reviewed the medical records for information regarding demographic parameters, smoking status, spirometry indexes, job history, and the worker's respiratory health. These workers had performed annual spirometry from 1980 to 1991 at least once and up to 12 times. We compared the prevalence of medical conditions in 203 male never-smoking steelworkers in this group of 1171 workers by separating workers into three groups on the basis of final predicted FEV1 values (< 65%, between 65% and 79%, and > or = 80%). We also evaluated the prevalence of medical conditions and the association between these conditions and the rate of annual decline in FEV1 in 475 steelworkers who had at least three valid tests and at least 5 years separating the first and last test by multiple logistic regression analysis. Of the 475 steelworkers, 121 were categorized as rapid decliners (an annual rate of decline in FEV1 exceeding the 75th percentile of the slope distribution), whereas the remaining workers served as controls. Three of 203 and 17 of the remaining 200 in the cross-sectional survey had final predicted FEV1 values < 65% or between 65% and 79%, respectively. Among these 20 never-smokers, the accelerated rate of decline could be reasonably explained by factors independent of dust and age in all but two. In the 203 never-smokers, hay fever and trauma occurred more frequently in those with a decreased predicted FEV1. In the longitudinal study of 475 workers, the prevalence of pneumonia was significantly greater in the rapid decliners, whereas the prevalence of allergy, asthma or hay fever, and trauma approached a significant excess in number. Logistic regression models demonstrated that aging, weight gain, smoking, trauma, pneumonia, and a history of allergy, asthma, or hay fever were independently related to the risk of a clinically important decline of FEV1 in this group. In summary, there are multiple risk factors for an accelerated rate of decline in workers with dust exposure. An accurate assessment of the causes for an excessive rate of lung function decline in an individual worker within a population requires an understanding of the relationship between environmental exposures, lung function decline, and the individual worker's underlying health. In addition to the three traditionally recognized variables--age, smoking, and dust exposure--the medical conditions of trauma, pneumonia, and allergy, asthma, or hay fever were related to a clinically important decline of FEV1 in this industrial population.

Assessment of the relationship between isocyanate exposure levels and occupational asthma.

As part of a previous study, we identified Ontario cases of isocyanate-induced occupational asthma (OA) and the companies at which they worked. The Ontario Ministry of Labour maintained a computerized database including isocyanate air sampling determinations conducted by the Ministry. Within this database, we compared levels of isocyanate concentrations measured at 20 case companies [with compensated isocyanate asthma (OA) claims] with 203 noncase companies, based on air samples collected during the same 4-year period during which the OA claims arose. The proportion of case companies that were ever recorded as having a measured ambient isocyanate concentration of > or = 0.005 ppm was greater than that for noncase companies, for TDI users (43% vs 22%), and for MDI users (40% vs 27%). This reached conventional significance when combined across companies and isocyanate types (50% vs 25%; P < 0.05). This provides some evidence that facilities having OA claims have higher isocyanate exposures than do those without claims.

Immunodominance of a low-affinity major histocompatibility complex-binding myelin basic protein epitope (residues 111-129) in HLA-DR4 (B1*0401) subjects is associated with a restricted T cell receptor repertoire.

The pathogenesis of multiple sclerosis (MS) is currently ascribed in part to a T cell-mediated process targeting myelin components. The T cell response to one candidate autoantigen, myelin basic protein (MBP), in the context of HLA-DR15Dw2, has been previously studied in detail. However, the characteristics of cellular immunity in the context of other MS-associated HLA-DR haplotypes are scarcely known. MBP-specific T cell lines (TCL) were generated from HLA-DR4 (B1*0401)-positive MS subjects. Out of 275 MBP-specific TCL, 178 (64. 7%) specifically recognized region MBP(111-129), predominantly in the context of DRB1*0401. The major T cell epitope for MBP recognition corresponded to residues MBP(116-123). These TCL expressed disparate profiles of cytokine secretion and cytotoxicity. T cell receptor analysis, on the other hand, revealed a strikingly limited heterogeneity of rearrangements. In contrast to MBP(81-99), which binds with high affinity to HLA-DR15 and is recognized by a diverse T cell repertoire, MBP(111-129) binds weakly to DRB1*0401, suggesting that only high affinity T cell receptors might be able to efficiently engage such unstable MHC/peptide complexes, thus accounting for the T cell receptor restriction we observed. This study provides new insight about MBP recognition and proposes an alternative mechanism for immunodominance of self-antigen T cell epitopes in humans.

Weight gain and longitudinal changes in lung function in steel workers.

Associations among dust exposure, smoking habits, and demographic factors and longitudinal changes of lung function were assessed among male steel workers. Cohort descriptive data analysis was conducted in 541 steel workers who had performed spirometry at least twice between 1982 and 1991 (mean follow-up, 6.1 years). The annual change (slope) in FVC, FEV1, FEV1/FVC%, and in body weight was determined by simple linear regression. The Pearson correlation coefficient between weight change and spirometry changes was calculated. Comparisons were also done in 75 pairs of steel workers matched by age, height, initial FEV1, and smoking status, but whose FEV1 declines differed by > or = 60 mL/yr. The FEV1 and FVC declined an average of 44 and 50 mL/yr, respectively, for the cohort as a whole. The FEV1 and FVC declined 52 and 54 mL/yr for current smokers, 43 and 53 mL/yr for ex-smokers, and 36 and 43 mL/yr for nonsmokers, respectively. Increasing weight was highly correlated with accelerated decline in lung function (p<0.0001). In the matched pairs, mean slopes for FVC, FEV1, and FEV1/FVC ratio were -96 mL/yr, -95 mL/yr, and -0.40%/yr for the rapid decliners; and +5 mL/yr, +10 mL/yr, and +0.10%/yr for their partners (p<0.0001). Matched pair comparisons showed that the rapid decliners averaged a 4.313 kg weight gain, while their partners gained 1.044 kg during the follow-up period. The slope of weight gain was 0.708 kg/yr for rapid decliners and 0.191 kg/yr for comparison workers (p<0.0036). Weight gain, in addition to aging and cigarette smoking, was found to be associated with the longitudinal rate of decline in FVC, FEV1, and FEV1/FVC ratio.

Clinical perspective of inorganic dusts, metals, and fumes exposures.

Although the clinical presentations of illnesses associated with dusts, metals, and fumes exposures remain unchanged, there is increasing insight into the mechanisms of these diseases, how these illnesses occur, and what might be necessary to alter their natural history. It is discouraging to note that despite aggressive measures designed to make workplace environments safe, workers continue to develop these preventable illnesses.

Reduction of lung dust burden in pneumoconiosis by whole-lung lavage.

Pneumoconioses are characterized as irreversible, progressive respiratory diseases. No effective therapy exists to prevent progression of these diseases. Whole-lung lavage (WLL) might limit the rate of disease progression through the removal of dust, inflammatory cells, and cytokines. We performed WLL on a 54-year-old underground miner employed as a motorman and roof bolter and a 55-year-old driller at a surface coal mine. Both demonstrated normal lung function and chest radiographs showing ILO profusion category 2 nodular interstitial changes. From Subject 1, we recovered 5.24 x 10(8) cells (90% macrophages) from the right lung and 3.45 x 10(8) cells (94% macrophages) from the left lung. WLL removed 1.82 g of mineral dust (non-coal) on the right and 1.64 g on the left. From Subject 2, we recovered 7.49 x 10(8) cells (46% macrophages) from the right and 9.78 x 10(8) cells (69% macrophages) from the left lung. WLL removed 0.40 g of mineral dust on the right and 0.53 g on the left. Proinflammatory cytokines, growth factors, and cellular enzymes were also recovered. In cases of pneumoconiosis, WLL is capable of removing relatively large quantities of dust, cells, and soluble materials from the lungs. Only long-term follow-ups of individuals with progressive dust-induced disease who receive WLL therapy in the context of a clinical trial will provide information regarding the importance of removing mineral dust and inflammatory cells from the lung.

Longitudinal and cross-sectional analyses of lung function in steelworkers.

We evaluated associations between dust exposure, demographic factors, and lung function by longitudinal and cross-sectional analyses in 475 steelworkers who participated in at least three spirometry tests over 5 yr between 1982 and 1991. Baseline and follow-up spirometry and changes between baseline and final follow-up assessment attributable to age, height, weight, weight gain, smoking status, pack-years, and years worked in dusty areas were examined using stepwise multiple linear regression techniques. Smoking, aging, being overweight, excessive weight gain, and dust exposure were related to a lower level and a steeper slope of decline of pulmonary function. Cigarette smoking was also an important risk factor. Dust exposure was related to the level of lung function, with a stronger effect at baseline than at follow-up. Estimated loss at baseline of FEV1, FVC, and FEV1/FVC% was 9.3, 6.4 ml, and 0.1 % per year of employment in a dusty area, respectively, whereas the association between dust exposure and longitudinal decline of lung function was weak. However, a strong relationship between weight gain and longitudinal decline of FEV1 and FVC was found. Estimated decreases in FEV1 and FVC attributable to weight gain were 4.7 and 6.3 ml per lb/yr, respectively. This work suggests that weight gain is an important determinant for longitudinal lung function decline. This large impact of weight gain in the decline of lung function in a middle-age and relatively overweight working population has not been previously reported. Additional work needs to be undertaken to show the strength of this relationship in other populations.

The relationship between latex skin prick test responses and clinical allergic responses.

BACKGROUND: Allergic responses to latex have been reported more frequently in the past 5 years. Although commercial skin prick test solutions are available and can be used in the diagnosis of latex allergy in some countries, the characteristics of patients sensitized to latex relative to their skin test responses have not been reported. OBJECTIVE: The purpose of this study is to relate the clinical characteristics of patients with latex sensitivity to the size of their latex skin prick test response. METHODS: A retrospective review of patients who were attending a hospital-based allergy and asthma clinic and who had positive skin test responses to a commercial latex skin test solution was undertaken. RESULTS: Of 47 patients who had skin test responses to latex, 36 had a mean wheal diameter at least 3 mm greater than the negative control (diluent). Sixty-eight percent were health care workers. There was a positive association between the size of skin test response and severity of latex-induced symptoms (p < 0.001). A history of banana sensitivity was also associated with larger skin test responses (p < 0.05). CONCLUSION: The size of the skin prick test response to latex solution that is commercially available in Canada reflects the severity of latex-induced clinical allergic responses.

Bronchoprovocation tests in the diagnosis of isocyanate-induced asthma.

Over the past 25 years, investigators have continued to improve on the approach to providing nonirritant exposures for the accurate diagnosis of isocyanate-induced asthma. Although the technology used in testing has become more sophisticated and may be fairly considered the domain of the bioengineer, the chemist, and the industrial hygienist, the requirements of the physician have remained unchanged. The physician must observe the level of exposure closely and monitor the worker's symptoms and lung function. Direct physician involvement in the testing procedure remains critical to the worker's safety and for the accurate diagnosis of isocyanate-induced asthma.

Improvement in lung function measurements using a flow spirometer that emphasizes computer assessment of test quality.

We compared retrospective measurements of lung function from 101 steel workers using a commercially available spirometer to prospective lung function measurements performed, on average, 1.3 years later, with a newly developed spirometer. This spirometer was designed and developed to incorporate technology that provides immediate feedback on the quantitative and qualitative aspects of each forced expiratory effort. Of the 101 workers, 82 who had spirometry performed with each spirometer had at least two acceptable curves, and 51 workers tested with each spirometer had curves that met all American Thoracic Society (ATS) criteria for spirometry. No group showed the anticipated decline in forced expiratory volume in 1 second (FEV1) over time. The results showed an increased number of curves meeting ATS acceptability and reproducibility criteria, and a statistically significant increase in the FVC in all groups, and an increase in the FEV1 in the group encompassing all workers. Use of technology that strengthens the interaction between the spirometry technician, the data available to the technician on the computer, and the participant appears to represent true underlying lung function more accurately. Such an approach to the collection of lung function data should be considered by those evaluating spirometers for implementation in the workplace or pulmonary function laboratory as well as by those planning future spirometer development.

Pulmonary response to hyperoxia: effects of magnesium.

Animals and humans rapidly develop respiratory failure and die within a few days when exposed to 100% oxygen. Postmortem examination of the lungs shows histopathologic features characteristic of diffuse alveolar damage, clinically recognized as adult respiratory distress syndrome (ARDS). At the present time, there is no effective therapy available to alter outcomes in ARDS. Importantly, hypomagnesemia also is frequently observed in critically ill patients at risk of developing ARDS. In a model of hyperoxic lung injury, rats were exposed to 100% oxygen for 48, 64, and 96 hr and several experiments were performed. First, changes in the features of bronchoalveolar lavage and in alveolar macrophage function were compared in rats exposed to room air and those exposed to hyperoxia. Second, we studied the effect of hypomagnesemia on the severity of hyperoxic lung injury. Third, we evaluated the pulmonary responses to high-dose and normal-dose Mg therapy in rats exposed to hyperoxia. In all groups, hyperoxia induced significant changes in the total and differential cell counts with increased lipid peroxidation of lavaged cells, enhanced chemiluminescence from alveolar macrophages, and protein leakage into the alveolar spaces. After 48 hr of hyperoxia, oxygen-free radical formation and hydrogen peroxide production by the alveolar macrophage were diminished compared to baseline, implying a toxic effect of hyperoxia on the alveolar macrophages. Overall, hypomagnesemia tended to magnify the degree of hyperoxic lung injury, while high-dose Mg therapy tended to attenuate the effects of hyperoxia. In conclusion, in this animal model of diffuse alveolar damage, alterations in host serum magnesium levels may modulate the degree of lung damage.