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.

Excess respiratory symptoms in full-time male and female workers in large-scale swine operations.

BACKGROUND: The respiratory health effects of working in swine operations have been previously investigated mainly in male owner/operators with intermittent exposure to indoor air contaminants. OBJECTIVES: To examine the respiratory health of male and female workers employed full time in large-scale intensive swine operations in Saskatchewan. DESIGN: A cross-sectional study of male and female swine workers employed full time and nonfarming control subjects. RESULTS: In total, 374 swine farmers (240 men and 134 women) and 411 nonfarming rural control subjects (184 men and 227 women) participated in the study. After controlling for age and smoking, male and female workers were significantly more likely to have chronic and usual cough, and chronic and usual phlegm in comparison to male and female nonfarming control subjects, respectively. The risks of these symptoms were greater in female workers (chronic cough: odds ratio [OR], 5.14; 95% confidence interval, 2.67 to 9.89; chronic phlegm: OR, 4.26; 95% confidence interval, 1.86 to 9.73) than in male workers (chronic cough: OR, 3.47; 95% confidence interval, 1.77 to 6.81; chronic phlegm: OR, 3.22; 95% confidence interval, 1.76 to 5.89). These increased risks were not observed for asthma and asthma-like symptoms in female workers. Male workers had an increased risk of shortness of breath in comparison to their nonfarming counter parts. CONCLUSIONS: Swine workers had increased risk of chronic and usual bronchitis-like symptoms. Female workers in swine operations appear to have greater risk of these symptoms. Future surveillance programs should include both male and female workers.

Lung function and farm size predict healthy worker effect in swine farmers.

BACKGROUND: Swine farmers are exposed to a number of airborne contaminants associated with respiratory ill health. OBJECTIVES: To examine the factors associated with healthy worker effect in the swine industry from a longitudinal follow-up of farmers at 4 years and 13 years. DESIGN: A prospective study of swine farmers and nonexposed rural residents was conducted using similar questionnaires and same spirometer at each time point. RESULTS: In the original observations in 1990/1991, we studied 302 swine farmers and 261 nonfarming control subjects. Four years later in 1994/1995, 217 swine farmers and 171 nonfarming control subjects of the original group participated again. In 2003/2004, 163 swine farmers and 118 control subjects were retested. Of the 163 swine farmers, 52 remained active swine farmers and 111 were no longer swine farming, thus providing the opportunity to evaluate work continuity in the industry. Among farmers studied in 2003/2004, mean values for percentage of predicted FEV(1)/FVC ratio and forced expiratory flow between 25% and 75% of FVC were lower in those who had quit swine farming compared to those still swine farming and nonfarming control subjects. The herd size in the barn at baseline in 1990/1991 and at interim follow-up in 1994/1995 was a significant predictor of quitting swine farming. In addition, percentage of predicted FEV(1)/FVC at the interim observation was a significant predictor of quitting swine farming. CONCLUSIONS: There is a significant healthy worker effect among swine farmers. The continuation of work in the facilities may be predicted by herd size and interim lung function.

Excess longitudinal decline in lung function in grain farmers.

Workers in intensive agricultural operations are exposed to dust and endotoxin that are associated with respiratory effects. The authors investigated the longitudinal changes in lung function in male grain farmers. In this study, male grain farmers (n = 263) and male nonfarming control subjects (n = 261) studies initially in 1990/91 were followed-up in 1994/95 and 2003/04. After controlling for potential confounders, grain farmers had an excess annual decline of 9.2 ml/year (95% confidence interval [CI]: 2.7, 15.8, p = .006) in forced vital capacity (FVC) in comparison to control. Long-term exposure to grain dust and other substances in lifetime grain farmers results in progressive loss in lung function.

Reciprocal association between atopy and respiratory symptoms in fully employed female, but not male, workers in swine operations.

In large commercial swine operations, workers are exposed to indoor air-contaminants during their work-shift. In recently developed large swine operations, exposures are typically 8 or 12 hours/day and females account for a sizeable proportion of the workers. Implications of enhanced exposures and gender require evaluation. Two hundred and forty male and 134 female swine barn workers and 184 male and 227 female nonfarming rural dwellers (controls) (mean age +/- SD males: 36.2 +/- 11.9; females: 34.9 +/- 10.7) completed respiratory questionnaires. Of these, 348 workers (93.0%) and 401 controls (97.6%) underwent allergy skin prick tests (house dust mite, Alternaria sp., hog, cat, mixed grass). The number of hours worked per day was 8.2 for female workers and 7.7 for male workers. Atopy was present in 38.7% and 29.4% of male and female workers, and 46.9% and 38.3% of male and female controls. There was a 72% reduction in risk for chronic phlegm and 70% reduction in usual phlegm in female workers with atopy in comparison to female controls without atopy. There was a significantly increased risk for chronic and usual phlegm, and chronic and usual cough in male workers with atopy. Female workers with atopy were at increased risk for asthma. These findings, that atopy in exposed female workers may be protective of symptoms suggestive of chronic bronchitis but that atopic female workers may be more susceptible to the development of asthma, suggest that exposures to inhaled substances in the workplace may be mediated differently in male and female workers.

Gender-related tumor necrosis factor-alpha responses in naïve volunteers with Toll-like receptor 4 polymorphisms exposed in a swine confinement facility.

The aim of this work is to better understand the responses of people that are exposed to agricultural organic dust and other factors in modern swine production. We investigated the effects of toll-like receptor 4 (TLR4) genotype and gender on respiratory responses of naïve volunteers (18-28 years) to swine barn exposure. Non-smoking healthy subjects (16 men and 13 women) with TLR4 299 (Asp299Gly) and/or 399 (Thr399Ile) polymorphisms (TLR4 299/399) and age-sex matched subjects with TLR4 wild-type alleles spent 5 h in a nonexposed environment (baseline day) and 5 h in a swine facility (exposure day). The results showed significant decreases between baseline and exposure days in across-shift forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced midexpiratory flow rate (FEF(25-75)), and FEV(1)/FVC ratio and in methacholine concentration that reduced FEV1 by 20% (PC(20)) in all groups; however, there were no differences by sex or genotype. Similarly, nasal cytokines, serum cytokines, and blood neutrophil count increased after exposure; in contrast, however, these were influenced by gender. The increase in serum tumor necrosis factor-alpha (TNF-alpha) between baseline and exposure was gender-dependent with male sex associated with a significant increase in the wild-type group and female sex associated with a significant increase in the polymorphic group. These results suggest that for persons exposed to a swine facility, one's immunological response varies with gender as well as TLR4 genotype.

Association of polymorphisms of toll-like receptor 4 with a reduced prevalence of hay fever and atopy.

BACKGROUND: The response to innate immune stimuli seems to be critical to conditioning adaptive immunity. Early exposure to endotoxin initiates immune responses that have been shown to alter the risk of asthma and allergic diseases. The toll-like receptor 4 (TLR4) gene encodes the principal innate immunity receptor in humans for bacterial endotoxin. Polymorphisms in the TLR4 gene may regulate the effects of endotoxin exposure and could play a role in the development of asthma and atopy-related phenotypes. OBJECTIVE: To investigate the association between TLR4 polymorphisms and allergic phenotypes in nonsmokers. METHODS: The data from 915 nonsmoking students were available for the study. The TLR4 299 and 399 polymorphisms were genotyped using mouthwash samples. The TLR4 299 and 399 polymorphisms were grouped together to define the TLR4 polymorphic group. Skin prick tests were conducted in a subgroup of healthy participants. A brief questionnaire was administered to determine demographic characteristics and chronic health conditions. RESULTS: The prevalence of hay fever was 0% in the TLR4 polymorphic group and 7.5% in the wild-type group (P = .01). After controlling for age group and sex using logistic regression, the odds of having hay fever were reduced by 88% (P = .009) in the TLR4 polymorphic group compared with the wild-type group. In a subgroup analysis, the association between TLR4 polymorphisms and atopy was only observed among females. CONCLUSIONS: To our knowledge, this study is the first to report an association between TLR4 polymorphisms and atopy-related phenotypes in a nonsmoking population. Further investigation of the role of TLR4 polymorphisms in asthma and atopy-related phenotypes is warranted.