PURPOSE: Exposure to high levels of endotoxin is a major occupational hazard for agricultural workers, which may in part induce lung inflammation and airflow obstruction consistent with chronic obstructive pulmonary disease (COPD). Cellular responses to endotoxin depend on the transmembrane complex, toll-like receptor-4 (TLR4)/MD-2, which results in intracellular signaling and the production of inflammatory mediators such as tumor necrosis factor alpha (TNF-α). Among veterans with agricultural work exposure, we hypothesized that subjects with impaired lung function have increased responsiveness to endotoxin and increased inflammatory mediators.
METHODS: Twenty-eight veterans with agricultural work exposure were recruited from a Veterans Administration Medical Center. Cases were patients with COPD as determined by spirometry and the GOLD criteria. Controls were patients without COPD or asthma. Blood samples were obtained and in vitro dose response curves with endotoxin (0, 0.01, 0.1, 1 and 10 ng\ml) were performed using whole blood. TNF-α was measured by ELISA.
RESULTS: There was an inverse correlation between maximum production of TNF-α in whole blood and FEV1 (% predicted, r= -0.450, p=0.016) and FEF 25-75 (% predicted, r=-0.470, p=0.012). In concordance subjects with COPD had higher levels of TNF-α production compared to controls (GeoMean 1649.68 pg/mL versus 1175.71 pg/mL, respectively, p=0.082), although this association was of borderline statistical significance.
CONCLUSION: Among veterans with agricultural work exposure, individuals with lower lung function produced higher levels of TNF-α in response to endotoxin stimulation in a whole blood assay.
CLINICAL IMPLICATIONS: Increased endotoxin responsiveness in a whole blood assay, as measured by TNF-α production, may be an important phenotype of agriculturally exposed individuals with impaired lung function or COPD.
DISCLOSURE: Pradeep Ramachandran, No Financial Disclosure Information; No Product/Research Disclosure Information