Role of clusterin/progranulin in toluene diisocyanate-inducedoccupational asthma

Abstract

Toluene diisocyanate (TDI) exposure induces oxidative stress andepithelial cell-derived inflammation, which affect the pathogenesis of TDI-inducedoccupational asthma (TDI-OA). Recent studies suggested a role for clusterin (CLU)and progranulin (PGRN) in oxidative stress-mediated airway inflammation. To evaluateCLU and PGRN involvement in airway inflammation in TDI-OA, we measured their serumlevels in patients with TDI-OA, asymptomatic exposed controls (AECs), and unexposedhealthy normal controls (NCs). Serum CLU and PGRN levels were significantly lower inthe TDI-OA group than in the AEC and NC groups (P < 0.05). The sensitivity and specificity for predicting the TDI-OAphenotype were 72.4% and 53.4% when either CLU or PGRN levels were below the cutoffvalues (≤125 μg/mL and ≤68.4 ng/mL, respectively). If both parameters were below thecutoff levels, the sensitivity and specificity were 58.6% and 89.8%, respectively.To investigate CLU and PGRN function, we evaluated their production by human airwayepithelial cells (HAECs) in response to TDI exposure and co-culturing withneutrophils. TDI-human serum albumin stimulation induced significant CLU/PGRNrelease from HAECs in a dose-dependent manner, which positively correlated with IL-8and folliculin levels. Co-culturing with neutrophils significantly decreasedCLU/PGRN production by HAECs. Intracellular ROS production in epithelial cellsco-cultured with neutrophils tended to increase initially, but the ROS productiondecreased gradually at a higher ratio of neutrophils. Our results suggest that CLUand PGRN may be involved in TDI-OA pathogenesis by protecting against TDI-inducedoxidative stress-mediated inflammation. The combined CLU/PGRN serum level may beused as a potential serological marker for identifying patients with TDI-OA amongTDI-exposed workers.