Epithelial folliculin is involved in airway inflammation in workers exposed to toluene diisocyanate

Abstract

Toluene diisocyanate (TDI) exposure can directly activate and damage airway epithelium. Folliculin (FLCN) is a protein expressed by human airway epithelial cells (HAECs) to maintain airway epithelial integrity and survival. This study investigated the involvement of FLCN in the pathogenesis of TDI-induced occupational asthma (OA). Enzyme-linked immunosorbent assay was used to measure serum levels of FLCN in TDI-exposed subjects (93 TDI-OA patients and 119 asymptomatic exposed controls (AEC)), 200 non-occupational asthma (NOA) patients and 71 unexposed healthy normal controls (NCs). Significantly more subjects in the TDI-OA and AEC groups had high serum levels of FLCN compared to those in the NOA group (P=0.002 and P=0.001, respectively), all of which were higher than the NC group (all P<0.001). The serum level of FLCN was positively correlated with TDI exposure duration (r=0.251, P=0.027), but was negatively correlated with asthma duration of TDI-OA patients (r=−0.329, P=0.029). TDI-exposed subjects with high FLCN levels had higher serum levels of total IgE than those with lower levels. The effects of TDI exposure on FLCN production was investigated by treating HAECs (A549 cells) with TDI-human serum albumin conjugate, which showed increased expression and release of FLCN and interleukin-8 from HAECs. Co-culture with peripheral blood neutrophils also induced FLCN expression and release from HAECs. In conclusion, TDI exposure and TDI-induced neutrophil recruitment into the airways can activate and stimulate HAECs to produce FLCN, which could be involved in airway inflammation in workers exposed to TDI.

Epithelial folliculin enhances airway inflammation in aspirin‐exacerbated respiratory disease

“…however, there is only 1 report showing the association of FLCN in TDI-induced occupational asthma. 18 In the present study, the asthmatic patients with highFLCN were associated with airway hyperresponsiveness to MCh. However, among the patients with AERD, highFLCN was not directly associated with the features of AERD such as severe asthma, airway hyperresponsiveness and CRS/NPs, indicating that serum FLCN may not be directly associated with key clinical features, but contribute to aggravating the severity of airway inflammation in AERD, as AERD subjects with highFLCN had a higher serum TGF-β1 level.…”

“…Previous work has generally focused on the role of FLCN in the Birt‐Hogg‐Dubé syndrome and pneumothorax in adults,; however, there is only 1 report showing the association of FLCN in TDI‐induced occupational asthma . In the present study, the asthmatic patients with highFLCN were associated with airway hyperresponsiveness to MCh.…”

“…In patients with asthma and AERD, the role of FLCN is not clearly understood. In subjects who were exposed to toluene‐diisocyanate (TDI), higher serum FLCN levels were noted in association with epithelial cell activation . Hence, this study was aimed to investigate the role of FLCN in airway epithelial cells in AERD.…”

Pathology of Birt–Hogg–Dubé syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review

“…A study by Pham et al . demonstrated that inflammatory conditions such as asthma and chemical exposure induced FLCN production in human airway epithelial cells . They suggested that FLCN may have a protective function in pneumocytes, and that dysregulated FLCN may affect cellular homeostasis, contributing to lung disease.…”

Serum potential biomarkers according to sputum inflammatory cell profiles in adult asthmatics

“…Additionally, folliculin is a protein derived from airway epithelial cells. Its production is increased by epithelial cell activation in asthmatic patients [9].…”