Polyhexamethylene Biguanide-Induced Pulmonary Fibrotic Inflammation Can be Controlled By the Modulaiton of ER Stress Linked to TGF-Beta Production

Accumulating evidence has demonstreated that endoplasmic reticulum (ER) stress is a critical role in the pathogenesis of various pulmonary disorders. Inhaled polyhexamethylene biguanide (PHMG) has been recently reported to cause interstitial lung inflammation with fibrosis. This study aimed to define the mechanisms implicated in the development of lung inflammation and fibrosis by inhaled PHMG, specifically focusing on the role of ER stress. The PHMG-inhaled mice showed the similar pathologic features of pulmonary fibrosis with acute inflammation; increased the expression of ER stress markers and the protein levels of unfolded-protein response (UPR)-related markers in lung tissues, increased numbers of airway inflammatory cells, increased collagen accumulation, smooth muscle hyperplasia, and increased levels of pro-inflammatory cytokines, TGF-β1 expression, and nuclear translocation of NF-κB. The administration of 4-phenylbutyric acid (4-PBA) significantrly reduced the levels of expression of ER stress markers and UPR proteins, attenuates the pathologic changes, and decreased the numbers of airway inflammatory cells, pro-inflammatory cytokines, collagen accumulation, the smooth muscle actin expression, and TGF-β1 expression. These results indicate that ER stress and UPR plays a critical role in the pathogenesis of PHMG-inhaled lung inflammation and fibrosis via the modulation of TGF- β1 production linked to pro-inflamamtory and pro-fibrotic responses.