Interaction between mitochondrial ROS and ER stress on PHMG-induced pulmonary fibrosis

Abstract

Subcellular organelles including mitochondria are now considered as one major target for many therapeutic approaches. Each subcellular organelle seems to have uncanonical actions implicated in various inflammatory/immune responses as well as classic functions to maintain the cell fate physiologically. Among them, mitochondrial metabolic dysfunction such as reactive oxygen species (ROS) over production leads to damage to lung and consequently various disease states. In addition, accumulating evidence has demonstrated that endoplasmic reticulum (ER) stress is a critical role in the pathogenesis of various pulmonary disorders. In this study, we used polyhexamethylene biguanide (PHMG)-inhaled mice which show the similar pathologic features of pulmonary fibrosis with acute inflammation; increased the generation of moitochondrial ROS in lung tissues and inflammatory cells, increased numbers of airway inflammatory cells, increased ER stress markers, 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 NecroX-5 and -7 significantrly reduced the levels of mitochondrial ROS and the expression of ER stress markers, attenuates the pathologic changes, and decreased the increased levels NF-κB activity, the numbers of airway inflammatory cells, pro-inflammatory cytokines, collagen accumulation, the smooth muscle actin expression, and TGF-β1 expression. These results indicate that mitochondrial ROS play a critical role in the pathogenesis of PHMG-inhaled lung fibrotic inflammation via the modulation of ER stress as well as NF-κB pathway.