The role of GRP78 and CHOP in the development of bleomycin-induced pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is an irreversible progressive fibrotic disorder. The activation of the unfolded protein response (UPR) has been found to be critical in the differentiation of different cell types from quiescent states to more active forms [...]
Idiopathic pulmonary fibrosis (IPF) is an irreversible progressive fibrotic disorder. The activation of the unfolded protein response (UPR) has been found to be critical in the differentiation of different cell types from quiescent states to more active forms. UPR may also initiate apoptotic cell death by upregulating the C/EBP homologous protein (CHOP). Both endoplasmic reticulum stress, along with the unfolded protein response (UPR), have been associated with fibrotic lung disease, however the mechanism remains unknown. A recent study published by PhD student Ehab Ayaub in Dr. Kjetil Aski’s lab demonstrated that fibrotic response to bleomycin is dependent on events mediated by GRP78, the main UPR regulator. Furthermore, they suggested that macrophage polarization and apoptosis may play a role. The study used an experimental mouse model of lung injury and fibrosis to study the role of GRP78. GRP78 +/- mice were protected from bleomycin-induced fibrosis, with reduced number of lung macrophages. Conversely, Chop -/- mice showed opposite outcomes. In addition, GRP78- and CHOP-mediated macrophage apoptosis was protective against bleomycin-induced fibrosis, demonstrating that macrophages play an important role in fibrosis. This study provides better understanding of the mechanism involved in the development of bleomycin-mediated fibrosis, and the findings have implications in the development of novel therapies. Read More.
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