title: GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis.
abstract: Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been associated with fibrotic lung disease, although exactly how they modulate this process remains unclear. Here we investigated the role of GRP78, the main UPR regulator, in an experimental model of lung injury and fibrosis. Grp78(+/-) , Chop(-/-) and wild type C57BL6/J mice were exposed to bleomycin by oropharyngeal intubation and lungs were examined at days 7 and 21. We demonstrate here that Grp78(+/-) mice were strongly protected from bleomycin-induced fibrosis, as shown by immunohistochemical analysis, collagen content and lung function measurements. In the inflammatory phase of this model, a reduced number of lung macrophages associated with an increased number of TUNEL-positive cells were observed in Grp78(+/-) mice. Dual immunohistochemical and in situ hybridization experiments showed that the macrophage population from the protected Grp78(+/-) mice was also strongly positive for cleaved caspase-3 and Chop mRNA, respectively. In contrast, the administration of bleomycin to Chop(-/-) mice resulted in increased quasi-static elastance and extracellular matrix deposition associated with an increased number of parenchymal arginase-1-positive macrophages that were negative for cleaved caspase-3. The data presented indicate that the UPR is activated in fibrotic lung tissue and strongly localized to macrophages. GRP78- and CHOP-mediated macrophage apoptosis was found to protect against bleomycin-induced fibrosis. Overall, we demonstrate here that the fibrotic response to bleomycin is dependent on GRP78-mediated events and provides evidence that macrophage polarization and apoptosis may play a role in this process. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
authors.forename: Ehab A
authors.initials: EA
authors.lastname: Ayaub
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Kolb
authors.affiliation: Department of Medicine, Hamilton Centre for Kidney Research, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Zahraa
authors.initials: Z
authors.lastname: Mohammed-Ali
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Tat
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Pierre-Simon
authors.initials: PS
authors.lastname: Bellaye
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Chiko
authors.initials: C
authors.lastname: Shimbori
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Boivin
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
authors.forename: Rocky
authors.initials: R
authors.lastname: Lai
authors.affiliation: Department of Medicine, Hamilton Centre for Kidney Research, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Edward G
authors.identifier: 0000-0002-8011-5558
authors.initials: EG
authors.lastname: Lynn
authors.affiliation: Department of Medicine, Hamilton Centre for Kidney Research, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Lhoták
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
authors.forename: Darren
authors.initials: D
authors.lastname: Bridgewater
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
authors.forename: Martin Rj
authors.initials: MR
authors.lastname: Kolb
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Inman
authors.affiliation: Department of Medicine, Hamilton Centre for Kidney Research, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Dickhout
authors.affiliation: Department of Medicine, Hamilton Centre for Kidney Research, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.affiliation: Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and the Research Institute of St. Joe's Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster Immunology Research Center, McMaster University, Hamilton, ON, Canada.
authors.forename: Kjetil
authors.identifier: 0000-0002-0202-735X
authors.initials: K
authors.lastname: Ask
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001761:Bleomycin; D053148:Caspase 3 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D001761:Bleomycin; D051742:Transcription Factor CHOP; D053148:Caspase 3
keywords: ER stress; GRP78; alternatively activated macrophages; lung fibrosis; unfolded protein response