title: Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF.
abstract: Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors.
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Young-So
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Youn-Hee
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Molecular medicine, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Park
authors.affiliation: Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D000577:Amides / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009578:Nitrobenzenes / Q000008:administration & dosage; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D020742:rhoA GTP-Binding Protein
chemical_list: D000577:Amides; D017077:Culture Media, Conditioned; D052246:Cyclooxygenase 2 Inhibitors; C553307:HGF protein, mouse; D009578:Nitrobenzenes; D011725:Pyridines; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C108830:Y 27632; D017228:Hepatocyte Growth Factor; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D015232:Dinoprostone; D015230:Prostaglandin D2