title: PPARγ activation following apoptotic cell instillation promotes resolution of lung inflammation and fibrosis via regulation of efferocytosis and proresolving cytokines.
abstract: Changes in macrophage phenotype have been implicated in apoptotic cell-mediated immune modulation via induction of peroxisome proliferator-activated receptor-γ (PPARγ). In this study, we characterized PPARγ induction by apoptotic cell instillation over the course of bleomycin-induced lung injury in C57BL/6 mice. Next, the role of PPARγ activation in resolving lung inflammation and fibrosis was investigated. Our data demonstrate that apoptotic cell instillation after bleomycin results in immediate and prolonged enhancement of PPARγ mRNA and protein in alveolar macrophages and lung. Moreover, PPARγ activity and expression of its target molecules, including CD36, macrophage mannose receptor, and arginase 1, were persistently enhanced following apoptotic cell instillation. Coadministration of the PPARγ antagonist, GW9662, reversed the enhanced efferocytosis, and the reduced proinflammatory cytokine expression, neutrophil recruitment, myeloperoxidase activity, hydroxyproline contents, and fibrosis markers, including type 1 collagen α2, fibronectin and α-smooth muscle actin (α-SMA), in the lung by apoptotic cell instillation. In addition, inhibition of PPARγ activity reversed the expression of transforming growth factor-β (TGF-β), interleukin (IL)-10, and hepatocyte growth factor (HGF). These findings indicate that one-time apoptotic cell instillation contributes to anti-inflammatory and antifibrotic responses via upregulation of PPARγ expression and subsequent activation, leading to regulation of efferocytosis and production of proresolving cytokines.
authors.affiliation: 1] Department of Physiology, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea [2] Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Yoon
authors.affiliation: 1] Department of Physiology, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea [2] Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: 1] Department of Physiology, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea [2] Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Lim
authors.affiliation: Department of Pathology, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea.
authors.forename: M-S
authors.initials: MS
authors.lastname: Cho
authors.affiliation: 1] Department of Physiology, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea [2] Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea [3] Global Top 5 Research Program, School of Medicine, Ewha Womans University, Yangcheon-ku, Seoul, Korea.
authors.forename: J L
authors.initials: JL
authors.lastname: Kang
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000276:immunology*; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D047495:PPAR gamma; D001761:Bleomycin