title: Accelerated development of pulmonary fibrosis via Cu,Zn-superoxide dismutase-induced alternative activation of macrophages.
abstract: Macrophages not only initiate and accentuate inflammation after tissue injury, but they are also involved in resolution and repair. This difference in macrophage activity is the result of a differentiation process to either M1 or M2 phenotypes. M1 macrophages are pro-inflammatory and have microbicidal and tumoricidal activity, whereas the M2 macrophages are involved in tumor progression and tissue remodeling and can be profibrotic in certain conditions. Because mitochondrial Cu,Zn-superoxide dismutase (Cu,Zn-SOD)-mediated H2O2 is crucial for development of pulmonary fibrosis, we hypothesized that Cu,Zn-SOD modulated the macrophage phenotype. In this study, we demonstrate that Cu,Zn-SOD polarized macrophages to an M2 phenotype, and Cu,Zn-SOD-mediated H2O2 levels modulated M2 gene expression at the transcriptional level by redox regulation of a critical cysteine in STAT6. Furthermore, overexpression of Cu,Zn-SOD in mice resulted in a profibrotic environment and accelerated the development of pulmonary fibrosis, whereas polarization of macrophages to the M1 phenotype attenuated pulmonary fibrosis. Taken together, these observations provide a novel mechanism of Cu,Zn-SOD-mediated and Th2-independent M2 polarization and provide a potential therapeutic target for attenuating the accelerated development of pulmonary fibrosis.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015151:Immunoblotting; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000145:classification / Q000201:enzymology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000145:classification / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase
keywords: Hydrogen Peroxide; Macrophage Phenotype; Mitochondria; Oxidative Stress; Pulmonary Fibrosis; STAT6; Superoxide Dismutase (SOD)