PPAR activation following apoptotic cell instillation promotes resolution of lung inflammation and fibrosis
Young-So Yoon, Si-Yoon Kim, Myeong-Joo Kim, and Jihee Lee
Department of Physiology, Tissue Injury Defense Research Center, Global Top 5 Research Program, School of Medicine, Ewha Womans University, Seoul 158-710, Korea
Changes in macrophage phenotype have been implicated in apoptotic cell-mediated immune modulation via induction of peroxisome proliferator-activated receptorgamma (PPAR). In this study, we characterized PPAR induction by apoptotic cell instillation over the course of bleomycin-induced lung injury in C57BL/6 mice. Next, the role of PPAR activation in resolvinglung inflammation and fibrosis was investigated. Our data demonstrate that apoptotic cell instillation after bleomycin results in immediate and prolonged enhancement of PPAR mRNA and protein in alveolar macrophages and lung. Moreover, PPAR activity and expression of its target molecules, including CD36, macrophage mannose receptor, and arginase 1, were persistently enhanced following apoptotic cell instillation. Co-administration of the PPARantagonist, GW9662,reversed the enhanced efferocytosis, and the reduced pro-inflammatory cytokine expression, neutrophil recruitment, myeloperoxidase activity, apoptotic activity, fibrogenic markers and hydroxyproline contents in the lung by apoptotic cell instillation. In addition, inhibition of PPAR activity reversed the expressionof transforming growth factor beta, interleukin-10, and hepatocyte growth factor. These findings indicate that one-timeapoptotic cell instillationcontributes to anti-inflammatory and anti-fibrotic responses via upregulation of PPARexpression and subsequent activation, leading to regulation of efferocytosis and production of pro-resolving cytokines.
References
[1]Lee, Y.J.et al. Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction. Eur. Respir. J.40, 424-435(2012).
[2]Kiss, R.S. et al. Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes. Curr. Biol.16, 2252-2258 (2006).
[3]Standiford, T.J., Keshamouni, V.G. & Reddy, R.C.Peroxisome proliferator-activated receptor-{gamma} as a regulator of lung inflammation and repair.Proc. Am. Thorac. Soc.2, 226-231 (2005).
Keywords
PPAR, apoptotic cell instillation, pulmonary fibrosis, efferocytosis, pro-resolving cytokines
BPA-induced cell death via superoxide anion production and a deficit in β-catenin signaling in hBMSCs
Yea-Hyun Leem, Ji-Yeon Yu, Seong-Eun Jo, Kyunghwa Yun, Seikwan Oh
Department of molecular Medicine and TIDRC, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
Bisphenol A (BPA), used in the manufacture of products based on polycarbonate plastics and epoxy resins, is well known as an endocrine-disrupting monomer. In the current study, BPA increased cytotoxicity in hBMSCs in a dose- and time-dependent manner, concomitantly with increased lipid peroxidation. Increased cell death in BPA-treated cells was markedly blocked by pretreatment with the superoxide dismutase (SOD) mimetic MnTBAP, but not by catalase, glutathione, the glutathione peroxidase mimetic ebselen, or the NOS inhibitor NAME. In addition, the reduction in BPA toxicity induced by MnTBAP was blocked by treatment with the Mn-SOD inhibitor 2-methoxyestradiol (2-ME) and/or the Cu/Zn-SOD inhibitor diethyldithiocarbamate. Increased BPA toxicity was significantly blocked by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenyleneiodonium. Furthermore, the decline in nuclear β-catenin and cyclin D1 levels in hBMSCs exposed to BPA was reversed by MnTBAP treatment. Finally, treatment of hBMSCs with the GSK3βinhibitor LiCl2 increased nuclear β-catenin levels and significantly attenuated cytotoxicity compared with BPA treatment. Our current results in hBMSCs exposed to BPA suggest that BPA causes a disturbance in β-catenin signaling via a superoxide anion overload derived from NADPH oxidase and mitochondria.
References
[1] Kabuto, H., Hasuike, S., Minagawa, N., Shishibori, T., 2003. Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ. Res. 93, 31-35.
[2] Lin, C.L., Wang, J.Y., Ko, J.Y., Surendran, K., Huang, Y.T., Kuo, Y.H., Wang, F.S. 2008. Superoxude destabilization of β-catenin augments apoptosis of high-glucose-stressed mesangial cells. Endocrinology 146, 2934-2942.
[3] Schug, T., Janesick, A., Blumberg, B., Heindela, J.J., 2011. Endocrine disrupting chemicals and disease susceptibility. J. Steroid Biochem. Mol. Biol. 127, 204-215.
Keywords
Bisphenol A; superoxide dismutase; human bone mesenchymal stem cells; NADPH oxidase