Radiation-induced pulmonary gene expression changes are attenuated by the CTGF antibody Pamrevlumab
Tóm tắt
Fibrosis is a delayed side effect of radiation therapy (RT). Connective tissue growth factor (CTGF) promotes the development of fibrosis in multiple settings, including pulmonary radiation injury. To better understand the cellular interactions involved in RT-induced lung injury and the role of CTGF in these responses, microarray expression profiling was performed on lungs of irradiated and non-irradiated mice, including mice treated with the anti-CTGF antibody pamrevlumab (FG-3019). Between group comparisons (Welch’s t-tests) and principal components analyses were performed in Genespring. At the mRNA level, the ability of pamrevlumab to prolong survival and ameliorate RT-induced radiologic, histologic and functional lung deficits was correlated with the reversal of a clear enrichment in mast cell, macrophage, dendritic cell and mesenchymal gene signatures. Cytokine, growth factor and matrix remodeling genes that are likely to contribute to RT pneumonitis and fibrosis were elevated by RT and attenuated by pamrevlumab, and likely contribute to the cross-talk between enriched cell-types in injured lung. CTGF inhibition had a normalizing effect on select cell-types, including immune cells not typically regarded as being regulated by CTGF. These results suggest that interactions between RT-recruited cell-types are critical to maintaining the injured state; that CTGF plays a key role in this process; and that pamrevlumab can ameliorate RT-induced lung injury in mice and may provide therapeutic benefit in other immune and fibrotic disorders.
Tài liệu tham khảo
Williams JP, Johnston CJ, Finkelstein JN. Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr Drug Targets. 2010;11:1386–94.
Gan L, Xue JX, Li X, Liu DS, Ge Y, Ni PY, Deng L, Lu Y, Jiang W. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation. Biochem Biophys Res Commun. 2011;409:7–13.
Bickelhaupt S, Erbel C, Timke C, Wirkner U, Dadrich M, Flechsig P, Tietz A, Pfohler J, Gross W, Peschke P, et al. Effects of CTGF blockade on attenuation and reversal of radiation-induced pulmonary fibrosis. J Natl Cancer Inst. 2017;109:djw339.
Wang Q, Usinger W, Nichols B, Gray J, Xu L, Seeley TW, Brenner M, Guo G, Zhang W, Oliver N, et al. Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease. Fibrogenesis Tissue Repair. 2011;4:4.
Ponticos M, Holmes AM, Shi-wen X, Leoni P, Khan K, Rajkumar VS, Hoyles RK, Bou GG, Black CM, Denton CP, et al. Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. Arthritis Rheum. 2009;60:2142–55.
Alapati D, Rong M, Chen S, Hehre D, Rodriguez MM, Lipson KE, Wu S. Connective tissue growth factor antibody therapy attenuates hyperoxia-induced lung injury in neonatal rats. Am J Respir Cell Mol Biol. 2011;45:1169–77.
Kalash R, Berhane H, Au J, Rhieu BH, Epperly MW, Goff J, Dixon T, Wang H, Zhang X, Franicola D, et al. Differences in irradiated lung gene transcription between fibrosis-prone C57BL/6NHsd and fibrosis-resistant C3H/HeNHsd mice. In Vivo. 2014;28:147–71.
Baran CP, Opalek JM, McMaken S, Newland CA, O'brien JM Jr, Hunter MG, Bringardner BD, Monick MM, Brigstock DR, Stromberg PC, et al. Important roles for macrophage colony-stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176:78–89.
Howell DC, Johns RH, Lasky JA, Shan B, Scotton CJ, Laurent GJ, Chambers RC. Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. Am J Pathol. 2005;166:1353–65.
Lasky JA, Ortiz LA, Tonthat B, Hoyle GW, Corti M, Athas G, Lungarella G, Brody A, Friedman M. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis. Am J Phys. 1998;275:L365–71.
Bonniaud P, Martin G, Margetts PJ, Ask K, Robertson J, Gauldie J, Kolb M. Connective tissue growth factor is crucial to inducing a profibrotic environment in “fibrosis-resistant” BALB/c mouse lungs. Am J Respir Cell Mol Biol. 2004;31:510–6.
Sonnylal S, Shi-wen X, Leoni P, Naff K, Van Pelt C, Nakamura H, Leask A, Abraham D, Bou GG, de Crombrugghe B. Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis Rheum. 2010;62:1523–32.
Xu S-W, Pennington D, Holmes A, Leask A, Bradham D, Beauchamp JR, Fonseca C, du Bois RM, Martin GR, Black CM, Abraham DJ. Autocrine overexpression of CTGF maintains fibrosis: RDA analysis of fibrosis genes in systemic sclerosis. Exp Cell Res. 2000;259:213–24.
Pan LH, Yamauchi K, Uzuki M, Nakanishi T, Takigawa M, Inoue H, Sawai T. Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF. Eur Respir J. 2001;17:1220–7.
Golec M, Lambers C, Hofbauer E, Geleff S, Bankier A, Czerny M, Ziesche R. Assessment of gene transcription demonstrates connection with the clinical course of idiopathic interstitial pneumonia. Respiration. 2008;76:261–9.
Kono M, Nakamura Y, Suda T, Kato M, Kaida Y, Hashimoto D, Inui N, Hamada E, Miyazaki O, Kurashita S, et al. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin Chim Acta. 2011;412:2211–5.
Allen JT, Knight RA, Bloor CA, Spiteri MA. Enhanced insulin-like growth factor binding protein-related protein 2 (connective tissue growth factor) expression in patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Cell Mol Biol. 1999;21:693–700.
Sato S, Nagaoka T, Hasegawa M, Tamatani T, Nakanishi T, Takigawa M, Takehara K. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol. 2000;27:149–54.
Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.
Pathway Studio. http://www.pathwaystudio.com/. Accesssed 18 Aug 2017.
Lian X, Yan C, Qin Y, Knox L, Li T, Du H. Neutral lipids and peroxisome proliferator-activated receptor-{gamma} control pulmonary gene expression and inflammation-triggered pathogenesis in lysosomal acid lipase knockout mice. Am J Pathol. 2005;167:813–21.
Al-Shaibi N, Ghosh SK. A novel cell-surface protein CSP82 on bone marrow stem cells and a cytosolic phosphoprotein DP58 (ankyrinRD 34B) are involved in promyeloid progenitor induction. Cell Immunol. 2009;258:172–80.
Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.
Usher MG, Duan SZ, Ivaschenko CY, Frieler RA, Berger S, Schutz G, Lumeng CN, Mortensen RM. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J Clin Invest. 2010;120:3350–64.
Juremalm M, Hjertson M, Olsson N, Harvima I, Nilsson K, Nilsson G. The chemokine receptor CXCR4 is expressed within the mast cell lineage and its ligand stromal cell-derived factor-1a acts as a mast cell chemotaxin. Eur J Immunol. 2000;30:3614–22.
Stellos K, Seizer P, Bigalke B, Daub K, Geisler T, Gawaz M. Platelet aggregates-induced human CD34+ progenitor cell proliferation and differentiation to macrophages and foam cells is mediated by stromal cell derived factor 1 in vitro. Semin Thromb Hemost. 2010;36:139–45.
Marchal-Somme J, Uzunhan Y, Marchand-Adam S, Kambouchner M, Valeyre D, Crestani B, Soler P. Dendritic cells accumulate in human fibrotic interstitial lung disease. Am J Respir Crit Care Med. 2007;176:1007–14.
Xu J, Mora A, Shim H, Stecenko A, Brigham KL, Rojas M. Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol. 2007;37:291–9.
Smith DR, Kunkel SL, Standiford TJ, Rolfe MW, Lynch JP III, Arenberg DA, Wilke CA, Burdick MD, Martinez FJ, Hampton JN. Increased interleukin-1 receptor antagonist in idiopathic pulmonary fibrosis. A compartmental analysis. Am J Respir Crit Care Med. 1995;151:1965–73.
Ando M, Miyazaki E, Fukami T, Kumamoto T, Tsuda T. Interleukin-4-producing cells in idiopathic pulmonary fibrosis: an immunohistochemical study. Respirology. 1999;4:383–91.
Wynes MW, Frankel SK, Riches DW. IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. J Leukoc Biol. 2004;76:1019–27.
Ding NH, Li JJ, Sun LQ. Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets. 2013;14:1347–56.
Lipson KE, Wong C, Teng Y, Spong S. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair. 2012;5:S24.
Paun A, Lemay AM, Haston CK. Gene expression profiling distinguishes radiation-induced fibrosing alveolitis from alveolitis in mice. Radiat Res. 2010;173:512–21.
Mathew B, Jacobson JR, Berdyshev E, Huang Y, Sun X, Zhao Y, Gerhold LM, Siegler J, Evenoski C, Wang T, et al. Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs. FASEB J. 2011;25:3388–400.
Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science. 2017;356:1026–30.
Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017;356:1072–6.
Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest. 2004;114:438–46.
Xue J, Li X, Lu Y, Gan L, Zhou L, Wang Y, Lan J, Liu S, Sun L, Jia L, et al. Gene-modified mesenchymal stem cells protect against radiation-induced lung injury. Mol Ther. 2013;21:456–65.
Szabo S, Ghosh SN, Fish BL, Bodiga S, Tomic R, Kumar G, Morrow NV, Moulder JE, Jacobs ER, Medhora M. Cellular inflammatory infiltrate in pneumonitis induced by a single moderate dose of thoracic x radiation in rats. Radiat Res. 2010;173:545–56.
Thomas DM, Fox J, Haston CK. Imatinib therapy reduces radiation-induced pulmonary mast cell influx and delays lung disease in the mouse. Int J Radiat Biol. 2010;86:436–44.
Adawi A, Zhang Y, Baggs R, Rubin P, Williams J, Finkelstein J, Phipps RP. Blockade of CD40-CD40 ligand interactions protects against radiation-induced pulmonary inflammation and fibrosis. Clin Immunol Immunopathol. 1998;89:222–30.
Boerma M, Wang J, Wondergem J, Joseph J, Qiu X, Kennedy RH, Hauer-Jensen M. Influence of mast cells on structural and functional manifestations of radiation-induced heart disease. Cancer Res. 2005;65:3100–7.
Zheng H, Wang J, Hauer-Jensen M. Role of mast cells in early and delayed radiation injury in rat intestine. Radiat Res. 2000;153:533–9.
Blirando K, Milliat F, Martelly I, Sabourin JC, Benderitter M, Francois A. Mast cells are an essential component of human radiation proctitis and contribute to experimental colorectal damage in mice. Am J Pathol. 2011;178:640–51.
Sugihara A, Tsujimura T, Fujita Y, Nakata Y, Terada N. Evaluation of role of mast cells in the development of liver fibrosis using mast cell-deficient rats and mice. J Hepatol. 1999;30:859–67.
Kosanovic D, Dahal BK, Wygrecka M, Reiss I, Gunther A, Ghofrani HA, Weissmann N, Grimminger F, Seeger W, Schermuly RT, Banat GA. Mast cell Chymase: an indispensable instrument in the pathological symphony of idiopathic pulmonary fibrosis? Histol Histopathol. 2013;28:691–9.
Ma B, Blackburn MR, Lee CG, Homer RJ, Liu W, Flavell RA, Boyden L, Lifton RP, Sun CX, Young HW, Elias JA. Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis. J Clin Invest. 2006;116:1274–83.
Huaux F, Liu T, McGarry B, Ullenbruch M, Phan SH. Dual roles of IL-4 in lung injury and fibrosis. J Immunol. 2003;170:2083–92.
Trautmann A, Krohne G, Brocker EB, Klein CE. Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. J Immunol. 1998;160:5053–7.
Atamas SP, Luzina IG, Dai H, Wilt SG, White B. Synergy between CD40 ligation and IL-4 on fibroblast proliferation involves IL-4 receptor signaling. J Immunol. 2002;168:1139–45.
Cook PC, Jones LH, Jenkins SJ, Wynn TA, Allen JE, MacDonald AS. Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo. Proc Natl Acad Sci U S A. 2012;109:9977–82.
Toru H, Eguchi M, Matsumoto R, Yanagida M, Yata J, Nakahata T. Interleukin-4 promotes the development of tryptase and chymase double-positive human mast cells accompanied by cell maturation. Blood. 1998;91:187–95.
Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30:245–57.
Yang X, Walton W, Cook DN, Hua X, Tilley S, Haskell CA, Horuk R, Blackstock AW, Kirby SL. The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2011;45:127–35.
Liu T, Jin H, Ullenbruch M, Hu B, Hashimoto N, Moore B, McKenzie A, Lukacs NW, Phan SH. Regulation of found in inflammatory zone 1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J Immunol. 2004;173:3425–31.
Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol. 2010;108:111–65.
Moore BB, Murray L, Das A, Wilke CA, Herrygers AB, Toews GB. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol. 2006;35:175–81.
Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, Pilarsky C, Jodrell DI, Spong SM, Tuveson DA. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci U S A. 2013;110:12325–30.
Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006;3:350–6.
Dendooven A, van Oostrom O, van der Giezen DM, Leeuwis JW, Snijckers C, Joles JA, Robertson EJ, Verhaar MC, Nguyen TQ, Goldschmeding R. Loss of endogenous bone morphogenetic protein-6 aggravates renal fibrosis. Am J Pathol. 2011;178:1069–79.