The online version of this article (https://doi.org/10.1186/s12931-018-0720-4) contains supplementary material, which is available to authorized users.
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.
Additional file 1: Table S1. Array Files used to Assemble a Human Cell-Type Expression Atlas and Normailzed CTGF Expression. (XLSX 20 kb)12931_2018_720_MOESM1_ESM.xlsx
Additional file 2: Table S2. Cell-Type Distinguishing Gene Lists. (XLSX 59 kb)12931_2018_720_MOESM2_ESM.xlsx
Additional file 3: Table S3. Radiation and FG-3019 Responsive Genes (n = 2754). (XLSX 674 kb)12931_2018_720_MOESM3_ESM.xlsx
Additional file 4: Table S4. GO categories associated with the RT-elevated gene set. (XLSX 24 kb)12931_2018_720_MOESM4_ESM.xlsx
Additional file 5; Table S5. GO categories associated with the RT-diminished gene set. (XLSX 12 kb)12931_2018_720_MOESM5_ESM.xlsx
Additional file 6: Table S6. Broad Gene Sets Associated with Radiation and FG-3019 Responsive Genes. (XLSX 18 kb)12931_2018_720_MOESM6_ESM.xlsx
Additional file 7: Table S7. Enrichment of RT and FG-3019 Responsive Genes and Cell-Type Distinguishing Genes in Other Public Lung RT Gene Sets. (XLSX 19 kb)12931_2018_720_MOESM7_ESM.xlsx
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. CrossRef
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. CrossRefPubMedPubMedCentral
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.
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. CrossRef
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. PubMed
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. CrossRefPubMedPubMedCentral
Pathway Studio. http://www.pathwaystudio.com/. Accesssed 18 Aug 2017.
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. PubMed
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. PubMed
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. PubMed
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. CrossRefPubMedPubMedCentral
- Radiation-induced pulmonary gene expression changes are attenuated by the CTGF antibody Pamrevlumab
Mark D. Sternlicht
Ramon Lopez Perez
Kenneth E. Lipson
Todd W. Seeley
Peter E. Huber
- BioMed Central
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