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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Respiratory Research 1/2018

Radiation-induced pulmonary gene expression changes are attenuated by the CTGF antibody Pamrevlumab

Zeitschrift:
Respiratory Research > Ausgabe 1/2018
Autoren:
Mark D. Sternlicht, Ute Wirkner, Sebastian Bickelhaupt, Ramon Lopez Perez, Alexandra Tietz, Kenneth E. Lipson, Todd W. Seeley, Peter E. Huber
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12931-018-0720-4) contains supplementary material, which is available to authorized users.

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
Zusatzmaterial
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
Literatur
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