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Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

The Preventive Effect of Endostar on Radiation-induced Pulmonary Fibrosis

Author(s): Hangjie Ying, Cheng Zhou, Qingqing Hang and Min Fang*

Volume 24, Issue 5, 2024

Published on: 08 May, 2023

Page: [610 - 619] Pages: 10

DOI: 10.2174/1566524023666230406134640

Price: $65

Abstract

Background: Radiation-induced pulmonary fibrosis (RIPF) is a long-term complication of thoracic radiotherapy without effective treatment available.

Objective: This study aimed to establish a RIPF mouse model and explore the therapeutic effects and mechanisms of recombinant human endostatin (Endostar).

Methods: C57BL/6 mice received a 16-Gy dose of X-rays to the whole thorax with or without the administration of Endostar for 24 weeks.

Results: Radiation-induced body weight loss was partially attenuated by Endostar (P<0.05). Endostar significantly reduced alveolar inflammation (P<0.05) and pulmonary fibrosis (P<0.001), as indicated by a decrease in the expression levels of collagen I and collagen IV in lung tissue (both P<0.001). Angiogenesis (as shown by CD31 immunohistochemistry) was also decreased (P<0.01). In irradiated mice, Endostar inhibited the transforming growth factor-β1 (TGF-β1)/drosophila mothers against the decapentaplegic 3 (Smad3)/extracellular regulated protein kinases (ERK) signaling pathway (all P<0.05). In vitro, Endostar treatment decreased the radiation-induced expression of TGF-β1, vascular endothelial growth factor (VEGF), p-Smad3, and p-ERK in alveolar epithelial cells and vascular endothelial cells (all P<0.05).

Conclusion: Endostar could alleviate RIPF through decreased antiangiogenic activity and inhibition of the TGF-β1/Smad3/ERK pathway.

[1]
Finazzi T, Schneiders FL, Senan S. Developments in radiation techniques for thoracic malignancies. Eur Respir Rev 2021; 30(160): 200224.
[http://dx.doi.org/10.1183/16000617.0224-2020] [PMID: 33952599]
[2]
Han S, Gu F, Lin G, et al. Analysis of clinical and dosimetric factors influencing radiation-induced lung injury in patients with lung cancer. J Cancer 2015; 6(11): 1172-8.
[http://dx.doi.org/10.7150/jca.12314] [PMID: 26516366]
[3]
Rajan Radha R, Chandrasekharan G. Pulmonary injury associated with radiation therapy-Assessment, complications and therapeutic targets. Biomed Pharmacother 2017; 89: 1092-104.
[http://dx.doi.org/10.1016/j.biopha.2017.02.106] [PMID: 28298070]
[4]
Arroyo-Hernández M, Maldonado F, Lozano-Ruiz F, Muñoz-Montaño W, Nuñez-Baez M, Arrieta O. Radiation-induced lung injury: Current evidence. BMC Pulm Med 2021; 21(1): 9.
[http://dx.doi.org/10.1186/s12890-020-01376-4] [PMID: 33407290]
[5]
Giridhar P, Mallick S, Rath GK, Julka PK. Radiation induced lung injury: Prediction, assessment and management. Asian Pac J Cancer Prev 2015; 16(7): 2613-7.
[http://dx.doi.org/10.7314/APJCP.2015.16.7.2613] [PMID: 25854336]
[6]
O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88(2): 277-85.
[http://dx.doi.org/10.1016/S0092-8674(00)81848-6] [PMID: 9008168]
[7]
Folkman J. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 2006; 312(5): 594-607.
[http://dx.doi.org/10.1016/j.yexcr.2005.11.015] [PMID: 16376330]
[8]
Herbst RS, Hess KR, Tran HT, et al. Phase I study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2002; 20(18): 3792-803.
[http://dx.doi.org/10.1200/JCO.2002.11.061] [PMID: 12228199]
[9]
Thomas JP, Arzoomanian RZ, Alberti D, et al. Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 2003; 21(2): 223-31.
[http://dx.doi.org/10.1200/JCO.2003.12.120] [PMID: 12525513]
[10]
Song H, Liu X, Zhang H, et al. Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys1. Acta Pharmacol Sin 2005; 26(1): 124-8.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00009.x] [PMID: 15659125]
[11]
Jia H, Kling J. China offers alternative gateway for experimental drugs. Nat Biotechnol 2006; 24(2): 117-8.
[http://dx.doi.org/10.1038/nbt0206-117] [PMID: 16465139]
[12]
Rh-endostatin (YH-16) in combination with vinorelbine and cisplatin for advanced non-small cell lung cancer: A multicenter phase II trial. Chin New Drug J 2005; 14: 204-7.
[13]
Shi H, Xu L, Liu Z. Phase II clinical trial of homemade human rh-endostatin in the treatment of patients with stage IIIB-IV non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 2004; 7(4): 325-8.
[PMID: 21241552]
[14]
Phase III. Clinical trial of recombinant human endostatin in the treatment for advanced non-small cell lung cancer patients. Chin Cancer 2005; 14: 398-400.
[15]
Ling Y, Yang Y, Lu N, et al. Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells. Biochem Biophys Res Commun 2007; 361(1): 79-84.
[http://dx.doi.org/10.1016/j.bbrc.2007.06.155] [PMID: 17644065]
[16]
Kropski JA, Richmond BW, Gaskill CF, Foronjy RF, Majka SM. Deregulated angiogenesis in chronic lung diseases: A possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series). Pulm Circ 2018; 8(1): 1-18.
[http://dx.doi.org/10.1177/2045893217739807] [PMID: 29040010]
[17]
Hanumegowda C, Farkas L, Kolb M. Angiogenesis in pulmonary fibrosis: Too much or not enough? Chest 2012; 142(1): 200-7.
[http://dx.doi.org/10.1378/chest.11-1962] [PMID: 22796840]
[18]
Ackermann M, Kim YO, Wagner WL, et al. Effects of nintedanib on the microvascular architecture in a lung fibrosis model. Angiogenesis 2017; 20(3): 359-72.
[http://dx.doi.org/10.1007/s10456-017-9543-z] [PMID: 28283856]
[19]
Li X, Yao QY, Liu HC, et al. Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease. J Cell Mol Med 2017; 21(10): 2370-85.
[http://dx.doi.org/10.1111/jcmm.13158] [PMID: 28378526]
[20]
Li Z, Yan H, Yuan J, et al. Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model. Clin Exp Nephrol 2018; 22(2): 257-65.
[http://dx.doi.org/10.1007/s10157-017-1440-7] [PMID: 28710535]
[21]
Wan YY, Tian GY, Guo HS, et al. Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats. Respir Res 2013; 14(1): 56.
[http://dx.doi.org/10.1186/1465-9921-14-56] [PMID: 23688086]
[22]
Yamaguchi Y, Takihara T, Chambers RA, Veraldi KL, Larregina AT, Feghali-Bostwick CA. A peptide derived from endostatin ameliorates organ fibrosis. Sci Transl Med 2012; 4(136): 136ra71.
[http://dx.doi.org/10.1126/scitranslmed.3003421] [PMID: 22649092]
[23]
Richter AG, McKeown S, Rathinam S, et al. Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis. Thorax 2009; 64(2): 156-61.
[http://dx.doi.org/10.1136/thx.2008.102814] [PMID: 18852160]
[24]
He N, Bai S, Huang Y, et al. Evaluation of glutathione S-Transferase inhibition effects on idiopathic pulmonary fibrosis therapy with a near-infrared fluorescent probe in cell and mice models. Anal Chem 2019; 91(8): 5424-32.
[http://dx.doi.org/10.1021/acs.analchem.9b00713] [PMID: 30869868]
[25]
Zhang K, Yang S, Zhu Y, Mo A, Zhang D, Liu L. Protection against acute radiation-induced lung injury: A novel role for the anti-angiogenic agent Endostar. Mol Med Rep 2012; 6(2): 309-15.
[http://dx.doi.org/10.3892/mmr.2012.903] [PMID: 22562140]
[26]
Li R, Chen G, Zhou L, et al. The fatty acid amide hydrolase inhibitor URB937 ameliorates radiation-induced lung injury in a mouse model. Inflammation 2017; 40(4): 1254-63.
[http://dx.doi.org/10.1007/s10753-017-0568-7] [PMID: 28478515]
[27]
Zheng YF, Ge W, Xu HL, et al. Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model. Oncol Lett 2015; 10(5): 3067-72.
[http://dx.doi.org/10.3892/ol.2015.3679] [PMID: 26722291]
[28]
Chen J, Liu DG, Yang G, et al. Endostar, a novel human recombinant endostatin, attenuates liver fibrosis in CCl 4 -induced mice. Exp Biol Med 2014; 239(8): 998-1006.
[http://dx.doi.org/10.1177/1535370214532595] [PMID: 24872431]
[29]
Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 1988; 41(4): 467-70.
[http://dx.doi.org/10.1136/jcp.41.4.467] [PMID: 3366935]
[30]
Travis EL, Tucker SL. The relationship between functional assays of radiation response in the lung and target cell depletion. Br J Cancer Suppl 1986; 7: 304-19.
[PMID: 3087402]
[31]
Siemann DW, Hill RP, Penney DP. Early and late pulmonary toxicity in mice evaluated 180 and 420 days following localized lung irradiation. Radiat Res 1982; 89(2): 396-407.
[http://dx.doi.org/10.2307/3575784] [PMID: 7063621]
[32]
Li X, Xu G, Qiao T, et al. Effects of CpG Oligodeoxynucleotide 1826 on transforming growth factor beta 1 and radiation-induced pulmonary fibrosis in mice. J Inflamm 2016; 13(1): 16.
[http://dx.doi.org/10.1186/s12950-016-0125-4] [PMID: 27190497]
[33]
Zhang C, Zhao H, Li BL, et al. CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis. Toxicol Lett 2018; 292: 181-9.
[http://dx.doi.org/10.1016/j.toxlet.2018.04.009] [PMID: 29679710]
[34]
Bickelhaupt S, Erbel C, Timke C, et al. Effects of CTGF blockade on attenuation and reversal of radiation-induced pulmonary fibrosis. J Natl Cancer Inst 2017; 109(8)
[http://dx.doi.org/10.1093/jnci/djw339] [PMID: 28376190]
[35]
A phase I clinical trial for recombinant human endostatin. Chin New Drug J 2014; 13: 548-53.
[36]
Ren H, Hu H, Li Y, Jiang H, Hu X, Han C. Endostatin inhibits hypertrophic scarring in a rabbit ear model. J Zhejiang Univ Sci B 2013; 14(3): 224-30.
[http://dx.doi.org/10.1631/jzus.B1200077] [PMID: 23463765]
[37]
Nishimoto T, Mlakar L, Takihara T, Feghali-Bostwick C. An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model. Int Immunopharmacol 2015; 28(2): 1102-5.
[http://dx.doi.org/10.1016/j.intimp.2015.07.039] [PMID: 26315492]
[38]
Turner-Warwick M. Precapillary systemic-pulmonary anastomoses. Thorax 1963; 18(3): 225-37.
[http://dx.doi.org/10.1136/thx.18.3.225] [PMID: 14064617]
[39]
Selman M, Montaño M, Ramos C, Chapela R. Concentration, biosynthesis and degradation of collagen in idiopathic pulmonary fibrosis. Thorax 1986; 41(5): 355-9.
[http://dx.doi.org/10.1136/thx.41.5.355] [PMID: 3750241]
[40]
Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: A tail of a frog that became a prince. Nat Rev Mol Cell Biol 2002; 3(3): 207-14.
[http://dx.doi.org/10.1038/nrm763] [PMID: 11994741]
[41]
Ribatti D. The crucial role of vascular permeability factor/vascular endothelial growth factor in angiogenesis: A historical review. Br J Haematol 2005; 128(3): 303-9.
[http://dx.doi.org/10.1111/j.1365-2141.2004.05291.x] [PMID: 15667531]
[42]
Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018; 59(2): 455-67.
[PMID: 30173249]
[43]
Farkas L, Farkas D, Ask K, et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest 2009; 119(5): 1298-311.
[http://dx.doi.org/10.1172/JCI36136] [PMID: 19381013]
[44]
Abraham DJ, Eckes B, Rajkumar V, Krieg T. New developments in fibroblast and myofibroblast biology: Implications for fibrosis and scleroderma. Curr Rheumatol Rep 2007; 9(2): 136-43.
[http://dx.doi.org/10.1007/s11926-007-0008-z] [PMID: 17502044]
[45]
Yarnold J, Vozenin Brotons M-C. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol 2010; 97(1): 149-61.
[http://dx.doi.org/10.1016/j.radonc.2010.09.002] [PMID: 20888056]
[46]
Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134(6): 1655-69.
[http://dx.doi.org/10.1053/j.gastro.2008.03.003] [PMID: 18471545]
[47]
Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: Role of NAD(P)H oxidases. Kidney Int 2011; 79(9): 944-56.
[http://dx.doi.org/10.1038/ki.2010.516] [PMID: 21307839]
[48]
Jin H, Yoo Y, Kim Y, Kim Y, Cho J, Lee YS. Radiation induced lung fibrosis: Preclinical animal models and therapeutic strategies. Cancers 2020; 12(6): 1561.
[http://dx.doi.org/10.3390/cancers12061561] [PMID: 32545674]
[49]
Savary G, Dewaeles E, Diazzi S, et al. The Long Noncoding RNA DNM3OS is a reservoir of fibromirs with major functions in lung fibroblast response to TGF-β and pulmonary fibrosis. Am J Respir Crit Care Med 2019; 200(2): 184-98.
[http://dx.doi.org/10.1164/rccm.201807-1237OC] [PMID: 30964696]
[50]
Dadrich M, Nicolay NH, Flechsig P, et al. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis. OncoImmunology 2016; 5(5): e1123366.
[http://dx.doi.org/10.1080/2162402X.2015.1123366] [PMID: 27467922]
[51]
Reisdorf P, Lawrence DA, Sivan V, Klising E, Martin MT. Alteration of transforming growth factor-beta1 response involves down-regulation of Smad3 signaling in myofibroblasts from skin fibrosis. Am J Pathol 2001; 159(1): 263-72.
[http://dx.doi.org/10.1016/S0002-9440(10)61692-6] [PMID: 11438473]
[52]
Hayashida T, Caestecker M, Schnaper HW. Cross talk between ERK MAP kinase and Smad signaling pathways enhances TGF-β dependent responses in human mesangial cells. FASEB J 2003; 17(11): 1-21.
[http://dx.doi.org/10.1096/fj.03-0037fje] [PMID: 12824291]
[53]
Flanders KC. Smad3 as a mediator of the fibrotic response. Int J Exp Pathol 2004; 85(2): 47-64.
[http://dx.doi.org/10.1111/j.0959-9673.2004.00377.x] [PMID: 15154911]
[54]
Park SH, Kim JY, Kim JM, et al. PM014 attenuates radiation induced pulmonary fibrosis via regulating NF-kB and TGF b1/NOX4 pathways. Sci Rep 2020; 10(1): 16112.
[http://dx.doi.org/10.1038/s41598-020-72629-9] [PMID: 32999298]
[55]
Ding NH, Li J, Sun LQ. Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets 2013; 14(11): 1347-56.
[http://dx.doi.org/10.2174/13894501113149990198] [PMID: 23909719]
[56]
Huang Y, Zhang W, Yu F, Gao F. The cellular and molecular mechanism of radiation-induced lung injury. Med Sci Monit 2017; 23: 3446-50.
[http://dx.doi.org/10.12659/MSM.902353] [PMID: 28710886]

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