Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model.
Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF.



C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or a control diet 2 days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy of thoracic irradiation. Fibrosis was assessed with Masson trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real-time polymerase chain reaction. Senescence was assessed by staining for β-galactosidase activity.



Administration of rapamycin extended the median survival of irradiated mice compared with the control diet from 116 days to 156 days (P=.006, log-rank test). Treatment with rapamycin reduced hydroxyproline content compared with the control diet (irradiation plus vehicle, 45.9 ± 11.8 μg per lung; irradiation plus rapamycin, 21.4 ± 6.0 μg per lung; P=.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated interleukin 1β and transforming growth factor β induction in irradiated lungs compared with the control diet. Type II pneumocyte senescence after irradiation was reduced with rapamycin treatment at 16 weeks (3-fold reduction at 16 weeks, P<.001).



Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production, and senescence in type II pneumocytes.
Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Eun Joo
EJ
Chung
Radiation Biology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Anastasia
A
Sowers
Radiation Biology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Angela
A
Thetford
Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Grace
G
McKay-Corkum
Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Su I
SI
Chung
Radiation Biology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
James B
JB
Mitchell
Radiation Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: citrind@mail.nih.gov.
Deborah E
DE
Citrin
D056809:Alveolar Epithelial Cells / Q000187:drug effects; D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006909:Hydroxyproline / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017564:Radiation Pneumonitis / Q000188:drug therapy* / Q000401:mortality; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D053583:Interleukin-1beta; D011837:Radiation-Protective Agents; D016212:Transforming Growth Factor beta; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001616:beta-Galactosidase; D006909:Hydroxyproline; D020123:Sirolimus
Nat Rev Drug Discov. 2006 Aug;5(8):671-88
16883305
Annu Rev Pathol. 2010;5:99-118
20078217
J Clin Invest. 2013 Aug;123(8):3272-91
23863708
J Biol Chem. 2009 Mar 20;284(12):8023-32
19150980
Cancer Res. 2013 Jul 15;73(14):4267-77
23722550
Drug Des Devel Ther. 2013 Mar 19;7:149-59
23662044
Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):829-37
18411002
Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):862-71
15936571
Respir Res. 2006 Oct 11;7:125
17034639
Prostate. 2014 Jun;74(8):852-68
24715588
Nature. 2010 Dec 23;468(7327):1100-4
21179166
Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17414-9
18955708
Clin Cancer Res. 2008 Mar 15;14(6):1868-76
18347190
Cell Cycle. 2012 Jun 15;11(12):2391-401
22627671
Cell Cycle. 2009 Jun 15;8(12):1888-95
19471117
Clin Cancer Res. 2014 Jan 1;20(1):110-9
24198241
Radiat Res. 2006 Feb;165(2):181-91
16435917
Nat Cell Biol. 2015 Aug;17(8):1049-61
26147250
Nat Rev Drug Discov. 2011 Oct 31;10(11):868-80
22037041
Nature. 2013 Jan 17;493(7432):338-45
23325216
J Natl Cancer Inst. 2013 Oct 2;105(19):1474-84
24052614
Transplant Rev (Orlando). 2014 Jul;28(3):126-33
24685370
Cell. 2002 Jul 26;110(2):177-89
12150926
Cell Signal. 2009 Mar;21(3):378-83
18992324
PLoS One. 2013 Jun 17;8(6):e65257
23799002
Cell Cycle. 2012 Jun 15;11(12):2402-7
22672902
Am J Respir Crit Care Med. 2010 Feb 1;181(3):254-63
19850947
J Radiat Res. 2011;52(3):270-7
21628844
Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):1033-42
10863076
Transplantation. 2014 Jan 15;97(1):20-9
24092377
Nat Commun. 2015 May 22;6:7212
25998442
Nature. 2009 Jul 16;460(7253):392-5
19587680
PLoS One. 2014 Aug 27;9(8):e106155
25162417
PLoS One. 2013 Oct 24;8(10):e78589
24205274
Nat Rev Immunol. 2015 Oct;15(10):599-614
26403194
PLoS One. 2013 Aug 01;8(8):e70024
23936371
Aging (Albany NY). 2012 Mar;4(3):159-65
22394614
Cell. 2012 Apr 13;149(2):274-93
22500797
Respir Res. 2001;2(1):33-46
11686863
Aging (Albany NY). 2014 Mar;6(3):158-9
24670390
J Biol Chem. 2007 Jul 6;282(27):20036-44
17510057
J Radiat Res. 2015 Jul;56(4):663-8
25887043
Trends Mol Med. 2010 May;16(5):238-46
20444648
J Biol Chem. 1993 Apr 25;268(12):8466-72
8473290
N Engl J Med. 2011 Apr 28;364(17):1595-606
21410393
J Cell Biochem. 2013 Jun;114(6):1248-56
23592446
J Immunol. 2011 Nov 1;187(9):4835-43
21930960
Neuro Oncol. 2014 Jan;16(1):29-37
24311635
Cell Stem Cell. 2012 Sep 7;11(3):401-14
22958932
Nature. 2013 May 9;497(7448):217-23
23636326
Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1482-92
15817354
Biochem J. 2007 Aug 1;405(3):513-22
17461779
PLoS Biol. 2009 Feb 10;7(2):e38
19209957
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6432-7
9177235