Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis.
Triptolide (TPL) may mitigate radiation-induced late pulmonary side effects through its inhibition of global pro-inflammatory cytokines. In this study, we evaluated the effect of TPL in C57BL/6 mice, the animals were exposed to radiation with vehicle (15 Gy), radiation with TPL (0.25 mg/kg i.v., twice weekly for 1, 2 and 3 months), radiation and celecoxib (CLX) (30 mg/kg) and sham irradiation. Cultured supernatant of irradiated RAW 264.7 and MLE-15 cells and lung lysate in different groups were enzyme-linked immunosorbent assays at 33 h. Respiratory rate, pulmonary compliance and pulmonary density were measured at 5 months in all groups. The groups exposed to radiation with vehicle and radiation with TPL exhibited significant differences in respiratory rate and pulmonary compliance (480 ± 75/min vs. 378 ± 76/min; 0.6 ± 0.1 ml/cm H2O/p kg vs. 0.9 ± 0.2 ml/cm H2O/p kg). Seventeen cytokines were significantly reduced in the lung lysate of the radiation exposure with TPL group at 5 months compared to that of the radiation with vehicle group, including profibrotic cytokines implicated in pulmonary fibrosis, such as IL-1β, TGF- β1 and IL-13. The radiation exposure with TPL mice exhibited a 41% reduction of pulmonary density and a 25% reduction of hydroxyproline in the lung, compared to that of radiation with vehicle mice. The trichrome-stained area of fibrotic foci and pathological scaling in sections of the mice treated with radiation and TPL mice were significantly less than those of the radiation with vehicle-treated group. In addition, the radiation with TPL-treated mice exhibited a trend of improved survival rate compared to that of the radiation with vehicle-treated mice at 5 months (83% vs. 53%). Three radiation-induced profibrotic cytokines in the radiation with vehicle-treated group were significantly reduced by TPL treatment, and this partly contributed to the trend of improved survival rate and pulmonary density and function and the decreased severity of pulmonary fibrosis at 5 months. Our findings indicate that TPL could be a potential new agent to mitigate radiation-induced pulmonary fibrosis.
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Shanmin
S
Yang
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Mei
M
Zhang
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Chun
C
Chen
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Yongbin
Y
Cao
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Yeping
Y
Tian
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Yangsong
Y
Guo
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Bingrong
B
Zhang
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Xiaohui
X
Wang
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Liangjie
L
Yin
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Zhenhuan
Z
Zhang
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Walter
W
O'Dell
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Paul
P
Okunieff
Department of Radiation Oncology, UF Health Cancer Center, University of Florida, Gainesville, Florida 32610.
Lurong
L
Zhang
D000818:Animals; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects / Q000528:radiation effects; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000067996:RAW 264.7 Cells; D017564:Radiation Pneumonitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate
D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D011837:Radiation-Protective Agents; C001899:triptolide; D003094:Collagen