Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis

Abstract

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.

Triptolide mitigates radiation-induced pneumonitis via inhibition of alveolar macrophages and related inflammatory molecules

“…Our previous study showed that macrophage inflammatory protein-2 (MIP-2), which plays an important role in inflammatory cell migration [ 18 ], was the dominant chemokine in irradiated lung tissue [ 9 ]. As such, we examined the effect of TPL on MIP-2 production.…”

“…Although a report of pharmacokinetics of TPL in C57BL/6 mice is lack, logically the administration of TPL (0.25 mg/kg, IV) would reach a plasma concentration higher than 2 ng/ml. Furthermore, our previous in vitro dose-dependent study with 2, 5 and 10 ng/ml TPL indicated that all three doses inhibited cytokine production, with the most striking effect at 10 ng/ml [ 9 ]. To ensure an obvious effect while avoiding toxicity as well as to utilize concentrations close to those needed in vivo , we ultimately selected 5 ng/ml.…”

“…Unfortunately, there is no FDA-approved drug that can prevent or mitigate radiation-induced pulmonary toxicity; however, our research has shown that triptolide (TPL), a small molecule purified from the herb Tripterygium wilfordii Hook F (also known as Thunder God Vine), has the potential to eventually fill this gap in the armamentarium and counteract radiation-induced pulmonary toxicity through its anti-inflammatory, immunosuppressive, and antitumor effects [ 3 – 7 ]. Our previous work showed that TPL alleviates radiation-induced pulmonary injury, including pneumonitis and fibrosis, in a mouse model [ 8 , 9 ]. In the present study, we explored the underlying mechanism by which TPL mitigates the effects of radiotoxicity.…”

Development and assessment of countermeasure formulations for treatment of lung injury induced by chlorine inhalation

“…Triptolide treatment has been shown to inhibit lung inflammation and injury in multiple lung disease models, including lipopolysaccharide injury (Wei and Huang, 2014), pulmonary fibrosis induced by radiation (Yang et al, 2015) or bleomycin (Krishna et al, 2001), and allergic inflammation and airway remodeling (Chen et al, 2011; Chen et al, 2015). In the present study, three of the triptolide formulations that were tested in vivo produced significant inhibition of chlorine-induced inflammation.…”

Diterpenes and Their Derivatives as Potential Anticancer Agents

“…Moreover, the triptolide in a xenograft model of mouse pancreatic cancer showed an anticancer effect by downregulating of 11 genes, including c-myc, SRYrelated HMG-box 9 (SOX9) and ETS proto-oncogene 2 (Ets2), and an over-expression of c-myc in colon cancer cells promotes increased expression of HIF-1α and VEGF (Ding et al, 2015). Triptolide (0.25 mg/kg; i.v., 2 times/week for 1, 2 and 3 months) in C57BL/6 mice was also found to reduce a mitigated radiation-induced pulmonary fibrosis (Yang et al, 2015b). Additionally, this diterpene also exerted an anticancer effect via reverse transcriptase component of telomerase (hTERT) transcription, possibly by inhibiting transcription factor specificity protein 1 (Sp1) in primary effusion lymphoma cells (Long et al, 2016).…”