RESUMO
Radiation therapy is the mainstay in the treatment of lung cancer, and lung fibrosis is a radiotherapy-related major side effect that can seriously reduce patient's quality of life. Nevertheless, effective strategies for protecting against radiation therapy-induced fibrosis have not been developed. Hence, we investigated the radioprotective effects and the underlying mechanism of the standardized herbal extract PM014 on radiation-induced lung fibrosis. Ablative radiation dose of 75 Gy was focally delivered to the left lung of mice. We evaluated the effects of PM014 on radiation-induced lung fibrosis in vivo and in an in vitro model. Lung volume and functional changes were evaluated using the micro-CT and flexiVent system. Fibrosis-related molecules were evaluated by immunohistochemistry, western blot, and real-time PCR. A orthotopic lung tumour mouse model was established using LLC1 cells. Irradiated mice treated with PM014 showed a significant improvement in collagen deposition, normal lung volume, and functional lung parameters, and these therapeutic effects were better than those of amifostine. PM104 attenuated radiation-induced increases in NF-κB activity and inhibited radiation-induced p65 translocation, ROS production, DNA damage, and epithelial-mesenchymal transition. PM104 effectively alleviated fibrosis in an irradiated orthotopic mouse lung tumour model while not attenuating the efficacy of the radiation therapy by reduction of the tumour. Standardized herbal extract PM014 may be a potential therapeutic agent that is able to increase the efficacy of radiotherapy by alleviating radiation-induced lung fibrosis.
Assuntos
NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Qualidade de Vida , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/metabolismo , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/metabolismoRESUMO
Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Captopril/uso terapêutico , Colágeno/biossíntese , Enalapril/uso terapêutico , Fosinopril/uso terapêutico , Regulação da Expressão Gênica/efeitos da radiação , Fibrose Pulmonar/prevenção & controle , Pneumonite por Radiação/tratamento farmacológico , Tórax/efeitos da radiação , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/farmacologia , Relação Dose-Resposta à Radiação , Avaliação Pré-Clínica de Medicamentos , Enalapril/farmacologia , Feminino , Fibrose , Fosinopril/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Pneumonite por Radiação/complicações , Pneumonite por Radiação/metabolismo , Pneumonite por Radiação/patologia , Ratos , Sistema Renina-Angiotensina/fisiologiaRESUMO
Radiation pneumonitis (RP) is a serious complication of radiation therapy for thoracic tumors. Lysophosphatidic acid (LPA) and its receptors LPAâ were reported to participate in the processes of inflammation. We tested the hypothesis that LPA and its receptors LPAâ , take part in the pathogenesis of RP. In our study, irradiation increased LPA levels in the lung and expression of LPAâ . To further determine the role of LPAâ , we performed pharmacological knockout of LPAâ by a specific antagonist, VPC-12249. On day 60 post-irradiation, RP was significantly alleviated in a dose-dependent manner in mice treated with VPC-12249, as shown by H&E staining, malondialdehyde (MDA, an indicator of oxidative damage) assay in lung, and concentrations of proinflammatory and profibrotic cytokines in plasma, including IL-1ß, TNF-α, and TGF-ß1. Additionally, VPC-12249 administration decreased the phosphorylation of IκB-α (the initial event that activates the NF-κB signal way), and expression of TGF-ß1, CTGF, and α-SMA mRNA. Our findings suggest that LPA and LPAâ may play a pivotal role in RP, and LPA-LPAâ may serve as novel therapeutic targets for the treatment of RP.