PM014 attenuates radiation-induced pulmonary fibrosis via regulating NF-kB and TGF-b1/NOX4 pathways

Abstract

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.

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

“…We have previously shown that TGF-β is upregulated in a mouse model of fibrosis caused by SMG excretory duct ligation and that in vivo administration of TGF-β inhibitors reduces duct ligation-induced salivary gland fibrosis [ 97 ]. TGF-β inhibition also efficiently reduces IR-induced lung [ 98 , 99 ] and rectal [ 100 ] fibrosis in mouse models. Further investigation is needed on the relationship of TGF-β and fibrosis to IR-induced hyposalivation and whether this pathway plays a significant role in chronic salivary gland dysfunction in RT.…”

Pathophysiology of Post-COVID syndromes: a new perspective

“…Due to the uncontrolled release of TGF-β1 by a prolonged inflammatory state [ 198 ], pulmonary fibrosis is regarded as the main final fatal complication in PCS patients due to the uncontrolled release of TGF-β1 by a prolonged inflammatory state [ 198 ]. Therefore, TGF-β1 inhibitors like triptolide, azithromycin, and vitamin D could be effective in the attenuation of PCPF [ 199 ]. Of interest, pirfenidone, a TGF-β1 inhibitor that acts as an anti-fibrotic agent together with anti-inflammatory drugs, may reduce the risk of development of PCPF in COVID-19 survivors [ 200 ].…”

Muscle‐specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination

“…The underlying cellular and molecular mechanisms of radiation‐induced pro‐inflammatory and pro‐fibrotic signalling are being actively investigated in the lung, 13 liver, 14 and kidney 15,16 . Amongst these cytokines expressed after radiation are transforming growth factor‐β1 (TGF‐β1), C–C chemokine receptor type 2 (CCR2), and its associated ligands such as CCL2 17 . Chronic TGF‐β1 expression promotes fibroblast proliferation and myofibroblast differentiation, where these cells produce collagens and ECM proteins such as fibronectin (FN1) 18 .…”

“…15,16 Amongst these cytokines expressed after radiation are transforming growth factor-β1 (TGF-β1), C-C chemokine receptor type 2 (CCR2), and its associated ligands such as CCL2. 17 Chronic TGF-β1 expression promotes fibroblast proliferation and myofibroblast differentiation, where these cells produce collagens and ECM proteins such as fibronectin (FN1). 18 Additionally, CCR2-expressing immune cells are induced in irradiated pulmonary tissues 12 and colocalize to fibrotic areas.…”