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

Park, Sung Hyo; Kim, Jee Youn; Kim, Jin Mo; Yoo, Byeong Rok; Han, Song Yi; Jung, Yoo Jin; Bae, Hyunsu; Cho, Jaeho

doi:10.1038/s41598-020-72629-9

Cited by 15 publications

(11 citation statements)

References 48 publications

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“…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.…”

Section: Animal Models Provide Mechanistic Insight Into Radiation-mentioning

confidence: 99%

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

Jasmer

Gilman

Forti

et al. 2020

JCM

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Salivary glands sustain collateral damage following radiotherapy (RT) to treat cancers of the head and neck, leading to complications, including mucositis, xerostomia and hyposalivation. Despite salivary gland-sparing techniques and modified dosing strategies, long-term hypofunction remains a significant problem. Current therapeutic interventions provide temporary symptom relief, but do not address irreversible glandular damage. In this review, we summarize the current understanding of mechanisms involved in RT-induced hyposalivation and provide a framework for future mechanistic studies. One glaring gap in published studies investigating RT-induced mechanisms of salivary gland dysfunction concerns the effect of irradiation on adjacent non-irradiated tissue via paracrine, autocrine and direct cell–cell interactions, coined the bystander effect in other models of RT-induced damage. We hypothesize that purinergic receptor signaling involving P2 nucleotide receptors may play a key role in mediating the bystander effect. We also discuss promising new therapeutic approaches to prevent salivary gland damage due to RT.

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Section: Animal Models Provide Mechanistic Insight Into Radiation-mentioning

confidence: 99%

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

Jasmer

Gilman

Forti

et al. 2020

JCM

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology of Post-COVID syndromes: a new perspective

Batiha

Al-Kuraishy

Al-Gareeb

et al. 2022

Virol J

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Most COVID-19 patients recovered with low mortality; however, some patients experienced long-term symptoms described as “long-COVID” or “Post-COVID syndrome” (PCS). Patients may have persisting symptoms for weeks after acute SARS-CoV-2 infection, including dyspnea, fatigue, myalgia, insomnia, cognitive and olfactory disorders. These symptoms may last for months in some patients. PCS may progress in association with the development of mast cell activation syndrome (MCAS), which is a distinct kind of mast cell activation disorder, characterized by hyper-activation of mast cells with inappropriate and excessive release of chemical mediators. COVID-19 survivors, mainly women, and patients with persistent severe fatigue for 10 weeks after recovery with a history of neuropsychiatric disorders are more prone to develop PCS. High D-dimer levels and blood urea nitrogen were observed to be risk factors associated with pulmonary dysfunction in COVID-19 survivors 3 months post-hospital discharge with the development of PCS. PCS has systemic manifestations that resolve with time with no further complications. However, the final outcomes of PCS are chiefly unknown. Persistence of inflammatory reactions, autoimmune mimicry, and reactivation of pathogens together with host microbiome alterations may contribute to the development of PCS. The deregulated release of inflammatory mediators in MCAS produces extraordinary symptoms in patients with PCS. The development of MCAS during the course of SARS-CoV-2 infection is correlated to COVID-19 severity and the development of PCS. Therefore, MCAS is treated by antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells.

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Kallenbach

Bachman

Paris

et al. 2022

J cachexia sarcopenia muscle

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Background As paediatric cancer survivors are living into adulthood, they suffer from the age-related, accelerated decline of functional skeletal muscle tissue, termed sarcopenia. With ionizing radiation (radiotherapy) at the core of paediatric cancer therapies, its direct and indirect effects can have lifelong negative impacts on paediatric growth and maintenance of skeletal muscle. Utilizing our recently developed preclinical rhabdomyosarcoma mouse model, we investigated the late effects of paediatric radiation treatment on skeletal muscles from late adolescent (8 weeks old) and middle-aged (16 months old) mice. Methods Paediatric C57BL/6J male mice (3 weeks old) were injected with rhabdomyosarcoma cells into their right hindlimbs, and then fractionated irradiation (3 × 8.2 Gy) was administered to those limbs at 4 weeks old to eliminate the tumours. Radiation-alone and tumour-irradiated mice were assessed at either 8 weeks (3 weeks post-irradiation) or 16 months (14 months post-irradiation) of age for muscle physiology, myofibre characteristics, cell loss, histopathology, fibrosis, inflammatory gene expression, and fibrotic gene expression. Results Mice that received only paediatric radiation demonstrated reduced muscle mass (À17%, P < 0.001), muscle physiological function (À25%, P < 0.01), muscle contractile kinetics (À25%, P < 0.05), satellite cell number (À45%, P < 0.05), myofibre cross-sectional area (À30%, P < 0.0001), and myonuclear number (À17%, P < 0.001). Paediatric radiation increased inflammatory gene expression, increased fibrotic gene expression, and induced extracellular matrix protein deposition (fibrosis) with tumour elimination exacerbating some phenotypes. Paediatric tumour-eliminated mice demonstrated exacerbated deficits to function (À20%, P < 0.05) and myofibre size (À17%, P < 0.001) in some muscles as well as further increases to inflammatory and fibrotic gene expression. Examining the age-related effects of paediatric radiotherapy in middle-aged mice, we found persistent myofibre atrophy (À20%, P < 0.01), myonuclear loss (À18%, P < 0.001), up-regulated inflammatory and fibrotic signalling, and lifelong fibrosis. Conclusions The results from this paediatric radiotherapy model are consistent and recapitulate the clinical and molecular features of accelerated sarcopenia, musculoskeletal frailty, and radiation-induced fibrosis experienced by paediatric cancer survivors. We believe that this preclinical mouse model is well poised for future mechanistic insights and therapeutic interventions that improve the quality of life for paediatric cancer survivors.

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

Cited by 15 publications

References 48 publications

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

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

Pathophysiology of Post-COVID syndromes: a new perspective

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

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