IPW-5371 mitigates the delayed effects of acute radiation exposure in WAG/RijCmcr rats when started 15 days after PBI with bone marrow sparing

Fish, Brian L.; Hart, Barry; Gasperetti, Tracy; Narayanan, Jayashree; Gao, Feng; Veley, Dana; Pierce, Lauren; Himburg, Heather A.; MacVittie, Thomas J.; Medhora, Meetha

doi:10.1080/09553002.2023.2173825

Cited by 3 publications

(1 citation statement)

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“…Dysregulation of this growth factor or its signaling pathways contribute to adverse remodeling in cardiovascular disease including hypertension [ 26 ], atherosclerosis [ 24 ], and heart failure [ 27 ]. Previous studies have also implicated TGF-β in adverse remodeling in the heart after high-dose low-LET radiation exposure [ 28 , 29 , 30 ]. Therefore, the inhibition of the TGF-β signaling pathway could be an interesting target for a countermeasure against the biological effects of HZE radiation.…”

Section: Introductionmentioning

confidence: 99%

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart

Nemec-Bakk

Sridharan

Desai

et al. 2023

Life

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Missions into deep space will expose astronauts to the harsh space environment, and the degenerative tissue effects of space radiation are largely unknown. To assess the risks, in this study, male BALB/c mice were exposed to 500 mGy 5-ion simulated GCR (GCRsim) at the NASA Space Radiation Laboratory. In addition, male and female CD1 mice were exposed to GCRsim and administered a diet containing Transforming Growth Factor-beta (TGF-β)RI kinase (ALK5) inhibitor IPW-5371 as a potential countermeasure. An ultrasound was performed to investigate cardiac function. Cardiac tissue was collected to determine collagen deposition, the density of the capillary network, and the expression of the immune mediator toll-like receptor 4 (TLR4) and immune cell markers CD2, CD4, and CD45. In male BALB/c mice, the only significant effects of GCRsim were an increase in the CD2 and TLR4 markers. In male CD1 mice, GCRsim caused a significant increase in total collagens and a decrease in the expression of TLR4, both of which were mitigated by the TGF-β inhibitor diet. In female CD1 mice, GCRsim caused an increase in the number of capillaries per tissue area in the ventricles, which may be explained by the decrease in the left ventricular mass. However, this increase was not mitigated by TGF-β inhibition. In both male and female CD1 mice, the combination of GCRsim and TGF-β inhibition caused changes in left ventricular immune cell markers that were not seen with GCRsim alone. These data suggest that GCRsim results in minor changes to cardiac tissue in both an inbred and outbred mouse strain. While there were few GCRsim effects to be mitigated, results from the combination of GCRsim and the TGF-β inhibitor do point to a role for TGF-β in maintaining markers of immune cells in the heart after exposure to GCR.

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Section: Introductionmentioning

confidence: 99%

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart

Nemec-Bakk

Sridharan

Desai

et al. 2023

Life

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IEPA, a novel radiation countermeasure, alleviates acute radiation syndrome in rodents

Wesolowski,

Fish,

Eibl

et al. 2024

International Journal of Radiation Biology

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A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice

Szalanczy,

Sherrill,

Fanning

et al. 2024

Radiation Research

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As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize the delayed effects of radiation exposure and develop medical countermeasures. Radiation has been shown to damage adipose progenitor cells and increase liver fibrosis, such that it predisposes patients to developing metabolic-associated fatty liver disease (MAFLD) and insulin resistance. The risk of developing these conditions is compounded by the global rise of diets rich in carbohydrates and fats. Radiation persistently increases the signaling cascade of transforming growth factor β (TGFβ), leading to heightened fibrosis as characteristic of the delayed effects of radiation exposure. We investigate here a potential radiation medical countermeasure, IPW-5371, a small molecule inhibitor of TGFβRI kinase (ALK5). We found that mice exposed to sub-lethal whole-body irradiation and chronic Western diet consumption but treated with IPW-5371 had a similar body weight, food consumption, and fat mass compared to control mice exposed to radiation. The IPW-5371 treated mice maintained lower fibrosis and fat accumulation in the liver, were more responsive to insulin and had lower circulating triglycerides and better muscle endurance. Future studies are needed to verify the improvement by IPW-5371 on the structure and function of other metabolically active tissues such as adipose and skeletal muscle, but these data demonstrate that IPW-5371 protects liver and whole-body health in rodents exposed to radiation and a Western diet, and there may be promise in using IPW-5371 to prevent the development of MAFLD.

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IPW-5371 mitigates the delayed effects of acute radiation exposure in WAG/RijCmcr rats when started 15 days after PBI with bone marrow sparing

Cited by 3 publications

References 64 publications

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart

IEPA, a novel radiation countermeasure, alleviates acute radiation syndrome in rodents

A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice

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