Physiological Interaction of Heart and Lung in Thoracic Irradiation

Ghobadi, Ghazaleh; Veen, S. van der; Bartelds, Beatrijs; Boer, Rudolf A. de; Dickinson, Michael G.; Jong, Johan R. de; Faber, Hette; Niemantsverdriet, Maarten; Brandenburg, S.; Berger, Rolf M. F.; Langendijk, Johannes A.; Coppes, Robert P.; Luijk, Peter van

doi:10.1016/j.ijrobp.2012.07.2362

Cited by 129 publications

(96 citation statements)

References 21 publications

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“…Published reports using rats have demonstrated that while irradiation of the heart and lung induce cardiac and pulmonary dysfunction, respectively, whole-thoracic lung irradiation results in significantly enhanced morbidities (27,28). Clinical studies have also demonstrated that incidental irradiation of the heart increases the risk of radiation-induced pneumonitis in patients receiving radiotherapy for non-small cell lung cancer (NSCLC) (29).…”

Section: Discussionmentioning

confidence: 99%

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects

Rabender¹,

Mezzaroma²,

Mauro³

et al. 2016

Radiation Research

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There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic "top-up" of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O 2 saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that

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Section: Discussionmentioning

confidence: 99%

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects

Rabender¹,

Mezzaroma²,

Mauro³

et al. 2016

Radiation Research

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“…The special importance of the primary injury to the EC for radiation-induced late toxicity in the lungs is emphasized by studies on pulmonary arterial hypertension (PAH), where a functional impairment or even partial loss of the EC could be detected immediately after a selective lung irradiation and long before the manifestation of the first clinical symptoms (33). In this study, we show now that adoptive transfer of MSCs within the early phase after irradiation also provides long-term protection from radiation-induced EC damage, EC loss, and immune cell infiltration that translates in protection from fibrosis development.…”

Section: Murine Wt Bm (Xrt/bm) Cells From C57bl/6 Donor Mice Into Thementioning

confidence: 99%

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Klein

Steens

Wiesemann

et al. 2017

Antioxidants & Redox Signaling

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Aims: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. Results: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and longterm survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSCderived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. Innovation: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Conclusions: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

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“…There are concerns about the acute and late pulmonary and cardiovascular toxicity, especially for patients with a medical history of cardiovascular and/or pulmonary disease [4,5].…”

Section: Introductionmentioning

confidence: 99%

Should breathing adapted radiotherapy also be applied for right-sided breast irradiation?

et al. 2015

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Background: Voluntary moderate deep inspiration breath-hold (vmDIBH) is widely used for left sided breast cancer patients. The purpose of this study was to investigate the usefulness of vmDIBH in local and locoregional radiation therapy (RT) of right-sided breast cancer. Materials and Methods: For fourteen right-sided breast cancer patients, 3D-conformal (3D-CRT) RT plans (i.e., forward IMRT) were calculated on free-breathing (FB) 3D-CRT(FB) and vmDIBHCT-scans, for local-as well as locoregional breast treatment, with and without internal mammary nodes (IMN). Dose volume parameters were compared. Results: For local breast treatment, no relevant reduction in mean lung dose (MLD) was found. For locoregional breast treatment without IMN, the average MLD reduced from 6.5 to 5.4 Gy (p50.005) for the total lung and from 11.2 to 9.7 Gy (p50.005) for the ipsilateral lung. For locoregional breast treatment with IMN, the average MLD reduced from 10.8 to 9.1 Gy (p50.005) for the total lung and from 18.7 to 16.2 Gy (p50.005) for the ipsilateral lung, whilea small reduction in mean heart dose of 0.4 Gy (p ¼ 0.07) was also found. Conclusions: Breathing adapted radiation therapy in left-sided breast cancer patients is becoming widely introduced. As a result of the slight reduction in lung dose found for locoregional rightsided breast cancer treatment in this study, a slightly lower risk of pneumonitis and secondary lung cancer (in ever smoking patients) can be expected.In addition, for some patients the heart dose will also be reduced by more than 0.5 up to 2.6 Gy. We therefore suggest to also apply breath-hold for locoregional irradiation of right-sided breast cancer patients.

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Physiological Interaction of Heart and Lung in Thoracic Irradiation

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Cited by 129 publications

References 21 publications

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Should breathing adapted radiotherapy also be applied for right-sided breast irradiation?

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