Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

Boerma, Marjan; Wang, Junru; Sridharan, Vijayalakshmi; Herbert, Jean‐Marc; Hauer‐Jensen, Martin

doi:10.1371/journal.pone.0070479

Cited by 48 publications

(36 citation statements)

References 57 publications

(56 reference statements)

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“…TGF-β is known to play a critical role in cardiac injury, repair and remodeling (25). Using a TGF-β agonist, Boerma et al recently reported on a direct effect of TGF-β on radiation-induced cardiac injury (26).…”

Section: Discussionmentioning

confidence: 99%

“…TGF-β is involved in the pathogenesis of several cardiac diseases, affecting both the inflammatory and reparative responses to injury (25). The timing and levels of TGF-β inhibition appear to be crucial for preventing inflammation and/or excessive collagen deposition leading to cardiac dysfunction (26). IPW-5371 preserved the response to β-adrenergic stimulation and reduced collagen deposition after irradiation; however, we observed a slight reduction in right ventricular function (RVFAC and TAPSE) associated with IPW-5371 treatment.…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…Total cardiac RNA was isolated, cDNA synthesized, and steady-state mRNA levels were measured with real-time quantitative PCR (TaqMan™) as described before [19] and in the Supplementary Material, using the pre-designed TaqMan Gene Expression Assays™ listed in Supplementary Table 2.…”

Section: Methodsmentioning

confidence: 99%

A priming dose of protons alters the early cardiac cellular and molecular response to 56 Fe irradiation

Ramadan

Sridharan

Koturbash

et al. 2016

Life Sciences in Space Research

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Purpose Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a “priming” dose of protons on the cardiac cellular and molecular response to a “challenge” dose of 56Fe in a mouse model. Methods Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

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“…Strikingly, the predicted activation of the TGFβ1 regulatory pathway by RT appears to be significantly attenuated if HBOT is applied. The TGFβ-pathway is strongly associated with radiationinduced fibrosis in different organs, and is the subject of investigation regarding possible antifibrotic therapies (36)(37)(38)(39).…”

Section: Continued On Next Pagementioning

confidence: 99%

“…PDGF has been shown to influence the TGFβ-pathway and is implicated to be involved in fibrosis as well (63). The suppression of TGFβ and PDGF as potential antifibrotic therapies is of interest and has been investigated in several studies (37,41). Fibrosis is a complex process involving several pathways that are interconnected and the concurrent suppression of more of these factors is more likely to have an effect on a biological process.…”

Section: Continued On Next Pagementioning

confidence: 99%

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

Spiegelberg

Swagemakers

IJcken

et al. 2014

Mol Med

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A side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT) is clinically used to treat radiation-induced damage but its mechanism of action is largely unknown. In this study, we investigated the molecular pathways that are affected by HBOT in mouse salivary glands two weeks after radiation therapy by microarray analysis. Interestingly, HBOT led to significant attenuation of the radiation-induced expression of a set of genes and upstream regulators that are involved in processes such as fibrosis and tissue regeneration. Our data suggest that the TGFβ-pathway, which is involved in radiation-induced fibrosis and chronic loss of function after radiation therapy, is affected by HBOT. On the longer term, HBOT reduced the expression of the fibrosis-associated factor α-smooth muscle actin in irradiated salivary glands. This study highlights the potential of HBOT to inhibit the TGFβ-pathway in irradiated salivary glands and to restrain consequential radiation induced tissue injury.

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Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

Cited by 48 publications

References 57 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

A priming dose of protons alters the early cardiac cellular and molecular response to 56 Fe irradiation

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

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