Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

Mezzaroma, Eleonora; Mikkelsen, Ross B.; Toldo, Stefano; Mauro, Adolfo G; Sharma, Khushboo; Marchetti, Carlo; Alam, Asim; Tassell, Benjamín W. Van; Gewirtz, David A.; Abbate, Antonio

doi:10.2119/molmed.2014.00243

Cited by 32 publications

(18 citation statements)

References 61 publications

(85 reference statements)

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“…Decreased peak oxygen consumption is a measure of contractile reserve in patients and is a hallmark of heart failure. As already observed for low-dose exposure to the heart (7), there were no differences in LV function measured at rest in all groups of mice (see Table 1); however, as previously reported (7, 33), we observed a decrease in cardiac performance after β-adrenergic stimulation after irradiation. Long-term treatment with IPW-5371 preserved the contractile reserve in irradiated mice, however the improvement was not associated with a preservation of LV dimensions, the loss of which characterizes the development of restrictive cardiomyopathy (32, 34, 35).…”

Section: Discussionsupporting

confidence: 89%

“…As in RILI, cardiac fibrosis has been associated with cardiac damage leading to a decrease in cardiac function (7). TGF-β is known to play a critical role in cardiac injury, repair and remodeling (25).…”

Section: Discussionmentioning

confidence: 99%

“…The contractile reserve was assessed with a β-adrenergic receptor agonist (isoproterenol, 10 ng/mouse, Sigma-Aldrich® LLC; St. Louis, MO), as previously described (7). The contractile reserve was calculated as percentage change in LVEF measured at rest (LVEFr) and 3 min after isoproterenol injection (LVEFi) and calculated as [(LVEFi-LVEFr)/LVEFr] * 100.…”

Section: Methodsmentioning

confidence: 99%

“…The initial insult is followed by an inflammatory response resulting in increased multifunctional cytokine expression and significant cellular and molecular changes often characterized by the development of fibrosis resulting in loss of organ function (4–7). Transforming growth factor beta (TGF-β) has been implicated as a key mediator of this process, regulating cell proliferation, differentiation and migration.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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 O2 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 IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…The exact etiology of the acute tissue damage leading to long-term risks is not fully understood and may result from direct and indirect effects. Potential contributors include endothelial injury and dysfunction, DNA damage and altered cardiac gene expression, acute and chronic oxidative stress, microvascular damage, inflammation and other factors ( 1 – 6 ). Long-term cardiovascular disease (CVD) incidence data collected from survivors of accidental, malicious and therapeutic exposures highlight the need for well controlled studies to improve our understanding of RIHD pathophysiology so that targeted treatment and prevention strategies can be successfully developed and implemented.…”

Section: Introductionmentioning

confidence: 99%

Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques

et al. 2016

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Heart disease is an increasingly recognized, serious late effect of radiation exposure, most notably among breast cancer and Hodgkin’s disease survivors, as well as the Hiroshima and Nagasaki atomic bomb survivors. The purpose of this study was to evaluate the late effects of total-body irradiation (TBI) on cardiac morphology, function and selected circulating biomarkers in a well-established nonhuman primate model. For this study we used male rhesus macaques that were exposed to a single total-body dose of ionizing gamma radiation (6.5–8.4 Gy) 5.6–9.7 years earlier at ages ranging from ~3–10 years old and a cohort of nonirradiated controls. Transthoracic echocardiography was performed annually for 3 years on 20 irradiated and 11 control animals. Myocardium was examined grossly and histologically, and myocardial fibrosis/collagen was assessed microscopically and by morphometric analysis of Masson’s trichrome-stained sections. Serum/plasma from 27 irradiated and 13 control animals was evaluated for circulating biomarkers of cardiac damage [N-terminal pro B-type natriuretic protein (nt-proBNP) and troponin-I], inflammation (CRP, IL-6, MCP-1, sICAM) and microbial translocation [LPS-binding protein (LBP) and sCD14]. A higher prevalence of histological myocardial fibrosis was observed in the hearts obtained from the irradiated animals (9/14) relative to controls (0/3) (P = 0.04, χ2). Echocardiographically determined left ventricular end diastolic and systolic diameters were significantly smaller in irradiated animals (repeated measures ANOVA, P < 0.001 and P < 0.008, respectively). Histomorphometric analysis of trichrome-stained sections of heart tissue demonstrated ~14.9 ± 1.4% (mean ± SEM) of myocardial area staining for collagen in irradiated animals compared to 9.1 ± 0.9 % in control animals. Circulating levels of MCP-1 and LBP were significantly higher in irradiated animals (P < 0.05). A high incidence of diabetes in the irradiated animals was associated with higher plasma triglyceride and lower HDLc but did not appear to be associated with cardiovascular phenotypes. These results demonstrate that single total-body doses of 6.5–8.4 Gy produced long-term effects including a high incidence of myocardial fibrosis, reduced left ventricular diameter and elevated systemic inflammation. Additional prospective studies are required to define the time course and mechanisms underlying radiation-induced heart disease in this model.

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