Thiol/Redox Metabolomic Profiling Implicates GSH Dysregulation in Early Experimental Graft versus Host Disease (GVHD)

General Questions

What is Ionizing Radiation?

Ionizing radiation consists of subatomic particles or electromagnetic waves that are energetic enough to detach electrons from atoms or molecules, ionizing them.

Two of the most common forms of ionizing radiation are gamma rays and x-rays. Both forms of ionizing radiation are almost identical with exception to their source of origination.

How is Ionizing Radiation Generated?

Ionizing radiation comes from radioactive sources such as cobalt 60 and cesium 137 and non-radioactive sources such as x-ray tubes. Radioactive sources are unstable materials where gamma rays originate from the nucleus. x-rays originate in the electron fields surrounding the nucleus or are machine-produced.

What is Ionizing Radiation Used for?

Because of the penetrating properties of ionizing radiation and their ability to kill microorganisms, ionizing radiation is used to sterilize or reduce the microbial load of many different types of products such as medical devices, packaging, cosmetics, foods, and agricultural products. It is also used to alter the properties of many different polymers through recombination, cross-linkage, and cross scission.

Why use x-ray versus gamma produced Ionizing radiation?

Gamma ionizing radiation is produced by radioactive sources such as cobalt 60 or cesium 137 and is dangerous requiring heavy shielding and high levels of security to protect. The unstable material is constantly decaying and cannot be turned off. x-ray ionizing radiation is produced by a x-ray tube therefore it can be turned off when it is not being used and it requires much less shielding. At the end the of unit’s lifecycle, the unit does not have any radioactive source and therefore does not require the expensive disposal costs associated with radioactive sources that continue to degrade over hundreds of years.

Does the RS 3400 require external cooling?

No, the RS 3400 uses a self-contained water to air exchange system.

Is the RS 3400 Blood Irradiator cleared by the FDA for GVHD?

Yes, the RS 3400 was cleared by the USFDA for marketing for the irradiation of blood for the prevention of graft verses host disease (GVHD).

How does the RS 3400 differ from other x-ray irradiators?

The RS 3400 is designed to have the blood bags rotate around the Quastar™ x-ray emitter using our patented carousel and therefore delivers superior uniformity.
Unlike other x-ray blood irradiators, the RS 3400 is completely self-contained and requires no external water supply for tube cooling.
The RS 3400 is engineered for extreme reliability as it uses the proven Quastar™ x-ray emitter.
The RS 3400 has only ONE x-ray tube and ONE power supply.

How does the RS 3400 differ from a Cs-137 gamma irradiator??

The RS 3400 uses a Rad Source patented Quastar™ x-ray emitter and therefore contains NO radioactive isotopes. It can be turned on and off, similar to a light bulb. As a result, there is no Nuclear Site License, Homeland Security issues, or room shielding requirements.

Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation (BMT). Upregulation of inflammatory cytokines precedes the clinical presentation of GVHD and predicts its severity. In this report, thiol/redox metabolomics was used to identify metabolic perturbations associated with early preclinical (Day+4) and clinical (Day+10) stages of GVHD by comparing effects in Syngeneic (Syn; major histocompatibility complex- identical) and allogeneic transplant recipients (Allo BMT) in experimental models. While most metabolic changes were similar in both groups, plasma glutathione (GSH) was significantly decreased, and GSH disulfide (GSSG) was increased after allogeneic compared to syngeneic recipient and non-transplant controls. The early oxidation of the plasma GSH/GSSG redox couple was also observed irrespective of radiation conditioning treatment and was accompanied by significant rise in hepatic protein oxidative damage and ROS generation. Despite a significant rise in oxidative stress, compensatory increase in hepatic GSH synthesis was absent following Allo BMT. Early shifts in hepatic oxidative stress and plasma GSH loss preceded a statistically significant rise in TNF-α. To identify metabolomic biomarkers of hepatic GVHD injury, plasma metabolite concentrations analyzed at Day+10 were correlated with hepatic organ injury. GSSG (oxidized GSH) and β-alanine, were positively correlated, and plasma GSH cysteinylglycine, and branched chain amino acids were inversely correlated with hepatic injury. Although changes in plasma concentrations of cysteine, cystathionine (GSH precursors) and cysteinylglycine (a GSH catabolite) were not significant by univariate analysis, principal component analysis (PCA) indicated that accumulation of these metabolites after Allo BMT contributed significantly to early GVHD in contrast to Syn BMT. In conclusion, thiol/redox metabolomic profiling implicates that early dysregulation of host hepatic GSH metabolism and oxidative stress in sub-clinical GVHD before elevated TNF-α levels is associated with GVHD pathogenesis. Future studies will probe the mechanisms for these changes and examine the potential of antioxidant intervention strategies to modulate GVHD.
“Animals were given Pen/Strep antibiotic water at a dose of 100 units/ml following lethal-radiation.. Briefly, recipient mice received lethal (1100 cGy) x-ray irradiation using RS-2000 x-ray biological irradiator (160 kV, 4.2 kW, radiation dose of 96 rads/mt) (RadSource Technologies, Inc., Alpharetta, GA, USA).. Radiation was administered as two fractions, 4 hours apart, to minimize gastrointestinal toxicity.”

(PLoS One 2014 Jan 31)