PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model.

Abstract

Radiation combined injury (RCI, radiation exposure coupled with other forms of injury, such as burn, wound, hemorrhage, blast, trauma and/or sepsis) comprises approximately 65% of injuries from a nuclear explosion, and greatly increases the risk of morbidity and mortality when compared to that of radiation injury alone. To date, no U.S. Food and Drug Administration (FDA)-approved countermeasures are available for RCI. Currently, three leukocyte growth factors (Neupogen®, Neulasta® and Leukine®) have been approved by the FDA for mitigating the hematopoietic acute radiation syndrome. However these granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) products have failed to increase 30-day survival of mice after RCI, suggesting a more complicated biological mechanism is in play for RCI than for radiation injury. In the current study, the mitigative efficacy of combination therapy using pegylated (PEG)-G-CSF (Neulasta) and -citrulline was evaluated in an RCI mouse model. L-citrulline is a neutral alpha-amino acid shown to improve vascular endothelial function in cardiovascular diseases. Three doses of PEG-G-CSF at 1 mg/kg, subcutaneously administered on days 1, 8 and 15 postirradiation, were supplemented with oral -citrulline (1 g/kg), once daily from day 1 to day 21 postirradiation. The combination treatment significantly improved the 30-day survival of mice after RCI from 15% (vehicle-treated) to 42%, and extended the median survival time by 4 days, as compared to vehicle controls. In addition, the combination therapy significantly increased body weight and bone marrow stem and progenitor cell clonogenicity in RCI mice, and accelerated recovery from RCI-induced intestinal injury, compared to animals treated with vehicle. Treatment with -citrulline alone also accelerated skin wound healing after RCI. In conclusion, these data indicate that the PEG-G-CSF and -citrulline combination therapy is a potentially effective countermeasure for mitigating RCI, likely by enhancing survival of the hematopoietic stem/progenitor cells and accelerating recovery from the RCI-induced intestinal injury and skin wounds.

• Authors: Li Wang, Min Zhai, Bin Lin, Wanchang Cui, Lisa Hull, Xianghong Li, Marsha N Anderson, Joan T Smith, Maria Victoria Umali, Suping Jiang, Juliann G Kiang, Mang Xiao
• Journal: Radiation research (Radiat Res) Vol. 196 Issue 1 Pg. 113-127 (07 01 2021) ISSN: 1938-5404 [Electronic] United States
• PMID: 33914884 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 by Radiation Research Society. All rights of reproduction in any form reserved.

Chemical References

• Recombinant Proteins
• Granulocyte Colony-Stimulating Factor
• Citrulline
• Polyethylene Glycols
• pegylated granulocyte colony-stimulating factor

Topics

• Animals
• Body Weight (radiation effects)
• Bone Marrow (pathology, radiation effects)
• Burns (drug therapy, etiology)
• Citrulline (administration & dosage, pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Therapy, Combination
• Female
• Granulocyte Colony-Stimulating Factor (administration & dosage, pharmacology, therapeutic use)
• Mice
• Polyethylene Glycols (administration & dosage, pharmacology, therapeutic use)
• Radiation Injuries, Experimental (complications, drug therapy)
• Recombinant Proteins (administration & dosage, pharmacology, therapeutic use)
• Skin (injuries, radiation effects)
• Survival Analysis
• Weight Loss (radiation effects)
• Whole-Body Irradiation
• Wound Healing (drug effects)