학술논문
The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates.
Document Type
Article
Author
Brickey, W. June; Caudell, David L.; Macintyre, Andrew N.; Olson, John D.; Yanwan Dai; Sirui Li; Dugan, Gregory O.; Bourland, J. Daniel; O'Donnell, Lisa M.; Tooze, Janet A.; Guannan Huang; Shuangshuang Yang; Hao Guo; French, Matthew N.; Schorzman, Allison N.; Zamboni, William C.; Sempowski, Gregory D.; Zhiguo Li; Owzar, Kouros; Chao, Nelson J.
Source
Subject
*TOTAL body irradiation
*PRIMATES
*RADIATION injuries
*ERYTHROCYTES
*RADIATION exposure
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Language
ISSN
0027-8424
Abstract
Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS. [ABSTRACT FROM AUTHOR]