Mitigation effect of an FGF-2 peptide on acute gastrointestinal syndrome after high-dose ionizing radiation.
OBJECTIVE
Acute gastrointestinal syndrome (AGS) resulting from ionizing radiation causes death within 7 days. Currently, no satisfactory agent exists for mitigation of AGS. A peptide derived from the receptor binding domain of fibroblast growth factor 2 (FGF-P) was synthesized and its mitigation effect on AGS was examined.


METHODS
A subtotal body irradiation (sub-TBI) model was created to induce gastrointestinal (GI) death while avoiding bone marrow death. After 10.5 to 16 Gy sub-TBI, mice received an intramuscular injection of FGF-P (10 mg/kg/day) or saline (0.2 ml/day) for 5 days; survival (frequency and duration) was measured. Crypt cells and their proliferation were assessed by hematoxylin, eosin, and BrdU staining. In addition, GI hemoccult score, stool formation, and plasma levels of endotoxin, insulin, amylase, interleukin (IL)-6, keratinocyte-derived chemokine (KC) monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF)-alpha were evaluated.


RESULTS
Treatment with FGF-P rescued a significant fraction of four strains of mice (33-50%) exposed to a lethal dose of sub-TBI. Use of FGF-P improved crypt survival and repopulation and partially preserved or restored GI function. Furthermore, whereas sub-TBI increased plasma endotoxin levels and several pro-inflammation cytokines (IL-6, KC, MCP-1, and TNF-alpha), FGF-P reduced these adverse responses.


CONCLUSIONS
The study data support pursuing FGF-P as a mitigator for AGS.
Zhang
Lurong
L
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642-8647, USA.
Sun
Weimin
W
Wang
Jianjun
J
Zhang
Mei
M
Yang
Shanmin
S
Tian
Yeping
Y
Vidyasagar
Sadasivan
S
Peña
Louis A
LA
Zhang
Kunzhong
K
Cao
Yongbing
Y
Yin
Liangjie
L
Wang
Wei
W
Zhang
Lei
L
Schaefer
Katherine L
KL
Saubermann
Lawrence J
LJ
Swarts
Steven G
SG
Fenton
Bruce M
BM
Keng
Peter C
PC
Okunieff
Paul
P
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D018932:Chemokine CCL2 / Q000097:blood; D018925:Chemokines / Q000097:blood; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019446:Endotoxemia / Q000209:etiology / Q000517:prevention & control; D016222:Fibroblast Growth Factor 2 / Q000627:therapeutic use*; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000528:radiation effects*; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000627:therapeutic use*; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000401:mortality / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D013045:Species Specificity; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015415:Biomarkers; D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; C548915:FGF-P peptide; D007328:Insulin; D015850:Interleukin-6; D010446:Peptide Fragments; D011837:Radiation-Protective Agents; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; C074302:keratinocyte-derived chemokines
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