Abstract
Identification of safe, effective treatments to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the U.S. Food and Drug Administration has yet to approve any agent for a mass-casualty radiation disaster. Because patients undergoing hematopoietic stem cell transplantation undergo radiation treatment that produces toxicities similar to radiation-disaster exposure, we studied patients early after such treatment to identify new approaches to this problem. Patients rapidly developed endotoxemia and reduced plasma bactericidal/permeability-increasing protein (BPI), a potent endotoxin-neutralizing protein, in association with neutropenia. We hypothesized that a treatment supplying similar endotoxin-neutralizing activity might replace the BPI deficit and mitigate radiation toxicity and tested this idea in mice. A single 7-Gy radiation dose, which killed 95% of the mice by 30 days, was followed 24 hours later by twice-daily, subcutaneous injections of the recombinant BPI fragment rBPI21 or vehicle alone for 14 or 30 days, with or without an oral fluoroquinolone antibiotic with broad-spectrum antibacterial activity, including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle plus fluoroquinolone, the combined rBPI21plus fluoroquinolone treatment improved survival, accelerated hematopoietic recovery, and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 plus fluoroquinolone initiated 24 hours after lethal irradiation, combined with their established favorable bioactivity and safety profiles in critically ill humans, suggests the potential clinical use of this radiation mitigation strategy and supports its further evaluation.
Original language | English |
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Article number | 110ra118 |
Journal | Science Translational Medicine |
Volume | 3 |
Issue number | 110 |
DOIs | |
Publication status | Published - 23 Nov 2011 |
Funding
We thank P. Scannon, M. Wessels, and L. Nadler for their insights and support, and L. Brennan and V. Russo for their many contributions. Funding: Defense Advanced Research Projects Agency HR001-08-1-0011, NIH 5R21 HL089659 and 5U19 AI067751, the Dana Foundation, the G. Green Foundation, and Shea Family Fund. Author contributions: E.C.G. and O.L. conceived the studies, executed the clinical study, designed experiments, analyzed and interpreted data, and drafted the article. C.M.B. designed experiments, developed methods, performed experiments and data analysis, and drafted and reviewed the manuscript. L.A.K. analyzed and interpreted data and provided critical manuscript revision. J.K. and J.-A.V. analyzed murine data and reviewed the manuscript. K.P. contributed to initial murine experimental design, data interpretation, and manuscript review. A.D. provided important resources for murine studies and reviewed the manuscript. G.C. performed experiments and manuscript review. E.E.S., L.S.-B., C.D.P., C.J.M., J.D.R., L.C.G., K.Z., and A.V. contributed to experiment planning, execution, analysis, and manuscript preparation. R.S. contributed to human study execution and manuscript review. J.P.W. reviewed and interpreted data and contributed critical manuscript revisions. Competing interests: O.L.’s laboratory received sponsorship and reagent support from XOMA (US) LLC and Spectral Diagnostics. The other authors declare that they have no competing interests.
All Science Journal Classification (ASJC) codes
- General Medicine