Bactericidal/Permeability-Increasing Protein (rBPI ₂₁ ) and Fluoroquinolone Mitigate Radiation-Induced Bone Marrow Aplasia and Death

Abstract

Identification of safe, effective treatment strategies to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the Federal Drug Administration has yet to approve any agent for a mass-casualty radiation disaster indication. As preparative treatments for hematopoietic stem cell transplantation (HSCT) produce toxicities similar to such radiation exposures, we studied patients early after myeloablative HSCT 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. We tested this idea in mice. A single 7 Gy radiation dose, which was 95% lethal 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 anti-bacterial activity including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle/fluoroquinolone, combined rBPI21/fluoroquinolone treatment improved survival, accelerated hematopoietic recovery and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 and fluoroquinolones initiated 24 hours after lethal irradiation, combined with their favorable bioactivity and safety profiles in critically-ill humans, suggest the potential clinical utility of this radiation mitigation strategy and support its further evaluation.

Pleiotrophin mediates hematopoietic regeneration via activation of RAS

“…Recently, novel mechanisms have been described that may be targeted to mitigate radiation injury to the hematopoietic system (5,6,8,32,33). To our knowledge, PTN represents the first therapeutic demonstrated to improve survival when administered more than 24 hours after exposure.…”

“…Radiation causes toxicity to hematopoietic stem cells (HSCs) through the generation of ROS, induction of DNA strand breaks and apoptosis, and damage to the BM microenvironment (2)(3)(4). Despite an understanding of mechanisms through which ionizing radiation causes hematopoietic toxicity, few effective mitigators of radiation-induced hematopoietic injury have been developed (5)(6)(7)(8)(9). The lack of effective mitigators for acute radiation sickness (ARS) has become a public health concern, as the risk of terrorism using radiological or nuclear devices has escalated (10,11).…”

Catalase Inhibits Ionizing Radiation-Induced Apoptosis in Hematopoietic Stem and Progenitor Cells

“…Even a moderate dose (eg, 3 Gy) of IR exposure can cause acute myelosuppression characterized by neutropenia, lymphocytopenia, and thrombocytopenia. It is well documented that hematopoietic acute radiation syndrome increases the risk of infection, bleeding, and even death [4][5][6][7][8][9]. Moreover, during the course of radiation and chemotherapy, therapyinduced myelosuppression may cause high mortality and morbidity and worsen the outcome of cancer treatment [2,[4][5][6][7][8].…”

“…It is well documented that hematopoietic acute radiation syndrome increases the risk of infection, bleeding, and even death [4][5][6][7][8][9]. Moreover, during the course of radiation and chemotherapy, therapyinduced myelosuppression may cause high mortality and morbidity and worsen the outcome of cancer treatment [2,[4][5][6][7][8]. Studies from ours and other laboratories have demonstrated that radiation-caused acute myelosuppression is largely attributable to the induction of apoptosis in hematopoietic stem and progenitor cells (HSPCs) [3,6].…”

NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation

“…The hematopoietic system is highly sensitive to IR, and in particular, IR doses beyond 2 Gy can lead to myelosuppression that is characterized by neutropenia, lymphocytopenia, and thrombocytopenia. Collectively, hematopoietic acute radiation syndrome (H-ARS) increases the risk of infection, bleeding, and death (1)(2)(3)(4)(5)(6)(7)(8)(9). There is an unmet need for effective interventions to mitigate the progression of H-ARS after IR exposure (10).…”