Abstract
Ionizing radiation causes severe damage to human body, and normal tissue toxicity in cancer radiotherapy also limits its further application. It is urgently required to develop safe and effective radioprotector. Our previous study has shown that toll like receptor 4 (TLR4) was dispensable for basal radiation resistance. However, severe toxicity of its traditional agonist lipopolysaccharide limits the clinical application. In present study, we demonstrated that monophosphoryl lipid A (MPLA), a potent TLR4 agonist with low toxicity, effectively attenuated radiation injury on in vitro and in vivo. MPLA increased cell survival and inhibited cell apoptosis after irradiation, and cell cycle arrest was also inhibited. Radiosensitive tissues including spleen, intestine, bone marrow and testis were protected from radiation damages in a TLR4 dependent manner. We also found that myeloid differentiation factor 88 (MyD88) accounted more than Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) for the radioprotective effects of MPLA. In conclusion, our finding suggests TLR4 agonist MPLA as a safe and effective radioprotector for clinical application.
Highlights
Acute high dose radiation exposure could result from multiple potential disaster scenarios, such as nuclear reactor meltdown, dirty bomb, or nuclear bomb explosion etc. [1]
In Human umbilical vein endothelial cells (HUVEC) and L02 cells, we found that Ionizing radiation LPS (IR) significantly induced apoptosis at 24h and G2/M cell cycle arrest at 12h (Figure 1A, 1B, 1C)
We found that monophosphoryl lipid A (MPLA) treatment significantly increased the level of myeloid differentiation factor 88 (MyD88) (Figure 2D, 2F)
Summary
Acute high dose radiation exposure could result from multiple potential disaster scenarios, such as nuclear reactor meltdown, dirty bomb, or nuclear bomb explosion etc. [1]. Acute high dose radiation exposure could result from multiple potential disaster scenarios, such as nuclear reactor meltdown, dirty bomb, or nuclear bomb explosion etc. Side effects on normal tissues caused by cancer radiotherapy are barriers to further application of higher doses of radiation. It is critical to prevent further injury and protect the rescuers by using radioprotectors before irradiation [2, 3]. The current radioprotectors mainly fall into two categories: immunomodulators / cytokines/growth factors; antioxidants/free radical scavengers [4]. The efficacy and toxicity of these agents limits further applications in radiation protection. It is urgently required to develop safe and effective radioprotectors to protect against radiation injury
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