Radiation: a poly-traumatic hit leading to multi-organ injury

Abstract

The range of radiation threats we face today includes everything from individual radiation exposures to mass casualties resulting from a terrorist incident, and many of these exposure scenarios include the likelihood of additional traumatic injury as well. Radiation injury is defined as an ionizing radiation exposure inducing a series of organ injury within a specified time. Severity of organ injury depends on the radiation dose and the duration of radiation exposure. Organs and cells with high sensitivity to radiation injury are the skin, the hematopoietic system, the gastrointestinal (GI) tract, spermatogenic cells, and the vascular system. In general, acute radiation syndrome (ARS) includes DNA double strand breaks (DSB), hematopoietic syndrome (bone marrow cells and circulatory cells depletion), cutaneous injury, GI death, brain hemorrhage, and splenomegaly within 30 days after radiation exposure. Radiation injury sensitizes target organs and cells resulting in ARS. Among its many effects on tissue integrity at various levels, radiation exposure results in activation of the iNOS/NF-kB/NF-IL6 and p53/Bax pathways; and increases DNA single and double strand breaks, TLR signaling, cytokine concentrations, bacterial infection, cytochrome c release from mitochondria to cytoplasm, and possible PARP-dependent NAD and ATP-pool depletion. These alterations lead to apoptosis and autophagy and, as a result, increased mortality. In this review, we summarize what is known about how radiation exposure leads to the radiation response with time. We also describe current and prospective countermeasures relevant to the treatment and prevention of radiation injury.

Keywords: AKT; Acute GI death; Acute hematopoietic syndrome; Apoptosis; Autophagy; Brain injury; DNA damage; Free radical; Hemorrhage; MAPK; NF-IL6; NF-kB; PARP; Radiation injury; STAT3; iNOS.

Fig. 1

Simplified representation of the DNA-damage-induced checkpoint response. Ionizing radiation induces DNA breaks. After the detection of a given damage by sensor proteins, this signal is transduced to the effector protein CHK2 via the transducer protein ATM. This ATM activation induces γ-H2AX formation, used as a biomarker for DNA breaks. Depending on the phase of the cell cycle the cell is in, this can lead to activation of p53 and inactivation of CDC25, which eventually leads to cell cycle arrest. Mediator proteins mostly are cell cycle specific and associate with damage sensors, signal transducers, or effectors at particular phases of the cell cycle and, thus, help provide signal transduction specificity. The effect of UV light is via the transducer protein ATR and the effector protein CHK1. MRE11 meiotic recombination 11, NBS1 Nijmegen breakage syndrome 1, ATM ataxia telangiectasia mutated, ATR ataxia telangiectasia related, γ-H2AX phosphorylated form of Histone variant 2AX, MDC1 mediator of DNA damage checkpoint 1, 63BP p63 binding protein, BRCA1 breast cancer 1, TopBP1 topoisomerase binding protein 1, CHK1 check 1, CHK2 check 2, CDC25 cell division cycle 25, G1 gap 1, S synthesis, G2 gap 2, M mitosis

Fig. 2

RI and CI alter molecular mechanisms determining survival. RI and CI activate 4 signal transduction pathways. 1. RI and CI activate NF-κB. NF- κB binds onto 10 motif sites on the promoter region of iNOS gene to transcribe and translate iNOS protein. This protein catalyzes NO production so as to produce high levels of peroxynitrite, a free radical to nitrate other proteins. The free radical stimulates NF-κB that increases circulating cytokine/chemokine concentration and vice versa. As a result, cell death occurs. 2. RI and CI activate MAPK that is known anti-survival. 3. RI and CI decrease NRF1 and NRF2 so that B-ATP synthase, cytochrome c and cytochrome c oxidase IV are reduced. Then, ATP production is reduced, and cell death occurs. 4. RI and CI increase miR-34a that is evident to activate NF- κB. RI radiation injury, CI combined injury, MAPK mitogen-activated protein kinase, NF-κB nuclear factor-keppaB, Foxo3 forkhead box O3, PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha, NRF nuclear respiratory factor, iNOS inducible nitric oxide, ROS reactive oxygen species, RNS reactive nitrogen species, IL interleukin, TNF tumor necrosis factor

Fig. 3

Simple representation of the multi-organ dysfunction and multi-organ failure and resultant mortality. LET linear energy transfer, MOD multi-organ dysfunction, MOF multi-organ failure

Fig. 4

Radiation and combined injury attenuate the normal defenses. Various interventions to treat radiation and combined injury may be used alone or in combination to improve the chance of survival in severely injured patients