After the bomb drops: a new look at radiation-induced multiple organ dysfunction syndrome (MODS)

Abstract

Purpose: There is increasing concern that, since the Cold War era, there has been little progress regarding the availability of medical countermeasures in the event of either a radiological or nuclear incident. Fortunately, since much is known about the acute consequences that are likely to be experienced by an exposed population, the probability of survival from the immediate hematological crises after total body irradiation (TBI) has improved in recent years. Therefore focus has begun to shift towards later down-stream effects, seen in such organs as the gastrointestinal tract (GI), skin, and lung. However, the mechanisms underlying therapy-related normal tissue late effects, resulting from localised irradiation, have remained somewhat elusive and even less is known about the development of the delayed syndrome seen in the context of whole body exposures, when it is likely that systemic perturbations may alter tissue microenvironments and homeostasis.

Conclusions: The sequence of organ failures observed after near-lethal TBI doses are similar in many ways to that of multiple organ dysfunction syndrome (MODS), leading to multiple organ failure (MOF). In this review, we compare the mechanistic pathways that underlie both MODS and delayed normal tissue effects since these may impact on strategies to identify radiation countermeasures.

Figure 1

Stylised overview of the proposed mechanisms leading to radiation-induced multiple organ dysfunction syndrome (RI-MODS) or RI-multiple organ failure (MOF) following total body irradiation. We have hypothesised that the initiation and development of RI-MODS and RI-MOF involves three inter-connected pathways, all of which have their roots in fundamental radiobiological principles: Pathway 1 identifies the inter-relationship between radiation-induced alterations in both localised and systemic inflammatory and immune status, and the potential role played by chronic reactive oxygen species (ROS) production in these changes; Pathway 2 suggests a greater, more integrative role may be played in the development of delayed radiation effects by the disruption in barrier integrity, particularly at the vascular level, including the blood-brain barrier (BBB); Pathway 3 highlights the tissue deficit that may occur due to stem/progenitor cell loss. Without mitigation, the outcome for any single survivor of the acute radiation syndrome will be the result of the severity and deficits experienced in any or all of these related pathways.