Future space missions will involve extended time outside the Earth’s gravitational field with the loss of its protection from galactic cosmic rays and solar radiation. In addition to the factors that influence immune function that are associated with space exploration circling the Earth, including reduced weight bearing (1
), stress (2
), disturbance of circadian rhythms (5
), and altered nutritional intake (6
), the effect of radiation from SPEs must also be considered. Astronauts could receive up to 2 Gy to the bone marrow from an SPE (22
). This dose of proton radiation delivered at an energy and dose rate possible during an SPE results in a transient increase in the release of LPS into the circulation and potentially pathological changes to the GI tract. In our experiments, the increases in LPS were small, less than twofold, but were statistically significant. An increase in the acute-phase reactant LPS binding protein, which is required for LPS signaling, was also observed, as was a transient elevation in sCD14. Immunohistological analysis of GI tract tissue demonstrated occasional disruptions in the epithelial cell barrier as measured by a loss in tight junctions. Finally, the serum proinflammatory cytokines TNF-α, IL-1β and IL-6 increased 1 day after irradiation, demonstrating systemic activation of the innate immune system.
The expression of proinflammatory cytokines induced by translocation of bacterial products across the GI tract can have multiple effects on immune function. The induction of inflammatory cytokines occurs in a finely tuned time-dependent equilibrium. They can have multiple and opposite effects in the same subject depending on the time of expression. The aberrant expression of proinflammatory cytokines can result in unusual and unwanted regulation of an immune response [reviewed in ref. (32
)]. In an astronaut exposed to an SPE with resulting release of proinflammatory cytokines, exposure to a pathogenic insult could result in an altered immune response, resulting in incomplete protection from infection or immunopathology from an exaggerated response.
Previous studies of the effect of radiation on the immune system in space-flight models documented changes in cell numbers in immune organs and alterations of function based on in vitro
), which included alterations in T, B and NK cell numbers in blood and spleen (33
) and suppression of T-cell responses to mitogens (35
). These studies give important information on radiation-induced immune function alterations but do not investigate or identify important in vivo
interactions and mechanisms that could be responsible for the immune alterations measured in vitro
or that could predict potential pathological sequelae. Elevations in circulating LPS with associated immune activation are found in HIV infection, Crohn’s disease, systemic inflammatory response syndrome, and acute pancreatitis, all of which are associated with immune suppression, and the level of bacterial translocation is correlated with the amount of immune suppression (37
). The observation of defects in tight junctions and epithelial cell integrity in the GI tract may be the mechanism of increased translocation, as has been suggested in HIV infection (31
GI tract flora also affects the immune system in the gut. The first introduction of gut microbiota to an animal raised under axenic conditions results in a transient proinflammatory response that is replaced by an anti-inflammatory response by 7 days and is associated with inflammatory mononuclear cell infiltrates into the lamina propria (38
). Effects of gut microbiota and the amount of LPS in the diet also affect the acquired immune response in the gut and draining lymphoid organs (39
). We do not believe that the gut microbiota of SPF mice compared to feral mice would alter the responses to radiation we observed. Commensal bacteria have also been demonstrated to protect the GI tract from radiation-induced damage [reviewed in ref. (40
The consequences of radiation-induced damage to the GI tract are also relevant in clinical settings. One example is the GI tract injury that occurs in some cancer patients undergoing radiotherapy. Interactions between enteric microbes and the innate immune system have the potential to modulate the intestinal response to radiation, e.g., apoptosis and crypt survival (40
). In murine models of bone marrow transplantation, increased translocation of LPS into the circulation and the dysregulation of inflammatory cytokine production have been shown to reciprocally increase GI damage (41
). A study in which 5 Gy of total-body radiation of unspecified type and energy was delivered found a 10-fold increase in serum LPS with resulting activation of the innate immune system that led to an improvement in the function of adoptively transferred CD8+
T cells (42
). These and other similar findings have led to the search for countermeasures, including innate immune system modulators, with potential to minimize deleterious effects (40
The data presented in this study demonstrate that proton and reference γ radiation, whether delivered at dose rates expected during an SPE or 60 times higher, led to transient increases in bacterial translocation and immune activation. An impairment in the ability of the GI tract to exclude bacterial products and the resultant systemic activation of the immune system could have significant implications for astronaut safety during an extended mission in which an SPE occurred. Although the amount of bacterial translocation and immune activation observed likely would not lead directly to infectious complications, and we did not find replication-competent bacteria in the blood of irradiated animals; the addition of other immune alterations caused by microgravity, stress, circadian rhythm alterations, and nutrition or effects on other organ systems, including the immune system, caused by SPE radiation could lead to more pronounced effects. Immune activation also impairs immune function, adding an additional decrement in function. Further studies to determine the effect and possible synergy of additional space-flight factors, particularly simulated hypogravity, on immune function are needed.