Report on “Radiation Disaster Recovery Studies”
Course: Radiation Disaster Medicine
Name: Ho Minh Van

1. Regarding “Radiation Disaster Recovery Studies”(Describe your thoughts, the process you engaged in and your research progress regarding
Recovery from Radiation Disaster.)On outline of radiation disaster, Japan is the only country in the world experienced
with two radiation disasters (atomic bomb in 1945 and nuclear power plant accident in2011). For 7 years pasted from triple disaster in Fukushima, Japan still face with complex
scenarios on the way of recovery from radiation disaster. From the level of government tolocalized citizen, many efforts put on renaissance at Fukushima were done with hope tobuild up new life at exposure areas. In fact, many projects as such environmental cleaning,
health surveys, and social troubleshooting were going and achieved successful effectives
on soil decontamination, continuity health management, encourage people returning home,etc. However, recently remaining many social issues with anxiety, post-traumatic stressdisorder (PTSD) (Maeda and Oe 2017), discrimination, unbalance population due todifficult-to-return (Hasegawa et al. 2016), etc., that require actions of Japanese experts andinternational roles in process of resilience from radiation disaster at Fukushima (Tanigawa
et al. 2017).
Evacuees were living in temporary house or moved-place for a long time, they havebuilt a new life with job, education, etc., hence refused to return for building life again.
Moreover, lacking job opportunity at return-zone blocks the back of young citizen.
Consequently, leading to unbalance population structure and more overs. On the other hand,people do have high level of worries about healthy as cancer developments or any
radiation-associated disorders. Regarding on those concerns, Fukushima Health Survey
Project (Yasumura and Abe 2017) has conducted right after the disaster. Its goals were tomanage population health in term of general exam (physical and labs exam) for all citizen
at the contaminated zone. This project has contributed low level of radiation-based
evidences of health troubles. The data was open to public, as well as citizen via home visit.
Pooling with this trend, we are now looking for biomarkers, that support to detect thesuppression of immune system in radiation-exposure people.
The study considers on early detection of the paths, that radiation directs immune
disorders. Radiation victims might category into two groups as moderate and over1

exposure to radiation (in cases of radiation accident) and mild exposure to radiation(experienced with radiation at low dose). For moderate and over exposure patients, thedisease profiles character with multiple organ dysfunction, infection, and death. Typically,
sepsis with immunoparalysis is the common scenario of patient upon severe radiation
exposure. This scenario is a complicated medical trouble with many co-mortality factors
and poorly outcomes. However, the understanding of how immune system tolerated with
infection under irradiation remain unclear. Otherwise, mild exposure or lightly experienced
to radiation in environment (low dose exposure), the long-term effects and bio predictors
are currently medical issues. Among these, biomarkers derived by radiation, that canpredict the early development of immune disorders are placed on hot topics ofradiation-related research. In this threshold, our research conducts on relationship of innate
immune responses to danger-associated molecular patterns (DAMPs), that were releasedby cell deaths upon irradiation to human serum. We expect that the DAMPs activities inserum might reveal evidence of immune disorder development upon irradiation.
Our project planned as two steps such 1) attempting to assess the responses of innate
immune cells to DAMPs activities in serum from common clinical settings (healthy,trauma, and sepsis) with expectation of identifying the comparable baseline of thosepatient profiles; 2) attempting to assess the responses of innate immune cells to serum fromradiation victims with expectation of finding valuable biomarker of radiation-associateddisorder. At the time, we are anchored on the first step of plan. Further research related toradiation victims is required.
References:
Hasegawa, A., Ohira, T., Maeda, M., Yasumura, S. &Tanigawa, K. (2016) Emergency
Responses and Health Consequences after the Fukushima Accident; Evacuationand Relocation. Clinical Oncology. 28, 237-244.
Maeda, M. &Oe, M. (2017) Mental Health Consequences and Social Issues After theFukushima Disaster. Asia Pacific Journal of Public Health. 29, 36S-46S.
Tanigawa, K., Lochard, J., Abdel-Wahab, M. &Crick, M.J. (2017) Roles and Activitiesof International Organizations After the Fukushima Accident. Asia Pacific Journalof Public Health. 29, 90S-98S.
Yasumura, S. &Abe, M. (2017) Fukushima Health Management Survey and RelatedIssues. Asia Pacific Journal of Public Health. 29, 29S-35S.
2. Title of doctoral thesis
Sera from Septic Patients Contain the Inhibiting Activity of the Extracellular
ATP-Dependent Inflammasome Pathway(敗血症患者の血清には細胞外 ATP 依存性インフラマソーム経路の活性抑制物質が含まれる）
2

3. Summary of doctoral thesis(Describe so as to be easily understood, by relating it to “Radiation Disaster RecoveryStudies”)
Sepsis, a systemic inflammatory response to infection, causes multi-organ failure,severe morbidity, and death; endothelial dysfunction, metabolic changes, andoverwhelming or hyperinflammatory innate immune responses to pathogen-associatedmolecular patterns have been proposed to be the main underlying mechanisms of thiscondition. Sepsis-induced immunoparalysis, in which both innate and adaptive immunity
are suppressed, is also an active focus of research.
Inflammatory responses mediated by innate immunity generally promote healing andmicrobial clearance, although the massive production of pro- and anti-inflammatory
cytokines by macrophages might also lead to pathological inflammation. Primary
inflammatory cytokines include tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6,
which mediate acute inflammation but also cause cell injury and cell death. In turn, injured
tissues and dying cells generate damage-associated molecular patterns (DAMPs), whichfurther engage various inflammasomes to promote or suppress inflammation. Although theunderlying mechanisms are unknown, damage-associated molecular pattern molecules(DAMPs) from septic tissues might be involved. DAMPs stimulate nucleotide
oligomerization domain-like receptor (NLR) inflammasomes to activate caspase-1, whichthen cleaves pro-IL-1β to generate mature, bioactive IL-1β. One such NLRP3
inflammasome is particularly sensitive to a wide variety of DAMPs including adenosine
triphosphate (ATP), crystalline substances, nucleic acids, and hyaluronan. In this study, wescreened sera from septic patients for the ability to alter innate immune responses toDAMPs and inflammasomes, with the goal of defining mechanisms that drive
immunoparalysis during sepsis.
Macrophages derived from THP-1 human acute monocytic leukemia cells are one of
key points in innate immune response. THP-1-mediated macrophages were incubated witheach DAMP, in the presence or absence of sera that were collected from critically illpatients. Sera from critically-ill patients diagnosed with sepsis or trauma were collected at
the time of admission to Emergency and Critical Care Center. Secreted cytokines insupernatant were then quantified, and treated-cell lysates were assayed for relevant
intracellular signaling mediators.
The results indicated that sera collected from septic patients at the time of admission
tended to suppress the in vitro production of IL-1β by macrophages; however, sera fromtrauma patients or healthy volunteers did not. This result suggests that septic sera, collected
at the time of patient admission, are likely predominantly anti-inflammatory, despiteenhanced levels of both pro- and anti-inflammatory cytokines. Strikingly, sera from septicpatients who ultimately did not survive significantly suppressed IL-1β production in3

response to extracellular adenosine triphosphate (ATP) only. This effect was mostpronounced with sera collected on day 3, and persisted with sera collected on day 7.
However, this effect was not observed when THP-1 macrophages were treated with serafrom survivors of sepsis. Therefore, we hypothesize that sera from septic patients haveinherent anti-inflammatory functions and might contain factor(s) that suppress the response
to extracellular ATP by possibly mechanisms as ATP hydrolysis by ATPases in sera fromseptic patients, inhibition of P2X7, or inhibition of NLRP3 inflammasome.
The further experiments were setting up for identifying mechanisms of the observed
loss of ATP-induced IL-1β production. The results suggest that ATPase activity in serafrom septic patients is negligible, and septic sera from non-survivors enhance P2X7activity. Then cell lysates were subjected to the detection of cytosolic mediators associatedwith the ATP-dependent inflammasome pathway. Results shown that septic sera collected
at the time of admission (day 1) also diminished intracellular levels of inositol
1,4,5-triphosphate and cytosolic calcium (P < 0.01), both of which are essential for ATPsignaling. Finally, activated caspase-1 was significantly diminished in cells exposed to sera
collected on day 7 (P < 0.05). Taken together, these data suggest that activation of NLRP3and caspase-1 in response to extracellular ATP is suppressed by factors that are present insera from septic patients. This suppressive effect is clearly associated with prolonged
immunoparalysis and poor clinical outcomes since it was found to be more pronounced insera collected from patients who did not survive.
Our data indicated that sera from septic patients suppress IL-1β production in
macrophages stimulated with extracellular ATP, likely by antagonizing upstream NLRP3 orpro-inflammatory pathways. This suppressive effect peaked on day 3 after admission andpersisted until day 7 among patients who did not survive, but was lost by day 7 among
patients who survived. These observations suggest a new mechanism through which sepsis
mediates immunoparalysis, and partially support the prior hypothesis that persistent
suppression of innate and adaptive immunity can cause late-stage death in septic patients.
In conclusion, factors present in the sera of septic patients that persistently suppress theimmune response to extracellular ATP might trigger adverse clinical outcomes.
4. Other thesis published in academic research journals
 Title of thesis: Memorable experiences of U.S long-term internship, supported by
Phoenix Leader Education Program Joint authors: Van Minh Ho, Akira Nishisaki, Nobuyuki Hirohashi, Nobuaki Shime Journal: Anaesthesia and Resuscitation, 53(4):81-84 · March 20184