Radiation Injury Research Articles

Tubarial Salivary Gland – The New Member of Nasopharynx

Tubarial Salivary Gland – The New Member of Nasopharynx

Genitourinary Radiation Injury Following Prostate Cancer Treatment: Assessment of Cost and Health Care System Burden

To evaluate the healthcare resource impact of radiation injury following prostate cancer treatment. Using IBM MarketScan, we performed a retrospective study of men with prostate cancer who were treated with radiotherapy and subsequently developed low-grade (LGRI) and high-grade radiation injury (HGRI). Radiation injury diagnoses includedbladder neck stenosis, hematuria/cystitis, fistula, ureteral stricture, and incontinence. LGRI and HGRI included injury diagnosis without intervention and with intervention, respectively. Health care visits and costs were measured over 5 time periods including2 years before radiation, 1 year before radiation, radiation to injury diagnosis, injury diagnosis to first intervention (LGRI), and following first intervention (HGRI). Negative binomial regression modeling was used to assess the effect of radiation injury on average cost adjusting for demographics and comorbidities. Between 2008 and 2017, we identified 121,027 men who received radiotherapy following prostate cancer diagnosis of which 10,057 (8.3%) experienced aHGRI. The frequency of urologic visits and average costs were similar in those without injury and LGRI. However, men with HGRI experienced higher visit frequency and monthly costs. Amongst high-grade injuries, urinary fistula had the highest frequency of visit utilization at 378 visits before first intervention and 245 visits after first intervention. Following radiation injury diagnosis, the average monthly cost was twice as high in those with HGRI ($85.78) compared to LGRI ($38.66). HGRI was associated with increased urologic health care use and average monthly cost when compared to those who experienced LGRI or no injury. Urinary fistula was associated with the largest resource burden.

Polydatin radiosensitizes lung cancer while preventing radiation injuries by modulating tumor-infiltrating B cells

BackgroundAcquired radio-resistance and the undesired normal tissue radiation injuries seriously discount the therapeutic effect of lung cancer radiotherapy. In this study, we aimed to explore the role and potential mechanism of polydatin in simultaneously decreasing radioresistance and radiation injuries.MethodsThe tumor-bearing model of nude mice was used to investigate the tumor inhibition of polydatin on lung cancer and its effect on radiosensitivity, and the effect of polydatin on B cell infiltration in cancerous tissue was investigated. In addition, we performed systemic radiotherapy on BABL/C mice and evaluated the protective effect of polydatin on radiation injury by the Kaplan–Meier survival curve. Moreover, the regulation of polydatin on proliferation and apoptosis of A549 cells was also investigated in vitro.ResultsIn this study, it is first found that polydatin inhibits the growth and promotes the radiosensitivity of lung cancer while reducing the radiation damage of the healthy tissue. Further, it is evidenced that the major mechanism relies on its regulation on body’s immune function, and in particular, the inhibition of radiation-induced B cell infiltration in tumor tissue.ConclusionThese findings show that in addition to tumor inhibition, polydatin also promotes the sensitivity and reduces the adverse reactions of radiotherapy, making itself a promising candidate for boosting lung cancer radiotherapy efficacy.

Radiotherapy upregulated immune checkpoints contribute to the development of second primary OSCC.

Radiation injury is common after radiotherapy for head and neck cancer. Radiotherapy can reshape the immune microenvironment and cause immunosuppression, including dysregulation of immune checkpoints (ICs). However, the relationship between oral ICs expression after radiation and the development of second primary tumors is unclear. Clinical specimens of second primary oral squamous cell carcinoma after radiotherapy (s-OSCC) and primary OSCC (p-OSCC) were collected. The expression and prognostic value of PD-1, VISTA, and TIM-3 were analyzed using immunohistochemistry. To further clarify the relationship between radiation and ICs alteration, a rat model was constructed to explore the spatiotemporal changes of ICs in the oral mucosa after radiation. In carcinoma tissue, the expression of TIM-3 was higher in s-OSCC than in p-OSCC, while the expression of PD-1 and VISTA was similar between the groups. In para-carcinoma tissue, the expression of PD-1, VISTA, and TIM-3 was higher in s-OSCC. High ICs expression was associated with poor survival. In the rat model, ICs were locally upregulated in the irradiated tongue. Moreover, there was a bystander effect, in which the ICs were also upregulated in the unirradiated site. Radiation may upregulate ICs expression in oral mucosa and contribute to the development of s-OSCC.

The regulation of expression and splicing of transcription factors are related to the muscle damage caused by radiation in tree shrews

Radiotherapy-induced muscle injury (RIMI) is a major complication of radiotherapy for nasopharyngeal carcinoma. Transcription factor (TF) expression and alternative splicing are crucial events in transcriptional and posttranscriptional regulation, respectively, and are known to be involved in key signaling pathways contributing to a variety of human disorders, including radiation injury. To investigate the TFs and alternative splicing events involved in RIMI, we constructed a tree shrew model as described previously in which the RIMI group received 20 Gy of irradiation on the tensor veli palatini (TVP) muscles. The irradiated muscles were evaluated by RNA sequencing (RNA-seq) 6 months later, and the results compared with those for normal TVP muscles. The alt5p and alt3p events were the two main types of differentially regulated alternative splicing events (RASEs) identified via the Splice sites Usage Variation Analysis (SUVA) software, and these RASEs were highly conserved in RIMI. According to functional enrichment analysis, the differentially RASEs were primarily enriched in pathways related to transcriptional regulation. Furthermore, we identified 16 alternative splicing TFs (ASTFs) in ASTF–differentially expressed gene (DEG) networks based on co-expression analysis, and the regulatory networks were chiefly enriched in pathways linked to cell proliferation and differentiation. This study revealed that RASEs and ASTF–DEG networks may both play important regulatory roles in gene expression network alteration in RIMI. Future studies on the targeting mechanisms and early interventions directed at RASEs and ASTF–DEG networks may aid in the treatment of RIMI.

Transcriptome profile changes in the jejunum of nonhuman primates exposed to supralethal dose of total- or partial-body radiation

The risk of exposure of the general public or military personnel to high levels of ionizing radiation from nuclear weapons or radiological accidents is a dire national security matter. The development of advanced molecular biodosimetry methods, those that measure biological response, such as transcriptomics, to screen large populations of radiation-exposed victims is key to improving survival outcomes during radiological mass casualty scenarios. In this study, nonhuman primates were exposed to either 12.0 Gy cobalt-60 gamma (total-body irradiation, TBI) or X-ray (partial-body irradiation, PBI) 24 h after administration of a potential radiation medical countermeasure, gamma-tocotrienol (GT3). Changes in the jejunal transcriptomic profiles in GT3-treated and irradiated animals were compared to healthy controls to assess the extent of radiation damage. No major effect of GT3 on radiation-induced transcriptome at this radiation dose was identified. About 80% of the pathways with a known activation or repression state were commonly observed between both exposures. Several common pathways activated due to irradiation include FAK signaling, CREB signaling in the neurons, phagosome formation, and G-protein coupled signaling pathway. Sex-specific differences associated with excessive mortality among irradiated females were identified in this study, including Estrogen receptor signaling. Differential pathway activation was also identified across PBI and TBI, pointing towards altered molecular response for different degrees of bone marrow sparing and radiation doses. This study provides insight into radiation-induced changes in jejunal transcriptional profiles, supporting the investigation for the identification of biomarkers for radiation injury and countermeasure efficacy.

Biological sex differences in renin angiotensin system enzymes ACE and ACE2 regulate normal tissue response to radiation injury.

Introduction: In experimental animal models, biological sex-differences in the manifestation and severity of normal tissue radiation injury have been well-documented. Previously we demonstrated male and female rats have differential and highly reproducible responses to high-dose partial body irradiation (PBI) with male rats having greater susceptibility to both gastrointestinal acute radiation syndrome (GI-ARS) and radiation pneumonitis than female rats. Methods: In the current study, we have investigated whether differential expression of the renin-angiotensin system (RAS) enzymes angiotensin converting enzyme (ACE) and ACE2 contribute to the observed sex-related differences in radiation response. Results: During the period of symptomatic pneumonitis, the relative ratio of ACE to ACE2 (ACE/ACE2) protein in the whole lung was significantly increased by radiation in male rats alone. Systemic treatment with small molecule ACE2 agonist diminazene aceturate (DIZE) increased lung ACE2 activity and reduced morbidity during radiation pneumonitis in both sexes. Notably DIZE treatment also abrogated morbidity in male rats during GI-ARS. We then evaluated the contribution of the irradiated bone marrow (BM) compartment on lung immune cell infiltration and ACE imbalance during pneumonitis. Transplantation of bone marrow from irradiated donors increased both ACE-expressing myeloid cell infiltration and immune ACE activity in the lung during pneumonitis compared to non-irradiated donors. Discussion: Together, these data demonstrate radiation induces a sex-dependent imbalance in the renin-angiotensin system enzymes ACE and ACE2. Additionally, these data suggest a role for ACE-expressing myeloid cells in the pathogenesis of radiation pneumonitis. Finally, the observed sex-differences underscore the need for consideration of sex as a biological variable in the development of medical countermeasures for radiation exposure.

Injectable multifunctional chitosan/dextran-based hydrogel accelerates wound healing in combined radiation and burn injury

Clinical wound management of combined radiation and burn injury (CRBI) remains a huge challenge due to serious injuries induced by redundant reactive oxygen species (ROS), the accompanying hematopoietic, immunologic suppression and stem cell reduction. Herein, the injectable multifunctional Schiff base cross-linked with gallic acid modified chitosan (CSGA)/oxidized dextran (ODex) hydrogels were rationally designed to accelerate wound healing through elimination of ROS in CRBI. CSGA/ODex hydrogels, fabricated by mixing solutions of CSGA and Odex, displayed good self-healing ability, excellent injectability, strong antioxidant activity, and favorable biocompatibility. More importantly, CSGA/ODex hydrogels exhibited excellent antibacterial properties, which is facilitated for wound healing. Furthermore, CSGA/ODex hydrogels significantly suppressed the oxidative damage of L929 cells in an H2O2-induced ROS microenvironment. The recovery of mice with CRBI in mice demonstrated that CSGA/ODex hydrogels significantly reduced the hyperplasia of epithelial cells and the expression of proinflammatory cytokine, and accelerated wound healing which was superior to the treatment with commercial triethanolamine ointment. In conclusion, the CSGA/ODex hydrogels as a wound dressing could accelerate the wound healing and tissue regeneration of CRBI, which provides great potential in clinical treatment of CRBI.

Resilience, aging, and response to radiation exposure (RARRE) in nonhuman primates: a resource review.

The Wake Forest nonhuman primate (NHP) Radiation Late Effects Cohort (RLEC) is a unique and irreplaceable population of aging NHP radiation survivors which serves the nation's need to understand the late effects of radiation exposure. Over the past 16years, Wake Forest has evaluated > 250 previously irradiated rhesus macaques (Macaca mulatta) that were exposed to single total body irradiation (IR) doses of 1.14-8.5Gy or to partial body exposures of up to 10Gy (5% bone marrow sparing) or 10.75Gy (whole thorax). Though primarily used to examine IR effects on disease-specific processes or to develop radiation countermeasures, this resource provides insights on resilience across physiologic systems and its relationship with biological aging. Exposure to IR has well documented deleterious effects on health, but the late effects of IR are highly variable. Some animals exhibit multimorbidity and accumulated health deficits, whereas others remain relatively resilient years after exposure to total body IR. This provides an opportunity to evaluate biological aging at the nexus of resilient/vulnerable responses to a stressor. Consideration of inter-individual differences in response to this stressor can inform individualized strategies to manage late effects of radiation exposure, and provide insight into mechanisms underlying systemic resilience and aging. The utility of this cohort for age-related research questions was summarized at the 2022 Trans-NIH Geroscience Interest Group's Workshop on Animal Models for Geroscience. We present a brief review of radiation injury and its relationship to aging and resilience in NHPs with a focus on the RLEC.

RBM47 regulates intestinal injury and tumorigenesis by modifying proliferation, oxidative response, and inflammatory pathways.

RNA-binding protein 47 (RBM47) is required for embryonic endoderm development, but a role in adult intestine is unknown. We studied intestine-specific Rbm47-knockout mice (Rbm47-IKO) following intestinal injury and made crosses into ApcMin/+ mice to examine alterations in intestinal proliferation, response to injury, and tumorigenesis. We also interrogated human colorectal polyps and colon carcinoma tissue. Rbm47-IKO mice exhibited increased proliferation and abnormal villus morphology and cellularity, with corresponding changes in Rbm47-IKO organoids. Rbm47-IKO mice adapted to radiation injury and were protected against chemical-induced colitis, with Rbm47-IKO intestine showing upregulation of antioxidant and Wnt signaling pathways as well as stem cell and developmental genes. Furthermore, Rbm47-IKO mice were protected against colitis-associated cancer. By contrast, aged Rbm47-IKO mice developed spontaneous polyposis, and Rbm47-IKO ApcMin/+ mice manifested an increased intestinal polyp burden. RBM47 mRNA was decreased in human colorectal cancer versus paired normal tissue, along with alternative splicing of tight junction protein 1 mRNA. Public databases revealed stage-specific reduction in RBM47 expression in colorectal cancer associated independently with decreased overall survival. These findings implicate RBM47 as a cell-intrinsic modifier of intestinal growth, inflammatory, and tumorigenic pathways.

Acute Radiation Exposure Increases Mortality to Traumatic Hemorrhage

It is anticipated that both ionizing radiation and traumatic injury may occur simultaneously in future terrorist attacks and battlefield scenarios. However, it is not known how radiation combined with injuries (RCI) will impact physiological compensatory responses to traumatic hemorrhage and survival. We hypothesized that the addition of radiation to our established traumatic hemorrhage model (Klemcke et al., J Appl Physiol 2021) would increase mortality. Male rats (n=6/group) were randomly assigned to 1 of 4 groups: sham (no injury; no radiation); radiation injury (RI) only; traumatic hemorrhage alone (CI); or RI combined with traumatic hemorrhage (RCI). For RI and RCI rats, whole-body irradiation was performed with a single, sub-lethal X-ray dose of 5.5 Gy delivered at 1 Gy/min (MultiRad 350). CI consisted of extremity trauma (fibular fracture + penetrating and soft tissue injury, performed under isoflurane anesthesia) followed by conscious hemorrhage of 37% of blood volume. Rats were monitored for 14 days following injury or sham procedures. Sham rats had 100% survival to Day 14, while RI and CI rats had 50% and 50% mortality, respectively, at this point. RCI rats, however, demonstrated 100% mortality at Day 14; differences in survival proportions were significant (P=0.005). We therefore developed a new rat model of RCI by combining X-ray irradiation with traumatic hemorrhage which allows acute (hours) as well as chronic (days) observations. While RI alone produced significant mortality, the addition of traumatic hemorrhage increased mortality to 100%. Future work will elucidate physiological mechanisms potentiating the lethal effect of either RI or CI alone. Biomedical Advanced Research and Development Authority (BARDA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ОСОБЕННОСТИ КЛИНИЧЕСКИХ ПРОЯВЛЕНИЙ ПЕРВИЧНОЙ РЕАКЦИИ ПРИ КОМБИНИРОВАННОМ РАДИАЦИОННОМ ПОРАЖЕНИИ (РАДИАЦИОННОЕ ВОЗДЕЙСТВИЕ И МЕХАНИЧЕСКАЯ ТРАВМА ГОЛОВЫ)

Purpose: To describe, on the basis of literature data, the features of the primary reaction of a person with a combined radiation injury – radiation exposure and mechanical head injury – in order to substantiate the possibility of using the symptoms of the primary reaction to predict the severity of acute radiation sickness (ARS). Material and methods: Analysis of literature data. Results: Based on the literature data, the clinical symptoms of the primary reaction in human radiation damage in a different dose range, and traumatic brain injuries are described: – concussion of the brain; – mild brain injury; – moderate brain injury. To characterize the clinical picture of the combined effects of radiation injury and mechanical head injury, the symptoms of the primary reaction were compared with the symptoms of traumatic brain injury. Such symptoms of the primary reaction as vomiting, nausea, headache, dizziness in the most severe form of traumatic brain injury – a moderate brain injury – are diagnosed somewhat more often than in acute radiation sickness. In less severe forms of traumatic brain injury – concussion, mild brain injury – the frequency and severity of these symptoms are close to ARS. In the complex clinical picture of combined radiation exposure and traumatic brain injury, the most different symptoms of the two components of combined radiation damage are the state of consciousness and the characteristics of the skin. Conclusion: Clinical symptoms of the primary reaction to radiation exposure in conditions of combined radiation damage in the presence of head trauma lose their diagnostic significance for the early prognosis of the severity of developing ARS. In the clinical picture of combined radiation exposure and mechanical head injury, the most pronounced leading components should be the state of consciousness and the characteristics of the skin.

Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling.

Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood. Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema. Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury. Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema.

Cholangioscopy-assisted extraction through novel papillary support for small-calibre and sediment-like common bile duct stones.

To date, endoscopic retrograde cholangiopancreatography has become a well-established treatment for common bile duct (CBD) stones. However, it is not suitable for some special patients, such as pregnant women, children or those who cannot stop taking anti-coagulation/anti-platelet agents because of radiation injury and the risk of postoperative bleeding resulting from endoscopic sphincterotomy. To overcome these two problems, this study introduced cholangioscopy-assisted extraction through a novel papillary support for small-calibre and sediment-like CBD stones. To assess the feasibility and safety of cholangioscopy-assisted extraction through a novel papillary support (CEPTS) for small-calibre and sediment-like common bile duct (CBD) stones. This Retrospective study was approved by the Ethics Committee of the Chinese PLA General Hospital. We designed a covered single dumbbell-style papillary support between 2021 and 2022. Between July 2022 and September 2022, 7 consecutive patients with small-calibre (cross diameter ≤ 1.0 cm) or sediment-like CBD stones underwent CETPS procedures in our center. The clinical characteristics and treatment outcomes of these 7 patients were extracted from a prospectively collected database. And the related data were analyzed. Informed consent was obtained from all participating patients. A total of 2 patients had yellow sediment-like CBD stones, and aspiration extraction was performed after the insertion of papillary support. Of the 5 patients with clumpy CBD stones (0.4-1.0 cm), 2 underwent basket extraction under direct vision for a single stone (0.5-1.0 cm, black and black grey), 1 underwent balloon plus aspiration extraction under direct vision for 5 stones (0.4-0.6 cm, brown), and 2 underwent aspiration extraction only for a single stone (0.5-0.6 cm, yellow, none). Technical success, namely, no residual stones in the CBD or left and right hepatic ducts, was achieved in all 7 cases (100%). The median operating time was 45.0 minutes (range 13.0-87.0 minutes). Postoperative pancreatitis (PEP) occurred in one case (14.3%). Hyperamylasaemia without abdominal pain was noted in 2 of 7 patients. No residual stones or cholangitis were found during the follow-up. CETPS appeared to be feasible to treat patients with small-calibre or sediment-like CBD stones. Patients, especially pregnant women and those who cannot stop anticoagulation/anti-platelet agents, could benefit from this technique.

An interactive murine single-cell atlas of the lung responses to radiation injury

Radiation Induced Lung Injury (RILI) is one of the main limiting factors of thorax irradiation, which can induce acute pneumonitis as well as pulmonary fibrosis, the latter being a life-threatening condition. The order of cellular and molecular events in the progression towards fibrosis is key to the physiopathogenesis of the disease, yet their coordination in space and time remains largely unexplored. Here, we present an interactive murine single cell atlas of the lung response to irradiation, generated from C57BL6/J female mice. This tool opens the door for exploration of the spatio-temporal dynamics of the mechanisms that lead to radiation-induced pulmonary fibrosis. It depicts with unprecedented detail cell type-specific radiation-induced responses associated with either lung regeneration or the failure thereof. A better understanding of the mechanisms leading to lung fibrosis will help finding new therapeutic options that could improve patients’ quality of life.

Early Post Radiation Neuropathy: Complex Pathogenesis Including Microvasculitis and Tumor Spread (P14-8.001)

<h3>Objective:</h3> To describe patients with early radiation-induced peripheral nerve injury and investigate potential pathogenic mechanism(s). <h3>Background:</h3> Radiation-induced neuropathy typically occurs up to decades after radiation from neural fibrosis with insidious, painless progressive weakness. Reports of early radiation-associated neuropathies are lacking. <h3>Design/Methods:</h3> Patient cases labeled as “radiation neuropathy” were electronically retrieved from our electromyography (EMG) and Mayo Data Explorer databases between January 2014 to August 2022. Inclusion criteria included neural deficits within 6 months of radiation, EMG testing, and available follow-up nerve imaging. <h3>Results:</h3> Twenty-two patients (9 female, mean age 63 years [range 34–84]) were identified with a history of squamous (n=6), prostate (n=5), breast (n=3), rectal (n=2), hematologic (n=2), and other (n=4) cancers. Average radiation dose was 4491 cGy (range 1000–7208). Time to symptom onset averaged 1.9 months (range 0–4). Pre-radiation chemotherapy occurred in most (n=16). All neuropathies occurred in the same radiation territory, but most neuropathies (n=17) occurred distal to the radiation site. EMG-confirmed neuropathies included radiculopathies (n=10), brachial and lumbosacral plexopathies (n=10), and mononeuropathies (n=2). EMG myokymia was seen in few (n=6). Patients reported primarily painful paresthesias (n=18) and weakness (n=18). Clinical courses were monophasic (n=8), progressive (n=8), static (n=2), and unclear without follow-up (n=4). Follow-up neural MRI did not suggest infiltrative disease (n=21), but based on tumor location and progressive course, microscopic infiltration was suspected. Two patients had nerve biopsies showing prominent inflammation around epineural microvessels with vessel wall injury (microvasculitis). One biopsy revealed neoplastic spread of rectal squamous cell cancer. Steroid burst therapy was attempted in 6 patients; 5 reported benefits, and 4 had monophasic courses. <h3>Conclusions:</h3> Early-onset post radiation neuropathies having pain and monophasic courses are supported by steroid response and biopsy-confirmed microvasculitis to have an inflammatory-immune mechanism. Exclusion of infiltrative cancer and an idiosyncratic radiation injury with progressive course are important to consider. <b>Disclosure:</b> Dr. Skolka has nothing to disclose. Dr. Uhm has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Zai Lab. Dr. Ma has nothing to disclose. Dr. Santilli has nothing to disclose. Mr. Meiling has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Staff has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Stem Cell Research &amp; Therapy. Dr. Pinto has nothing to disclose. Dr. Dyck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea/Ionis. Dr. Klein has a non-compensated relationship as a Klein with Neurology Journal that is relevant to AAN interests or activities.

Radiation upregulates macrophage TREM-1 expression to exacerbate injury in mice.

Exposure to high-dose ionizing radiation causes tissue injury, infections and even death due to immune dysfunction. The triggering receptor expressed on myeloid cells-1 (TREM-1) has been demonstrated to critically amplify and dysregulate immune responses. However, the role of TREM-1 in radiation injury remains unknown. Extracellular cold-inducible RNA-binding protein (eCIRP), a new damage-associated molecular pattern, is released from activated or stressed cells during inflammation. We hypothesized that ionizing radiation upregulates TREM-1 expression via eCIRP release to worsen survival. RAW264.7 cells and peritoneal macrophages collected from C57BL/6 wild-type (WT) mice were exposed to 5- and 10-Gray (Gy) radiation. C57BL/6 WT and CIRP-/- mice underwent 10-Gy total body irradiation (TBI). TREM-1 expression on RAW264.7 cells and peritoneal macrophages in vitro and in vivo were evaluated by flow cytometry. eCIRP levels in cell culture supernatants and in peritoneal lavage isolated from irradiated mice were evaluated by Western blotting. We also evaluated 30-day survival in C57BL/6 WT, CIRP-/- and TREM-1-/- mice after 6.5-Gy TBI. The surface protein and mRNA levels of TREM-1 in RAW264.7 cells were significantly increased at 24 h after 5- and 10-Gy radiation exposure. TREM-1 expression on peritoneal macrophages was significantly increased after radiation exposure in vitro and in vivo. eCIRP levels were significantly increased after radiation exposure in cell culture supernatants of peritoneal macrophages in vitro and in peritoneal lavage in vivo. Moreover, CIRP-/- mice exhibited increased survival after 6.5-Gy TBI compared to WT mice. Interestingly, TREM-1 expression on peritoneal macrophages in CIRP-/- mice was significantly decreased compared to that in WT mice at 24 h after 10-Gy TBI. Furthermore, 30-day survival in TREM-1-/- mice was significantly increased to 64% compared to 20% in WT mice after 6.5-Gy TBI. Our data indicate that ionizing radiation increases TREM-1 expression in macrophages via the release of eCIRP, and TREM-1 contributes to worse survival after total body irradiation. Thus, targeting TREM-1 could have the potential to be developed as a novel medical countermeasure for radiation injury.

Indole-3-carboxaldehyde ameliorates ionizing radiation-induced hematopoietic injury by enhancing hematopoietic stem and progenitor cell quiescence.

Indole-3-carboxaldehyde (I3A), one of tryptophan metabolites derived from gut microbiota, extends the lifespan of mice after high-dose ionizing radiation exposure. Persistent myelosuppression is the most common and fatal complication for victims of nuclear accidents and patients undergoing radiotherapy, with few therapeutic options available. However, whether and how I3A protects ionizing radiation-induced hematopoietic toxicity remain unknown. In this study, we demonstrated that I3A treatment effectively ameliorated radiation-induced hematopoietic injury through accelerating peripheral blood cells recovery, promoting bone marrow cellularity restoration and enhancing functional HSPC regeneration. Additionally, I3A also suppressed intracellular reactive oxygen species production and inhibited apoptosis in irradiated HSPCs. Mechanistically, I3A treatment significantly increased HSPC quiescence, thus conferring HSPCs with resistance against radiation injury. Finally, I3A treatment could improve survival of lethally irradiated mice. Taken together, our data suggest that I3A acts as a gut microbiota-derived paracrine factor that regulates HSPC regeneration and may serve as a promising therapeutic agent for ionizing radiation-induced myelosuppression.

Radiation Injury Therapy with Transdermal Deferoxamine Patch is Dose Dependent

Abbas, Darren MD; Griffin, Michelle; Lavin, Christopher V MS; Fahy, Evan J MB, Bch, BAO, MCh; Lintel, Hendrik BS; Guardino, Nicholas J BS; Guo, Jason L; Longaker, Michael T MD, MBA, FACS; Wan, Derrick C MD, FACS Author Information

Radiation Injury Genetically Alters Fibroblast Subpopulations to Induce Fibrosis

Abbas, Darren MD; Griffin, Michelle; Guo, Jason L; Lavin, Christopher V MS; Fahy, Evan J MB, Bch, BAO, MCh; Guardino, Nicholas J BS; Lintel, Hendrik BS; Januszyk, Michael; Longaker, Michael T MD, MBA, FACS; Wan, Derrick C MD, FACS Author Information