Glial cell response to constant low light exposure in rat retina.

To study the macroglia and microglia and the immune role in long-time light exposure in rat eyes, we performed glial cell characterization along the time-course of retinal degeneration induced by chronic exposure to low-intensity light. Animals were exposed to light for periods of 2, 4, 6, or 8 days, and the retinal glial response was evaluated by immunohistochemistry, western blot and real-time reverse transcription polymerase chain reaction. Retinal cells presented an increased expression of the macroglia marker GFAP, as well as increased mRNA levels of microglia markers Iba1 and CD68 after 6 days. Also, at this time-point, we found a higher number of Iba1-positive cells in the outer nuclear layer area; moreover, these cells showed the characteristic activated-microglia morphology. The expression levels of immune mediators TNF, IL-6, and chemokines CX3CR1 and CCL2 were also significantly increased after 6 days. All the events of glial activation occurred after 5-6 days of constant light exposure, when the number of photoreceptor cells has already decreased significantly. Herein, we demonstrated that glial and immune activation are secondary to neurodegeneration; in this scenario, our results suggest that photoreceptor death is an early event that occurs independently of glial-derived immune responses.

Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.

Radiation is associated with tissue damage and increased risk of atherosclerosis, but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known proresolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-ß-gal, COX-2, several proinflammatory cytokines/chemokines, and oxidative stress (OS) in vitro, and when transferred to mice, they exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis, and treatment with RvD1 reduced OS and improved efferocytosis. Sublethally irradiated Ldlr -/- mice exhibited increased plaque necrosis, p16INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque-resolving mediators. Our results demonstrate that sublethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling.

Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra-/- mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra-/- mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

EXPRESSION OF LIPOPROTEIN LIPASE AND c-MYC ONCOGENE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AFFECTED BY THE CHORNOBYL ACCIDENT. / EKSPRESIIa GENA LIPOPROTEÏNLIPAZY I ONKOGENA c-MYC U KhVORYKh NA KhRONIChNU LIMFOTsYTARNU LEIKEMIIu, IaKI POSTRAZhDALY VNASLIDOK AVARIÏ NA ChORNOBYL'S'KII AES.

OBJECTIVE: to determine the association between the expression of lipoprotein lipase (LPL) and c-MYC genes inperipheral blood cells of chronic lymphocytic leukemia (CLL) patients affected by the Chornobyl catastrophedepending on the mutational status of IGHV genes. METHODS: Analysis was performed in the group of 69 CLL patients irradiated due to the Chornobyl NPP accident (58clean-up workers of 1986 year, 6 inhabitants of radionuclide contaminated areas, and 5 evacuees). The IGHV genemutational status was studied by polymerase chain reaction (PCR) followed by direct sequencing. LPL and c-MYCexpression was evaluated by Quantitative Real-time PCR. Data were analyzed with the SPSS software package, version 20.0. RESULTS: Relative LPL expression levels in CLL samples ranged from 0 to 1663.5 (mean 138.47 ± 30.69, median 26.1).A strong correlation between individual LPL expression levels and IGHV mutational status was found (r = 0.684;p < 0.0001). The average relative c-MYC expression level was 5.7 ± 0.87 (median 2.86; range 0-48.5). No association between c-MYC expression and IGHV mutational status was found. Among unmutated IGHV cases, a correlationbetween LPL and c-MYC gene expression levels was identified: r = 0.351; p = 0.013. CONCLUSIONS: Our data confirm the dominant concept that unmutated IGHV CLL cases are more sensitive to the actionof proliferative stimuli compared to mutated IGHV CLL cases. This is manifested by an increase in the expression ofa functionally significant LPL gene, is one for the strongest negative prognostic markers in CLL.

Evaluation of cytokine expression and circulating immune cell subsets as potential parameters of acute radiation toxicity in prostate cancer patients.

One of the challenges of radiation oncology in the era of personalized medicine is identification of biomarkers associated with individual radiosensitivity. The aim of research was to evaluate the possible clinical value of the associations between clinical, physical, and biological factors, and risk for development of acute radiotoxicity in patients with prostate cancer. The study involved forty four patients treated with three-dimensional conformal radiotherapy. The concentrations of IL-1ß, IL-2, IL-6, IFN-γ and TGF-ß1 were assessed before radiotherapy, after 5th, 15th and 25th radiotherapy fractions, at the end, and 1 month after the end of radiotherapy. Cytokine gene expression was determined in peripheral blood mononuclear cells. The univariate analysis of circulating cytokine levels during radiotherapy showed that increased serum concentrations of IL-6 were significantly associated with higher grade of acute genitourinary toxicity. The multivariate analysis demonstrated that increased level of IL-6 during the radiotherapy was significantly associated with higher grade of acute genitourinary toxicity across treatment. TGF-ß expression levels significantly decreased during course of radiotherapy. Research indicates that changes in circulating cytokine levels might be important parameter of radiotoxicity in patients with prostate cancer. These findings suggest that future studies based on multi-parameter examination are necessary for prediction of individual radiosensitivity.

Patients with radiation enteritis present regulatory T cell impairment associated with CTLA-4.

Radiation enteritis is one of the most common side effects of ionizing radiation in patients with pelvic cancers. Increasing amounts of evidence indicate that pro-inflammatory responses significantly contribute to the development of radiation enteritis. In this study, we investigated the association between T regulatory (Treg) cells and the risk of developing radiation enteritis in cervical cancer patients. The following observations were made. First, the frequencies of CD25hiFoxp3+ Treg cells were significantly lower in patients with radiation enteritis than in both healthy subjects and cervical cancer patients without radiation enteritis. Also, patients with the more severe grade 3 enteritis presented significantly lower Treg levels than patients with the more common grade 1 enteritis. Second, the expression of several molecules associated with Treg function, including CTLA-4, IL-10, TGF-ß, and perforin, was significantly lower in patients with radiation enteritis than in healthy subjects. In patients without radiation enteritis, however, only CTLA-4, but not other Treg-associated suppressive molecules, was reduced in Treg cells. Third, Treg cells can markedly suppress CD8 T cell proliferation, but in patients with radiation enteritis, this function of Treg cells was significantly impaired, in a manner that was associated with lower CTLA-4 expression. Overall, these data suggest that the frequency and function of Treg cells is negatively associated with the risk of developing enteritis following radiation. In clinical practice, the characteristics of Treg cells may be considered to evaluate the risk of developing enteritis if the cancer patient is receiving ionizing radiation.

Human CCR6+ Th17 Lymphocytes Are Highly Sensitive to Radiation-Induced Senescence and Are a Potential Target for Prevention of Radiation-Induced Toxicity.

PURPOSE: This study addresses the sensitivity of different peripheral CD4+ T-lymphocyte subsets to irradiation (IR) and identifies potential targets for the prevention or treatment of radiation-induced toxicity. METHODS: This study was performed on peripheral blood mononuclear cells or sorted peripheral memory lymphocytes of CCR6+ mucosa-homing Th17/CCR6negTh and regulatory T subtypes of healthy volunteers. Cells were irradiated with a 2 Gy with or without pharmacologic inhibitors of different signaling pathways. Senescence of irradiated cells was assessed by resistance to apoptosis and determination of various senescence-associated biomarkers (senescence associated b-galactosidase activity, p16Ink4a-, p21Cdkn1a-, gH2A.X-, H2A.J expression). Cytokine production was measured in supernatants of irradiated cells by Luminex technology. RESULTS: Not all CD4+ memory T lymphocyte subsets were equally radiosensitive. High sensitivity of CCR6+Th17 lymphocytes to IR-induced senescence was shown by expression of the histone variant H2A.J, higher SA-b-Gal activity, and upregulation of p16Ink4a and p21Cdkn1a expression. Lower Annexin V staining and cleaved caspase-3, and higher expression of antiapoptotic genes Bcl-2 and Bcl-xL LF, showed that CCR6+Th17 lymphocytes were more resistant to IR-induced apoptosis than CCR6neg memory Th and regulatory T lymphocytes. After a 2 Gy IR, both CCR6+Th17 and CCR6neg cells acquired a moderate senescence-associated secretory phenotype, but only CCR6+Th17 cells secreted interleukin 8 (IL-8) and vascular endothelial growth factor-A (VEGF-A). Pharmacologic targeting of reactive oxygen species (ROS), mitogen-activated protein kinases (MAPKs), and mammalian target of rapamycin (mTOR) signaling pathways prevented the expression of senescent markers and IL-8 and VEGF-A expression by CCR6+Th17 cells after IR. CONCLUSIONS: This study suggests that IR induces senescence of CCR6+Th17 lymphocytes associated with secretion of IL-8 and VEGF-A that may be detrimental to the irradiated tissue. ROS-MAPKs signaling pathways are candidate targets to prevent this CCR6+Th17-dependent radiation-induced potential toxicity. Finally, the ratio of circulating H2A.J+ senescent CCR6+ Th17/CD4+ T lymphocytes may be a candidate marker of individual intrinsic radiosensitivity.

Search and Selection of Probiotics That Improve Mucositis Symptoms in Oncologic Patients. A Systematic Review.

Mucositis is a common and severe adverse effect of radiotherapy and/or chemotherapy treatments applied to oncologic patients. The development of effective therapies and adjuvant treatments to increase their efficacy and reduce adverse effect is a priority in cancer therapy. Probiotics are non-pathogenic live microorganisms that when ingested in adequate amounts can colonize the intestinal tract promoting the restoration of a healthy gut microbiota and contributing to all its functions including the maintenance of the integrity of the mucosa and the modulation of the immune system. In order to check the possible efficacy and safety of these microorganisms to prevent or ameliorate mucositis' symptoms, we have systematically searched the bibliographic databases MEDLINE (via Pubmed), EMBASE, The Cochrane library, Scopus, Web of science, and Latin American and Caribbean Literature in Health of Sciences (LILACS) using the descriptors "Mucositis", "Probiotics", "Neoplasms", "Humans", and "Clinical Trials". After applying our inclusion and exclusion criteria, 15 studies were accepted for review and critical analysis. Our analysis suggests that a combination of Bifidobacterium longum, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium infantis, and Saccharomyces boulardii could be a good combination of probiotics to reduce incident rates of mucositis or ameliorate its symptoms in chemo or radiotherapy treated patients.

Indicators of immunological and hormonal research in patients with non-hospital pneumonia-liquidators of the Chernobyl accident after treatment.

AIM: The aim of the study is to study the state of the immunological and hormonal background in patients with non-hospital pneumonia (NP) - liquidators of the accident at the Chernobyl nuclear power plant (ChNPP) after treatment. MATERIALS AND METHODS: Patients with NP were divided into 2 groups of liquidators of the Chernobyl accident (main group), patients with NP who did not participate in liquidation of the Chernobyl accident (control group), which determined immunological parameters [CD3+, CD4+, CD8+, CD16+, CD20+ expressing cells, immunoglobulin concentrations (Ig) A, M, G] and hormonal indicators (antibodies to thyroglobulin, thyroglobulin, triiodothyronine, thyroxin, cortisol, insulin, testosterone, estradiol, estriol). The main group - liquidators of the Chernobyl accident in an immunological study of 32 NP patients, hormonal - 20; control group - respectively 37 and 38. RESULTS: Combined therapy contributed to an increase in T-lymphocytes in the main and control groups, as well as T-suppressors (Tc) and T-helper cells (Tx), respectively (p<0.05). Also increased the content of B-lymphocytes, IgA, IgM, complement and phagocytic activity in the main and control groups. The ratio Tx/Tc decreased, also decreased IgG, load index, zero cells in the main and control groups.The study of hormonal background in patients with NP showed that the content of thyroglobulin after complex therapy in the main group increased, in the control group their content did not change. The content of triiodothyronine and thyroxine increased after treatment in the main group. In patients with NP of the control group, on the contrary, there was a decrease in thyroid function in terms of thyroglobulin. The study of sex hormones showed that the content of testosterone, estradiol, estriol in patients with NP of the main group increased after treatment, whereas in the control group there was a decrease in estradiol confidence, and testosterone level remained unchanged. The content of estriol increased (p<0.001) in the control group. The increased amount of insulin decreased (p<0.01) in the main group, whereas in the control group these indicators almost did not change. CONCLUSION: After complex therapy, immunological parameters in NP patients in both the main and control groups are normalized, however, recovery in the main group is slower, which requires continued immunological correction in the outpatient setting. Hormonal background approaching the norm more in patients with NP of the control group than the main one.

Gut microbiota: implications for radiotherapy response and radiotherapy-induced mucositis.

INTRODUCTION: Radiotherapy is a mainstay of solid tumor management but can be associated with unacceptable levels of off-target tissue toxicity which impact treatment outcomes and patients' quality of life. Tumour response to radiotherapy and the frequency and severity of radiotherapy-induced toxicities, especially mucositis, varies among patients. Gut microbiota has been found to modulate both the efficacy and toxicity of some types of cancer chemotherapies and immunotherapies but has yet to be investigated thoroughly in the setting of radiotherapy. Area covered: In this review, we discuss the potential role of gut microbiota on modulating radiotherapy-induced oral and gastrointestinal mucositis and the anti-tumor response to radiotherapy through modulation of immune responses. Expert opinion: The gut microbiota plays a major role in the modulation of systemic immune responses, which influence both radiotherapy response and gastrointestinal toxicities such as mucositis. Hence, investigating the gut microbiota link to the variation in radiotherapy responses and toxicities among patients is warranted. Future targeting of these responses with a patient-tailored restoration of optimal microbial composition could lead to a new era of mucositis prevention and enhanced tumor responses.

Podophyllotoxin and Rutin Modulate M1 (iNOS+) Macrophages and Mitigate Lethal Radiation (LR) Induced Inflammatory Responses in Mice.

Accidental exposure to lethal doses of Gamma radiation leads to the systemic inflammatory syndrome which causes mortality. In view of this, management of hemopoietic syndrome by modulating pro-inflammatory response in clinically manageable time period seems to be the most appropriate strategy for encountering radiation induced damage and recovery. As both tissue and peripheral macrophages are critical for the management of radiation induced injuries, we have unraveled the immunomodulatory potential of radioprotective formulation (G-003M) on peripheral macrophages populations in this study. G-003M inhibited lethal radiation induced NO and Th1 effector cytokines in the exposed macrophages indicating its M1 dim polarizing capacity. In similar lines, conditioning of mice with G-003M before lethal irradiation (LR) inhibited LR induced titre of Th1 effector cytokines in both serums as well as in lung, small intestine, and spleen tissue confirming its immunomodulatory potential. G-003M potentially down modulated inflammatory response in LPS induced inflammatory model and enhanced M2 polarization of iNOS+ M1 effector macrophages providing a molecular hint on G-003M mechanism of action on macrophages. These observations revealed that G-003M potentially modulate pro-inflammatory programming of macrophages and mitigate radiation-induced inflammatory stress which is believed to contribute significantly to radioprotective attribute of G-003M. In this study, we demonstrate that Rutin and Podophyllotoxin drive M1dim/M2 polarization of LR primed macrophages apart from protecting DNA from radiation. These drugs have the capacity to programme innate immune cells like macrophages which may be involved in homeostasis during recovery.

Tumor-Infiltrating T Cell Receptor-Beta Repertoires are Linked to the Risk of Late Chemoradiation-Induced Temporal Lobe Necrosis in Locally Advanced Nasopharyngeal Carcinoma.

PURPOSE: Temporal lobe necrosis (TLN), a late complication of nasopharyngeal carcinoma (NPC) after concurrent chemoradiotherapy (CCRT), causes permanent neurologic deficits. We aimed to investigate the risk factors for the development of CCRT-induced TLN in locally advanced NPC patients. METHODS AND MATERIALS: The incidence of CCRT-induced TLN was assessed in consecutive patients with NPC initially staged with T3-4N0-3M0 receiving curative intensity modulated radiation therapy (IMRT) and cisplatin-based chemotherapy with long-term follow-up. The TLN risk was evaluated with radiation dose-volume histograms (a dosimetric risk indicator of organ injury) and the dynamics of blood circulating neutrophil-to-lymphocyte ratios (a clinical indicator of systemic inflammation) by linear and logistic regression models. High-throughput unbiased T cell receptor-beta (TCRbeta) sequencing was performed to correlate the different TCRbeta repertoires of NPC-infiltrating lymphocytes (a biological factor of the immune microenvironment) with TLN incidence. RESULTS: In the era of modern IMRT-based CCRT, radiation doses of up to 74 Gy achieved local control rates of more than 90% in both T3 and T4 diseases but still induced a remarkably higher incidence of TLN in the T4 patients (30.14%) compared with the rare incidence of TLN observed in the T3 patients (2.78%) (P < .0001). We found that in the T4 NPC patients, univariate and multivariate analyses showed the radiation tolerance dose-volume effect was not an absolutely independent factor influencing TLN occurrence. However, increased TLN risk was observed in association with higher pre-CCRT baseline and post-CCRT neutrophil-to-lymphocyte ratios. There was also a link between intratumoral TCRbeta repertoire subtypes and TLN incidence. Combining the inherent TCRbeta genomic susceptibility with the clinical variable neutrophil-to-lymphocyte ratio better predicted the risk of TLN for T4 NPC patients after CCRT. CONCLUSIONS: The associations of tumor-infiltrating lymphocyte repertoires and blood circulating neutrophil-to-lymphocyte ratios with TLN occurrence in T4 NPC patients suggest that the immune and inflammatory milieus play roles in the late brain damage caused by CCRT. Modulated or provoked by CCRT locally and systemically, the reciprocal interactions of neutrophils and lymphocytes in the intracranial NPC-associated immune microenvironment could be a key driver of chronic TLN pathogenesis.

EXPRESSION OF BIOLOGICAL MARKERS INDUCED BY IONIZING RADIATION AT THE LATE PERIOD AFTER EXPOSURE IN A WIDE RANGE OF DOSES. / EKSPRESIIa RADIATsIINO-INDUKOVANYKh BIOLOGIChNYKh MARKERIV U VIDDALENOMU PERIODI PISLIa OPROMINENNIa U ShYROKOMU INTERVALI DOZ.

OBJECTIVE: To study radiation induced biological markers of the late period after exposure. SUBJECTS AND METHODS: A study was performed in 235 Chornobyl accident male clean-up workers exposed in 1986-1987 (doses of external exposure: (M ± SD: 419.48 ± 654.60; range 0.10-3,500 mSv); age 58,34 ± 6,57 years. Controlgroup included 45 non-exposed subjects (mean age: 50.60 ± 5.37 (M ± SD). Gene expression was performed by RT-PCR on 7900HT Analyzer using TLDA for BCL2, CDKN2A, CLSTN2, GSTM1, IFNG, IL1B, MCF2L, SERPINB9, STAT3, TERF1, TERF2,TERT, TNF, TP53, CCND1 genes. Relative telomere length (RTL) was analysed by flow-FISH; immune cell subsets,γ-H2AÐ¥ and CyclinD1 expression by flow cytometry. RESULTS: A statistically significant and dose-dependent decrease in expression of the BCL2, SERPINB9, CDKN2A, andSTAT3 genes was demonstrated in parallel to a dose-dependent overexpression of MCF2L and upregulation of TP53 (upto 100 mSv). IL1B expression was the highest in exposed to doses from 0.1 to 100 mSv with a negative correlationbetween at IL1B expression and CD19+3-, CD3-HLA-DR+, CD4+8- cell counts and CD4+/CD8+ ratio. Hyperexpression ofTNF gene in doses above 100 mSv to 1,000 mSv was shown, and in higher doses a combination of TNF downregula-tion with increase in IFNG gene expression were demonstrated with correlations with numbers of CD3+16+56+ andCD25+ lymphocytes and inhibition of expression CLSTN2. An increased expression of γ-H2AÐ¥ and Cyclin D1 corre-lated to radiation dose, telomere shortening to age and concommittant pathology. CONCLUSIONS: Cellular immunity, gene expression, telomere length, intracellular protein parameters are shown to beamong perspective biological markers at a late period after radiation exposure.

Pharmacology of natural radioprotectors.

Radiotherapy is one of the most efficient ways to treat cancer. However, deleterious effects, such as acute and chronic toxicities that reduce the quality of life, may result. Naturally occurring compounds have been shown to be non-toxic over wide dose ranges and are inexpensive and effective. Additionally, pharmacological strategies have been developed that use radioprotectors to inhibit radiation-induced toxicities. Currently available radioprotectors have several limitations, including toxicity. In this review, we present the mechanisms of proven radioprotectors, ranging from free radical scavenging (the best-known mechanism of radioprotection) to molecular-based radioprotection (e.g., upregulating expression of heat shock proteins). Finally, we discuss naturally occurring compounds with radioprotective properties in the context of these mechanisms.

First Insights Into the M2 Inflammatory Response After Adipose-Tissue-Derived Stem Cell Injections in Radiation-Injured Muscles.

The cutaneous radiation syndrome is the clinical consequence of local high-dose irradiation. It is characterized by extensive inflammation, necrosis, and poor revascularization of the skin, resulting in muscle inflammation and fibrosis. Based on these physiopathological processes, subcutaneous injections of adipose-tissue-derived stem/stromal cells have shown favorable effects on skin-wound healing in a minipig model of cutaneous radiation syndrome, in which muscle fibrosis persisted. Since fibrosis is mainly due to the inflammatory processes that often affect underlying tissues as well, the beneficial effects of intramuscular injections of adipose-tissue-derived stem/stromal cells on tissue recovery were evaluated. The polarization of the inflammatory response of irradiated muscle in a minipig model of cutaneous radiation syndrome was determined after acute local irradiation with 50 Gy gamma rays in a preliminary study (six minipigs). Analysis of the main inflammatory cytokines of the inflammatory response M1 (IL-1-beta and IL-6) and M2 (IL-10 and TGF-beta) by western blotting and in situ hybridization, as well as analysis of CD80/CD206 M1/M2 macrophage-specific markers by immunohistochemistry on minipig muscle samples, was performed 76 d after irradiation. The treatment of irradiated muscles with autologous adipose-tissue-derived stem/stromal cells led to an increase in IL-10 and TGF-beta, being associated with an increase in CD68+/CD206+ cells in this area. This highlights a polarization of M2 in the inflammatory response and indicates that adipose-tissue-derived stem/stromal cells may direct the irradiated tissues' inflammatory response towards a proregenerative outcome.

A model combining age, equivalent uniform dose and IL-8 may predict radiation esophagitis in patients with non-small cell lung cancer.

BACKGROUND AND PURPOSE: To study whether cytokine markers may improve predictive accuracy of radiation esophagitis (RE) in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 129 patients with stage I-III NSCLC treated with radiotherapy (RT) from prospective studies were included. Thirty inflammatory cytokines were measured in platelet-poor plasma samples. Logistic regression was performed to evaluate the risk factors of RE. Stepwise Akaike information criterion (AIC) and likelihood ratio test were used to assess model predictions. RESULTS: Forty-nine of 129 patients (38.0%) developed grade ≥2 RE. Univariate analysis showed that age, stage, concurrent chemotherapy, and eight dosimetric parameters were significantly associated with grade ≥2 RE (p < 0.05). IL-4, IL-5, IL-8, IL-13, IL-15, IL-1α, TGFα and eotaxin were also associated with grade ≥2 RE (p < 0.1). Age, esophagus generalized equivalent uniform dose (EUD), and baseline IL-8 were independently associated grade ≥2 RE. The combination of these three factors had significantly higher predictive power than any single factor alone. Addition of IL-8 to toxicity model significantly improves RE predictive accuracy (p = 0.019). CONCLUSIONS: Combining baseline level of IL-8, age and esophagus EUD may predict RE more accurately. Refinement of this model with larger sample sizes and validation from multicenter database are warranted.

[The roles of mast cells in radiation-induced damage are still an enigma]. / Les mastocytes, stakhanovistes de l'immunité - Un rôle énigmatique dans les lésions radiques .

Mast cells are immune cells that mature within the host tissue. The acquired phenotype is dictated by the tissue microenvironment, giving rise to diverse tissue-dependent phenotypes and functions. The lack of cellular models reflecting phenotypes found in vivo and important differences between human and rodent mast cells are obstacles to the understanding of their exact role in several pathophysiological processes. Studies published over the past few years showed that mast cells' role lies far beyond their involvement in allergy and anaphylaxis. Studies demonstrating their participation in innate immune responses as well as tissue scaring and vascular pathologies allowed the understanding of their role in several diseases, but also gave contradictory results, especially concerning tissue response to ionizing radiations. Nevertheless, therapeutic tools exist to target mast cells, such as degranulation inhibitors, antihistamine, protease inhibitors or tyrosine kinase receptors antagonists, and may offer some interesting new therapeutic perspectives to manage acute and chronic after-effects of radiation therapy.

Protective effect of rutin against brain injury induced by acrylamide or gamma radiation: role of PI3K/AKT/GSK-3ß/NRF-2 signalling pathway.

This study was designed to evaluate the effect of rutin on PI3K/AKT-signalling in case of acrylamide or γ-radiation-induced neurotoxicity. To induce brain damage, animals were received acrylamide (25 mg/kg b.wt./orally/day) or 5 Gy of γ-radiation exposure accompanied with an administration of rutin (200 mg/kg b.wt./orally/day). Our data revealed that, compared to acrylamide or γ-radiation, rutin activated PI3K/AKT/GSK-3ß/NRF-2-pathway through increased protein levels of p-PI3K, p-AKT and p-GSK-3ß and up-regulated the expression of NRF-2. This was achieved by modulating MDA, GST, IL-1ß, IL-6 and reduced the interference of ROS with IGF-1 and NGF stimulating the PI3K/AKT-signaling. Furthermore, histopathological examinations of brain tissues showed that rutin has modulated tissue architecture after acrylamide or γ-radiation induced tissue damage. It could be concluded that rutin provides protection effect against acrylamide or γ-radiation-induced neurotoxicity via activation of the PI3K/AKT/GSK-3ß/NRF-2-pathway by altering the phosphorylation state through its ability to scavenge free radicals generation, modulating gene expression and its anti-inflammatory effects.

Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction.

OBJECTIVE: Radiation proctitis (RP) is a complication of pelvic radiotherapy which affects both the host and microbiota. Herein we assessed the radiation effect on microbiota and its relationship to tissue damage using a rectal radiation mouse model. DESIGN: We evaluated luminal and mucosa-associated dysbiosis in irradiated and control mice at two postradiation time points and correlated it with clinical and immunological parameters. Epithelial cytokine response was evaluated using bacterial-epithelial co-cultures. Subsequently, germ-free (GF) mice were colonised with postradiation microbiota and controls and exposed to radiation, or dextran sulfate-sodium (DSS). Interleukin (IL)-1ß correlated with tissue damage and was induced by dysbiosis. Therefore, we tested its direct role in radiation-induced damage by IL-1 receptor antagonist administration to irradiated mice. RESULTS: A postradiation shift in microbiota was observed. A unique microbial signature correlated with histopathology. Increased colonic tumor necrosis factor (TNF)α, IL-1ß and IL-6 expression was observed at two different time points. Adherent microbiota from RP differed from those in uninvolved segments and was associated with tissue damage. Using bacterial-epithelial co-cultures, postradiation microbiota enhanced IL-1ß and TNFα expression compared with naïve microbiota. GF mice colonisation by irradiated microbiota versus controls predisposed mice to both radiation injury and DSS-induced colitis. IL-1 receptor antagonist administration ameliorated intestinal radiation injury. CONCLUSIONS: The results demonstrate that rectal radiation induces dysbiosis, which transmits radiation and inflammatory susceptibility and provide evidence that microbial-induced radiation tissue damage is at least in part mediated by IL-1ß. Environmental factors may affect the host via modifications of the microbiome and potentially allow for novel interventional approaches via its manipulation.