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CD8+ T cells are critical to the adaptive immune response against viral pathogens. However, overwhelming antigen exposure can result in their exhaustion, characterised by reduced effector function, failure to clear virus, and the upregulation of inhibitory receptors, including programmed cell death 1 (PD-1). However, exhausted T cell responses can be "re-invigorated" by inhibiting PD-1 or the primary ligand of PD-1: PD-L1. Further, the absence of the type I interferon receptor IFNAR1 also results in T cell exhaustion and virus persistence in lymphocytic choriomeningitis virus Armstrong (LCMV-Arm)-infected mice. In this study, utilizing single- and double-knockout mice, we aimed to determine whether ablation of PD-1 could restore T cell functionality in the absence of IFNAR1 signalling in LCMV-Arm-infected mice. Surprisingly, this did not re-invigorate the T cell response and instead, it converted chronic LCMV-Arm infection into a lethal disease characterized by severe lung inflammation with an infiltration of neutrophils and T cells. Depletion of CD8+ T cells, but not neutrophils, rescued mice from lethal disease, demonstrating that IFNAR1 is required to prevent T cell exhaustion and virus persistence in LCMV-Arm infection, and in the absence of IFNAR1, PD-L1 is required for survival. This reveals an important interplay between IFNAR1 and PD-L1 with implications for therapeutics targeting these pathways.
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Interferon Tipo I , Coriomeningite Linfocítica , Camundongos , Animais , Vírus da Coriomeningite Linfocítica , Linfócitos T CD8-Positivos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Camundongos Knockout , Interferon Tipo I/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma-bone fracture, muscle crush injury, and bowel ischemia-induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.
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MicroRNAs , Traumatismo Múltiplo , Humanos , Camundongos , Animais , Receptor 7 Toll-Like/metabolismo , Modelos Animais de Doenças , MicroRNAs/genética , Inflamação/genética , Citocinas/metabolismoRESUMO
Importance: This study quantifies the trends in trimodality therapy use and its association with pathologic stage and overall survival of patients with rectal cancer at the population level. Objective: To describe changes between 2006 and 2016 in the sequence and use of chemotherapy/radiation therapy (C/RT), multiagent (MA) chemotherapy, and total neoadjuvant therapy (TNT) for patients with stage 2/3 rectal cancer and identify associations with pathologic stage and survival over time. Design, Setting, and Participants: This retrospective cohort analysis included patient records from the National Cancer Database between 2006 and 2016. Of 110â¯372 patient records, 77â¯905 were excluded owing to not receiving trimodality therapy and other predefined exclusion criteria. The final analytic cohort comprised 32â¯467 patients records treated with trimodality therapy, with 24â¯297 considered in the survival analysis. Data analysis was performed between June 2020 and December 2021. Exposures: Trimodality therapy was defined as including all of the following: definitive surgery; radiation therapy (RT), alone or in combination with chemotherapy; and neoadjuvant/adjuvant single-agent (SA) or multiagent (MA) chemotherapy independent of RT. Main Outcomes and Measures: Using Cox multivariable survival analyses across demographics, surgery type, stage, year of diagnosis, and facility type, treatment groups were allocated as the following: group A: TNT (n = 8883 [27%]); group B: preoperative C/RT plus postoperative SA chemotherapy (n = 5967 [18%]); group C: preoperative C/RT plus postoperative MA chemotherapy (n = 12â¯926 [40%]); and group D: postoperative C/RT plus MA chemotherapy (n = 4689 [14%]). Results: The final analytic cohort comprised 32â¯467 patients (mean [SD] age at diagnosis, 57.6 [11.6] years; 12â¯549 [38.7%] women and 19â¯918 [61.3%] men). Comparing 2016 with 2006, treatment shifted to fewer patients receiving postoperative C/RT (group D) (28% vs 8%; P < .001), and more preoperative C/RT and postoperative MA chemotherapy (group C) (24% vs 45%; P < .001) being used. While clinical stage 2 and 3 distribution remained unchanged, pathologic downstaging was observed to stages 0, 1, 2, and 3: 0.60%, 10%, 31%, and 57% vs 2.8%, 22%, 29%, and 45%, from 2006 to 2015, respectively (P < .001). More recent year of diagnosis was associated with an adjusted hazard ratio of 0.77 (95% CI, 0.67-0.87) for mortality within 36 months after diagnosis (2015 vs 2006). Conclusions and Relevance: In this cohort study, the shift toward preoperative C/RT and lower pathologic stage was associated with improved overall survival in stage 2/3 rectal cancers.
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Neoplasias Retais , Humanos , Masculino , Feminino , Criança , Estudos Retrospectivos , Estudos de Coortes , Neoplasias Retais/patologia , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Estadiamento de Neoplasias , Quimioterapia AdjuvanteRESUMO
TLR7 (Toll-like receptor 7), the sensor for single-stranded RNA, contributes to systemic inflammation and mortality in murine polymicrobial sepsis. Recent studies show that extracellular miR-146a-5p serves as a TLR7 ligand and plays an important role in regulating host innate immunity. However, the role of miR-146a-5p and TLR7 signaling in pulmonary inflammation, endothelial activation, and sepsis-associated acute respiratory distress syndrome remains unclear. Here, we show that intratracheal administration of exogenous miR-146a-5p in mice evokes lung inflammation, activates endothelium, and increases endothelial permeability via TLR7-dependent mechanisms. TLR7 deficiency attenuates pulmonary barrier dysfunction and reduces lung inflammatory response in a murine sepsis model. Moreover, the impact of miR-146a-5p-TLR7 signaling on endothelial activation appears to be a secondary effect because TLR7 is undetectable in the human pulmonary artery and microvascular endothelial cells (ECs), which show no response to direct miR-146a-5p treatment in vitro. Both conditioned media of miR-146a-5p-treated macrophages (MÏ) and septic sera of wild-type mice induce a marked EC barrier disruption in vitro, whereas MÏ conditioned media or septic sera of TLR7-/- mice do not exhibit such effect. Cytokine array and pathway enrichment analysis of the MÏ conditioned media and septic sera identify TNFα (tumor necrosis factor α) as the main downstream effector of miR-146a-5p-TLR7 signaling responsible for the EC barrier dysfunction, which is further supported by neutralizing anti-TNFα antibody intervention. Together, these data demonstrate that TLR7 activation elicits pulmonary inflammation and endothelial barrier disruption by sensing extracellular miR-146a-5p and contributes to sepsis-associated acute respiratory distress syndrome.
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Glicoproteínas de Membrana , MicroRNAs , Síndrome do Desconforto Respiratório , Sepse , Receptor 7 Toll-Like , Animais , Meios de Cultivo Condicionados , Células Endoteliais/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Sepse/complicações , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismoRESUMO
Extracellular miRNAs (ex-miRNAs) mediate intercellular communication and play a role in diverse physiological and pathological processes. Using small RNA sequencing, we identify that miRNAs are the most abundant RNA species in the plasma and differentially expressed in murine and human sepsis, such as miR-146a-5p. Exogenous miR-146a-5p, but not its duplex precursor, induces a strong immunostimulatory response through a newly identified UU-containing motif and TLR7 activation, and an immunotolerance by rapid IRAK-1 protein degradation via TLR7âMyD88 signaling and proteasome activation, whereas its duplex precursor acts by targeting 3' UTR of Irak-1 gene via Ago2 binding. miR-146a knockout in mice offers protection against sepsis with attenuated interleukin-6 (IL-6) storm and organ injury, improved cardiac function, and better survival. In septic patients, the plasma miR-146a-5p concentrations are closely associated with the two sepsis outcome predictors, blood lactate and coagulopathy. These data demonstrate the importance of extracellular miR-146a-5p in innate immune regulation and sepsis pathogenesis.
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BACKGROUND: Aeromedical evacuation can expose traumatically injured patients to low pressure (hypobaria) and hypoxia. Here, we sought to assess the impact of hypobaria on inflammation, organ injury, and mortality in a mouse model of polytrauma. METHODS: Eight to 12-week-old male C57BL/6J mice were subjected to sham or polytrauma consisting of bowel ischemia by superior mesenteric artery occlusion, hindlimb muscle crush, and tibia fracture. Two hours after injury, animals were randomized to undergo either 6âh of hypobaria or sea-level, room air conditions. At 8 or 24âh after injury, transthoracic echocardiography was performed. Acute kidney injury (AKI) biomarkers were measured by qRT-PCR. Plasma cytokine and endothelial injury markers were determined by enzyme-linked immunosorbent assay. RESULTS: Eight hours after traumatic injury, mice exhibited a marked increase in plasma IL-6 (57 pg/mL vs. 1,216âpg/mL), AKI with increased Ngal and Kim-1, and endothelial injury as evidenced by significantly increased plasma hyaluronic acid (96âng/mL vs.199âng/mL), thrombomodulin (23.2âng/mL vs. 58.9âng/mL), syndecan-1 (0.99âng/mL vs. 4.34âng/mL), and E-selectin (38.6âng/mL vs. 62.7âng/mL). The trauma mice also developed cardiac dysfunction with decreased cardiac output and stroke volume at 8âh postinjury. Hypobaric exposure after polytrauma led to decreased ejection fraction (81.0% vs. 74.2%, Pâ<â0.01) and increased plasma hyaluronic acid (199âng/mL vs. 260âng/mL, Pâ<â0.05), thrombomodulin (58.9âng/mL vs. 75.4âng/mL, Pâ<â0.05), and syndecan-1 (4.34âng/mL vs. 8.33âng/mL, Pâ<â0.001) at 8âh postinjury. CONCLUSIONS: Hypobaria exposure appeared to worsen cardiac dysfunction and endothelial injury following polytrauma and thus may represent a physiological "second hit" following traumatic injury.
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Injúria Renal Aguda/etiologia , Resgate Aéreo , Pressão do Ar , Endotélio Vascular/lesões , Traumatismo Múltiplo/complicações , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo Múltiplo/terapiaRESUMO
Previous studies have demonstrated that transient myocardial ischemia leads to release of cellular nucleic acids such as RNA. Extracellular RNA reportedly plays a pivotal role in myocardial inflammation and ischemic injury in animals. RNA profiling has identified that numerous microRNA (miRNAs), such as ss-miR-146a-5p, are upregulated in plasma following myocardial ischemia, and certain uridine-rich miRNAs exhibit strong proinflammatory effects in immune cells via ssRNA-sensing mechanism. However, the effect of extracellular miRNAs on myocardial inflammation and cardiac cell function remains unknown. In this study, we treated adult mouse cardiomyocytes with miR-146a-5p loaded in extracellular vesicles and observed a dose- and TLR7-dependent production of CXCL-2, IL-6, and TNF-α. In vivo, a single dose of myocardial injection of miR-146a-5p induced both cytokine expression (CXCL2, IL-6, and TNF-α) and innate immune cell activation (CD45+ leukocytes, Ly6Cmid+ monocytes, Ly6G+ neutrophils), which was significantly attenuated in the hearts of TLR7 KO mice. We discovered that conditioned media from miR-146a-treated macrophages stimulated proinflammatory cytokine production in adult cardiomyocytes and significantly inhibited their sarcomere shortening. Finally, using an electric cell impedance-sensing assay, we found that the conditioned media from miR-146a-treated cardiac fibroblasts or cardiomyocytes impaired the barrier function of coronary artery endothelial cells. Taken together, these data demonstrate that extracellular miR-146a-5p activates multiple cardiac cells and induces myocardial inflammation and cardiomyocyte dysfunction via intercellular interaction and innate immune TLR7 nucleic acid sensing.
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Vasos Coronários/patologia , Vesículas Extracelulares/metabolismo , Imunidade Inata , Glicoproteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Receptor 7 Toll-Like/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Citocinas/metabolismo , Células Endoteliais/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , Receptor 7 Toll-Like/genéticaRESUMO
BACKGROUND: Sepsis is a life-threatening condition often manifested as marked inflammation and severe coagulopathy. Toll-like receptors (TLRs) play a pivotal role in inflammation, organ dysfunction and mortality in animal sepsis. OBJECTIVES: To investigate the role of TLR signaling in mediating sepsis-induced coagulopathy (SIC) in a mouse model. METHODS: Polymicrobial sepsis was created by cecal ligation and puncture (CLP) or fecal slurry peritoneal injection. To quantify global clotting function, two viscoelastic assays were performed with rotational thromboelastometry, and the results were presented as maximum clot firmness (MCF): (a) EXTEM to test tissue factor (TF)-initiated clot formation; and (b) FIBTEM to test EXTEM in the presence of a platelet inhibitor, cytochalasin D. Plasma coagulation factors were quantified with ELISA. TF gene expression and protein expression were determined with real-time quantitative reverse transcription PCR and flow cytometry, respectively. RESULTS: Between 4 and 24 hours after CLP surgery, wild-type mice showed significant MCF reduction in both EXTEM and FIBTEM tests. This was accompanied by marked thrombocytopenia and a significant increase in the levels of plasminogen activator inhibitor-1, plasma TF, and D-dimer. In comparison, TLR2-/- and TLR7-/- CLP mice showed preserved MCF and platelet counts, and near-normal plasma TF levels. Bone marrow-derived macrophages treated with a TLR2 agonist Pam3cys-Ser-(Lys)4 (Pam3cys) or a TLR7 agonist (R837) showed marked increases in TF gene expression and protein expression. MicroRNA-146a, a newly identified proinflammatory mediator that is upregulated during sepsis, induced TF production via a TLR7-dependent mechanism. CONCLUSIONS: Murine sepsis leads to an increased procoagulant response, thrombocytopenia, and global coagulopathy. TLR2 and TLR7 play an important role in procoagulant production and in SIC.
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Transtornos da Coagulação Sanguínea/etiologia , Coagulação Sanguínea , Macrófagos/metabolismo , Sepse/complicações , Receptor 2 Toll-Like/metabolismo , Receptor 3 Toll-Like/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/metabolismo , Células Cultivadas , Citocinas/sangue , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Sepse/sangue , Sepse/metabolismo , Transdução de Sinais , Trombocitopenia/sangue , Trombocitopenia/etiologia , Trombocitopenia/metabolismo , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genéticaRESUMO
BACKGROUND: In patients with predictive features associated with easy direct laryngoscopy, videolaryngoscoy with the GlideScope has been shown to require less force when compared with Macintosh direct laryngoscopy. OBJECTIVE: The aim of this study was to compare forces applied with Glidescope vs. Macintosh laryngoscopes in patients with predictive features associated with difficult direct laryngoscopy. DESIGN: A randomised study. SETTING: Toronto General Hospital, a university tertiary centre in Canada. PATIENTS: Forty-four patients aged over 18 years, with one or more features of difficult intubation, undergoing elective surgery requiring single-lumen tracheal intubation. INTERVENTION: We measured the force applied to oropharyngeal tissues by attaching three FlexiForce Sensors (A201-25) to the concave surface of Macintosh and GlideScope laryngoscope blades.Anaesthetists or experienced anaesthesia residents performed laryngoscopies with both devices in a randomised sequence. MAIN OUTCOME MEASURES: The primary outcome was peak force. The secondary outcomes were average force and impulse force. The latter is the integral of the force over the time during which the force acted. RESULTS: Complete data were available for 40 individuals. Peak and average forces decreased with GlideScope (17 vs. 21âN, Pâ=â0.03, and 6 vs. 11âN, Pâ<â0.001, respectively). Laryngoscopy time increased with the GlideScope (30 vs. 18âs, Pâ<â0.001), resulting in similar median impulse forces (206 vs. 175âN, Pâ=â0.92). CONCLUSION: GlideScope laryngoscopy resulted in reduced peak and average forces, but as the laryngoscopy duration increased, the product of force and time (impulse force) was similar with both devices. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01814176.
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Manuseio das Vias Aéreas/instrumentação , Desenho de Equipamento/instrumentação , Intubação Intratraqueal/instrumentação , Laringoscópios , Laringoscopia/instrumentação , Cirurgia Vídeoassistida/instrumentação , Adulto , Idoso , Manuseio das Vias Aéreas/métodos , Manuseio das Vias Aéreas/normas , Desenho de Equipamento/normas , Feminino , Humanos , Intubação Intratraqueal/métodos , Intubação Intratraqueal/normas , Laringoscópios/normas , Laringoscopia/métodos , Laringoscopia/normas , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Cirurgia Vídeoassistida/métodos , Cirurgia Vídeoassistida/normasRESUMO
PURPOSE: To examine the combination of radiation and the multikinase inhibitor sorafenib in human colorectal cancer cell lines and xenografts. METHODS AND MATERIALS: HT29 and SW48 colorectal cancer cells were studied in vitro using MTT assays to establish the optimal timing of radiation and sorafenib. This optimal timing was then investigated in clonogenic survival assays. Xenografts were established, and the effect of a 3-week schedule of daily radiation and sorafenib was studied by growth delay. RESULTS: Sorafenib predominantly had minimal effects on cell growth or radiation response in MTT growth assays, though growth inhibition was significantly enhanced in HT29 cells when sorafenib was administered after radiation. The highest dose of sorafenib altered the alpha component of the cell survival curve in clonogenic assays. The combination of radiation and sorafenib was synergistic in SW48 xenografts, with a mean time to threshold tumor size of 11.4 +/- 1.0 days, 37.0 +/- 9.5 days, 15.5 +/- 3.2 days, and 98.0 +/- 11.7 days in the control, radiation, sorafenib, and combined treatment group, respectively. The effect on HT29 tumors was additive, with mean time to threshold volume of 12.6 +/- 1.1 days, 61.0 +/- 4.3 days, 42.6 +/- 11.7 days, and 100.2 +/- 12.4 days. CONCLUSIONS: Sorafenib had little effect on radiation response in vitro but was highly effective when combined with radiation in vivo, suggesting that inhibition of proliferation and interference with angiogenesis may be the basis for the interaction.
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Antineoplásicos/administração & dosagem , Benzenossulfonatos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Piridinas/administração & dosagem , Tolerância a Radiação/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Animais , Divisão Celular/efeitos dos fármacos , Divisão Celular/efeitos da radiação , Terapia Combinada/métodos , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/administração & dosagem , Dosagem Radioterapêutica , Distribuição Aleatória , Sorafenibe , Fatores de Tempo , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco/métodosRESUMO
PURPOSE: To evaluate the dosimetric impact of online cone-beam computed tomography (CBCT) guided correction in lung stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Twenty planning and 162 CBCT images from 20 patients undergoing lung SBRT were analyzed. The precorrection CBCT (CBCT after patient setup, no couch correction) was registered to planning CT using soft tissue; couch shift was applied, with a second CBCT for verification (postcorrection CBCT). Targets and normal structures were delineated on CBCTs: gross tumor volume (GTV), clinical target volume (CTV), cord, esophagus, lung, proximal bronchial tree, and aorta. Dose distributions on all organs manifested on each CBCT were compared with those planned on the CT. RESULTS: Without CBCT guided target position correction, target dose reduced with respect to treatment plan. Mean and standard deviation of treatment dose discrepancy from the plan were -3.2% (4.9%), -2.1% (4.4%), -6.1% (10.7%), and -3.5% (7%) for GTV D(99%), GTV D(95%), CTV D(99%), and CTV D(95%), respectively. With CBCT correction, the results were -0.4% (2.6%), 0.1% (1.7%), -0.3% (4.2%), and 0.5% (3%). Mean and standard deviation of the difference in normal organ maximum dose were 2.2% (6.5%) before correction and 2.4% (5.9%) after correction for esophagus; 6.1% (14.1%) and 3.8% (8.1%) for cord; 3.1% (17.5%) and 6.2% (9.8%) for proximal bronchial tree; and 17.7% (19.5%) and 14.1% (17%) for aorta. CONCLUSION: Online CBCT guidance improves the accuracy of target dose delivery for lung SBRT. However, treatment dose to normal tissue can vary regardless of the correction. Normal tissues should be considered during target registration, according to target proximity.
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Carcinoma Pulmonar de Células não Pequenas , Tomografia Computadorizada de Feixe Cônico , Neoplasias Pulmonares , Pulmão/diagnóstico por imagem , Movimento , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Órgãos em Risco/diagnóstico por imagem , Respiração , Carga TumoralRESUMO
BACKGROUND: Accelerated atherosclerosis and carotid stenosis are well-established risks occurring after high radiation doses that are used to treat cancers of the head and neck. Noncoronary vascular disease has been observed and may relate to more moderate dose irradiation. METHODS: A search of patients treated for Hodgkin disease, non-Hodgkin lymphoma, or seminoma was performed to identify cases with noncoronary vascular complications after irradiation. These three groups were chosen because of the use of intermediate dose radiation and prevalence of long-term survivors. Individual patient records were reviewed to document the type and presentation of the stenosis and the clinical factors that may have contributed to this risk. RESULTS: Twenty-one patients were identified who developed disease in noncoronary arteries after treatment. The median time from irradiation to diagnosis of vascular stenosis was 15 years. Antecedent risk factors for vascular disease were prevalent. Five patients had disease identified by auscultation of bruits before an adverse clinical event occurred. Five patients died from complications related to their vascular disease, which included three deaths after stroke and two after small bowel infarction. CONCLUSION: Twelve cases arose at an atypically young age for atherosclerotic vascular disease and featured unusual clinical presentations. Nine cases identified occurred at an advanced aged and at a shorter median interval, making a causal relation to irradiation uncertain. Incorporating careful auscultation for bruits in followup evaluation of irradiated patients may identify individuals who are at risk for adverse vascular events. The potential for early vasculopathy in individuals exposed to intermediate dose irradiation suggests a need to manage dyslipidemia and reduce vascular risk factors throughout the posttreatment period.
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Aterosclerose/etiologia , Doença de Hodgkin/radioterapia , Linfoma não Hodgkin/radioterapia , Lesões por Radiação/patologia , Seminoma/radioterapia , Adolescente , Adulto , Fatores Etários , Idoso , Aterosclerose/patologia , Criança , Pré-Escolar , Constrição Patológica , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Testiculares/radioterapia , Fatores de TempoRESUMO
Although interleukin-1 (IL-1) has been implicated in the pathogenesis of inflammatory osteolysis, the means by which it recruits osteoclasts and promotes bone destruction are largely unknown. Recently, a cytokine-driven, stromal cell-free mouse osteoclastogenesis model was established. A combination of macrophage colony stimulating factor (M-CSF) and receptor activator of NFkappaB ligand (RANKL) was proven to be sufficient in inducing differentiation of bone marrow hematopoietic precursor cells to bone-resorbing osteoclasts in the absence of stromal cells or osteoblasts. This study utilizes this model to examine the impact of human IL-1beta on in vitro osteoclastogenesis of bone marrow progenitor cells. We found that osteoclast precursor cells failed to undergo osteoclastogenesis when treated with IL-1 alone. In contrast, IL-1 dramatically up-regulated osteoclastogenesis by 2.5- to 4-folds in the presence of RANKL and M-CSF. The effect can be significantly blocked by IL-1 receptor antagonist (p < 0.01). Tumor necrosis factor-alpha (TNF-alpha) was undetectable in the culture medium of differentiating osteoclasts induced by IL-1. Adding exogenous TNF-alpha neutralizing antibody had no influence on the IL-1-induced effect as well. These results show that in the absence of stromal cells, IL-1 exacerbates osteoclastogenesis by cooperating with RANKL and M-CSF, while TNF-alpha is not involved in this IL-1-stimulated osteoclast differentiation pathway.