ABSTRACT
SUMMARY: Systemic inflammatory response syndrome (SIRS) is a potentially fatal reaction to various forms of tissue damage and infections that cause damage to various organs. Furthermore, the brain is damaged earlier than other organs, resulting in diffuse brain dysfunction. The central clinical symptom of SIRS is delirium and emotional changes are involved in disease development. Although the amygdala is known to play a major role, the mechanisms underlying emotional changes in the early stages of SIRS have not been elucidated. Therefore, changes to dopamine levels in the amygdala were observed using an in vivo model of lipopolysaccharide (LPS)- induced SIRS to clarify the biochemical mechanisms activated in the early stages of SIRS. Extracellular dopamine was collected from the amygdala of free moving rats via microdialysis and then analyzed by high-performance liquid chromatography. In addition, emotional changes were assessed with the open field and sucrose preference tests. In the LPS group, dopamine release in the amygdala increased remarkably immediately after LPS administration, peaking at 120 min. Thereafter, dopamine release temporarily decreased, but then significantly increased again after 180 min. The present results suggest that diffuse brain dysfunction in the early stages of SIRS may involve altered dopamine levels in the amygdala.
El síndrome de respuesta inflamatoria sistémica (SRIS) es una reacción potencialmente fatal a diversas formas de daño tisular e infecciones que causan injuria a varios órganos. Además, el cerebro se daña antes que otros órganos, lo que provoca una disfunción cerebral difusa. El síntoma clínico central del SIRS es el delirio y los cambios emocionales están involucrados en el desarrollo de la enfermedad. Aunque se sabe que la amígdala desempeña un papel importante, no se han dilucidado los mecanismos que subyacen a los cambios emocionales en las primeras etapas del SRIS. Por lo tanto, en el estudio se provocaron cambios en los niveles de dopamina en la amígdala utilizando un modelo in vivo de SRIS inducido por lipopolisacáridos (LPS) para dilucidar los mecanismos bioquímicos activados en las primeras etapas del SRIS. La dopamina extracelular se recogió de la amígdala de ratas en movimiento libre mediante microdiálisis y luego se analizó mediante cromatografía líquida de alta resolución. Además, se evaluaron los cambios emocionales con las pruebas de campo abierto y de preferencia de sacarosa. En el grupo de LPS, la liberación de dopamina en la amígdala aumentó de manera notable inmediatamente después de la administración de LPS, alcanzando un máximo a los 120 minutos. A partir de entonces, la liberación de dopamina disminuyó temporalmente, pero luego volvió a aumentar significativamente después de 180 min. Los resultadosactuales sugieren que la disfunción cerebral difusa en las primeras etapas del SIRS puede implicar niveles alterados de dopamina en la amígdala.
Subject(s)
Animals , Male , Rats , Dopamine , Systemic Inflammatory Response Syndrome , Amygdala , Lipopolysaccharides/toxicity , Cytokines , Rats, Sprague-Dawley , Systemic Inflammatory Response Syndrome/chemically inducedABSTRACT
Systemic inflammatory response syndrome (SIRS), an exaggerated defense response of the organism to a noxious stressor, involves a massive inflammatory cascade that ultimately leads to reversible or irreversible end-organ dysfunction and even death. Suppressing RIPK1, a key protein in necroptosis pathway, has been proven to be an effective therapeutic strategy for inflammation and SIRS. In this study, a series of novel biaryl benzoxazepinone RIPK1 inhibitors were designed and synthesized by introducing different aryl substituents at the C7 position of benzoxazepinone. As a result, p-cyanophenyl substituted analog 19 exhibited the most potent in vitro anti-necroptotic effect in HT-29 cells (EC50 = 1.7 nM) and superior protection against temperature loss and death in mice in the TZ-induced SIRS model compared to GSK'772. What's more, in vivo analysis of the levels of inflammatory factors in mice also revealed that compound 19 had better anti-inflammatory activity than GSK'772.
Subject(s)
Inflammation , Receptor-Interacting Protein Serine-Threonine Kinases , Systemic Inflammatory Response Syndrome , Animals , Humans , Mice , Apoptosis , HT29 Cells , Inflammation/metabolism , Necrosis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/metabolism , Azepines/chemistry , Azepines/pharmacologyABSTRACT
Purpose: Excessive necroptosis contributes to the pathogenesis of several inflammatory and neurodegenerative diseases. Here, using a high-throughput screening approach, we investigated the anti-necroptosis effects of piperlongumine, an alkaloid isolated from the long pepper plant, in vitro and in a mouse model of systemic inflammatory response syndrome (SIRS). Methods: A natural compound library was screened for anti-necroptosis effects in cellular. The underlying mechanism of action of the top candidate piperlongumine was explored by quantifying the necroptosis marker phosphorylated receptor-interacting protein kinase 1 (p-RIPK1) by Western blotting. The anti-inflammatory effect of piperlongumine was assessed in a tumor necrosis factor α (TNFα)-induced SIRS model in mice. Results: Among the compounds investigated, piperlongumine significantly rescued cell viability. The half maximal effective concentration (EC50) of piperlongumine for inhibiting necroptosis was 0.47 µM in HT-29 cells, 6.41 µM in FADD-deficient Jurkat cells, and 2.33 µM in CCRF-CEM cells, while the half maximal inhibitory concentration (IC50) was 95.4 µM in HT-29 cells, 93.02 µM in FADD-deficient Jurkat cells, and 161.1 µM in CCRF-CEM cells. Piperlongumine also significantly inhibited TNFα-induced intracellular RIPK1 Ser166 phosphorylation in cell lines and significantly prevented decreases in body temperature and improved survival in SIRS mice. Conclusion: As a potent necroptosis inhibitor, piperlongumine prevents phosphorylation of RIPK1 at its activation residue Ser166. Piperlongumine thus potently inhibits necroptosis at concentrations safe enough for human cells in vitro and inhibits TNFα-induced SIRS in mice. Piperlongumine has potential clinical translational value for the treatment of the spectrum of diseases associated with necroptosis, including SIRS.
Subject(s)
Apoptosis , Tumor Necrosis Factor-alpha , Humans , Animals , Mice , Necrosis/metabolism , Tumor Necrosis Factor-alpha/metabolism , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/drug therapyABSTRACT
Multisystem inflammatory syndrome in children (MIS-C) is rare but can be a potentially serious complication following SARS-CoV-2 infection in children. 1 Introduction of coronavirus disease 2019 (COVID-19) vaccines are effective in lowering the burden due to SARS-CoV-2. However, there have been reports of MIS occurrence following COVID-19 vaccination in adults. 2 The potential public health implication of MIS-C following COVID-19 vaccination is not clear in children. Our objective is to describe the spectrum of clinical disease, therapy, and outcomes of MIS-C following COVID-19 vaccination in children.
Subject(s)
COVID-19 Vaccines , COVID-19 , Adult , COVID-19/complications , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/diagnosis , Vaccination/adverse effectsABSTRACT
BACKGROUND Nitrofurantoin is an antibiotic that is commonly used and preferred to treat lower urinary tract infections due to its relatively safe adverse effects profile. However, with the increased emphasis on antibiotic stewardship, it is important to recognize the rare, yet serious adverse effects profile of this medication. One of the rare adverse reactions is the development of systemic inflammatory response syndrome from nitrofurantoin. CASE REPORT We present a case of a 66-year-old woman who developed a classic systemic inflammatory response syndrome, including leukocytosis and fevers, after 2 repeated exposures to nitrofurantoin after a urological procedure. The patient had an initial infectious workup which was negative. A suspected adverse reaction to nitrofurantoin was suspected and the patient was found to have complete resolution of symptoms with discontinuation of the drug and with supportive treatment. CONCLUSIONS This case demonstrates that although nitrofurantoin is known to be relatively well tolerated, clinicians should still be aware of the adverse reactions, including a potential systemic inflammatory response, from nitrofurantoin use. This information should be used to educate patients going forward on potential adverse effects to be aware of.
Subject(s)
Nitrofurantoin , Systemic Inflammatory Response Syndrome , Aged , Anti-Bacterial Agents/adverse effects , Female , Fever/chemically induced , Humans , Leukocytosis , Nitrofurantoin/adverse effects , Systemic Inflammatory Response Syndrome/chemically inducedABSTRACT
We discuss a case of a young woman, presenting a constellation of clinical and biochemical features meeting the current case definition of multisystem inflammatory syndrome in adults (MIS-A), 18 days after receiving her first dose of the Oxford/AstraZeneca vaccine. Therapy by means of intravenous immunoglobulins was initiated, leading to clinical and biochemical recovery. Although a relationship between MIS-A and the preceding vaccination cannot be confirmed, it can also not be excluded, given the temporal association and the fact that there were no indicators of a preceding SARS-CoV-2 infection.
Subject(s)
COVID-19 Vaccines , COVID-19 , Systemic Inflammatory Response Syndrome , Adult , COVID-19 Vaccines/adverse effects , Female , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/chemically induced , VaccinationABSTRACT
Ticagrelor is anantiplatelet agent which acts through reversible binding to the P2Y12 adenosine-diphosphate receptors. In acute coronary syndromes it has been shown to reduce the risk of major cardiovascular events such as myocardial infarction, stroke and death. Although some hemorrhagic, kidney, liver and respiratory complications have been described in detail with the use of ticagrelor, other less frequent adverse effects are not so well clarified. We report the case of a patient with a systemic inflammatory response syndrome secondary to the use of ticagrelor.
El ticagrelor es un antiagregante plaquetario que actúa a través de la unión reversible a los receptores P2Y12 de la adenosina-difosfato. En el síndrome coronario agudo, ha demostrado reducir el riesgo de eventos cardiovasculares mayores como infarto de miocardio, accidente cerebrovascular y muerte. Si bien se han descripto en detalle ciertas complicaciones hemorrágicas, renales, hepáticas y respiratorias por el uso del ticagrelor, otros efectos adversos menos frecuentes de la droga no han sido adecuadamente esclarecidos. Presentamos el caso de un paciente con un síndrome de respuesta inflamatoria sistémica secundario al uso de ticagrelor.
Subject(s)
Acute Coronary Syndrome , Myocardial Infarction , Acute Coronary Syndrome/chemically induced , Acute Coronary Syndrome/drug therapy , Adenosine/adverse effects , Humans , Systemic Inflammatory Response Syndrome/chemically induced , Ticagrelor/adverse effectsABSTRACT
Resumen El ticagrelor es un antiagregante plaquetario que actúa a través de la unión reversible a los receptores P2Y12 de la adenosina-difosfato. En el síndrome coronario agudo, ha demostrado reducir el riesgo de eventos cardiovasculares mayores como infarto de miocardio, accidente cerebrovascular y muerte. Si bien se han descripto en detalle ciertas complicaciones hemorrágicas, renales, hepáticas y respiratorias por el uso del ticagrelor, otros efectos adversos menos frecuentes de la droga no han sido adecuadamente escla recidos. Presentamos el caso de un paciente con un síndrome de respuesta inflamatoria sistémica secundario al uso de ticagrelor.
Abstract Ticagrelor is anantiplatelet agent which acts through reversible binding to the P2Y12 adenosine-diphosphate recep tors. In acute coronary syndromes it has been shown to reduce the risk of major cardiovascular events such as myocardial infarction, stroke and death. Although some hemorrhagic, kidney, liver and respiratory complications have been described in detail with the use of ticagrelor, other less frequent adverse effects are not so well clari fied. We report the case of a patient with a systemic inflammatory response syndrome secondary to the use of ticagrelor.
Subject(s)
Humans , Acute Coronary Syndrome/chemically induced , Acute Coronary Syndrome/drug therapy , Myocardial Infarction , Adenosine/adverse effects , Systemic Inflammatory Response Syndrome/chemically induced , Ticagrelor/adverse effectsABSTRACT
SARS-CoV-2 vaccine roll-out has been successful in the UK and other parts of the world; however, there are increasing concerns about adverse events. A 44-year-old woman presented to a UK hospital with left upper arm pain at the vaccine site a couple of days after receiving the Pfizer-BioNTech mRNA vaccine, which progressed to fever, diarrhoea and abdominal pain over the next few days. She had an erythematous rash on the chest with subcutaneous oedema. Her C reactive protein was 539 mg/L, white cell count of 17×109/L (1.8-7.5), troponin-T of 1013 ng/L and creatine kinase of 572 u/L. She developed an unprovoked pulmonary embolism with acute kidney injury. After administration of intravenous methylprednisolone, the muscle oedema, skin rashes and acute kidney injury resolved. Although multisystem inflammatory syndrome (MIS) is described in children (MIS-C) and adults (MIS-A) following SARS-CoV-2 infection, we highlight the first reported MIS-V case after the SARS-CoV-2 vaccine.
Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 , Systemic Inflammatory Response Syndrome , Adult , COVID-19/prevention & control , Female , Humans , Systemic Inflammatory Response Syndrome/chemically inducedABSTRACT
Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.
Subject(s)
Apoptosis/drug effects , Butylated Hydroxyanisole/pharmacology , Fibroblasts/drug effects , Food Additives/pharmacology , Necroptosis/drug effects , Protein Kinase Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Systemic Inflammatory Response Syndrome/prevention & control , Animals , Antioxidants/pharmacology , Disease Models, Animal , Female , Fibroblasts/enzymology , Fibroblasts/pathology , HT29 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Molecular Docking Simulation , Protein Binding , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/enzymology , Systemic Inflammatory Response Syndrome/pathology , Tumor Necrosis Factor-alphaABSTRACT
The anti-inflammatory adipokine CTRP-3 might affect innate immune reactions such as NOD1. The impact of CTRP-3 on NOD1-mediated inflammation in adipocytes and monocytic cells as well as on NOD1 expression was investigated. Murine 3T3-L1 pre-adipocytes and adipocytes as well as human THP-1 monocyte-like cells were co-stimulated with the synthetic NOD1 agonist Tri-DAP and recombinant CTRP-3. Gonadal adipose tissue and primary adipocytes were obtained from a murine model carrying a knockout (KO) of CTRP-3 in adipocytes but not in stroma-vascular cells. Wildtype mice with lipopolysaccharide (LPS)-induced elevated NOD1 expression were treated with CTRP-3. Secreted inflammatory cytokines in cell supernatants were measured by ELISA and mRNA levels were quantified by RT-PCR. Pro-inflammatory chemokine and cytokine secretion (MCP-1, RANTES, TNFα) was induced by NOD1 activation in adipocytes and monocyte-like cells, and MCP-1 and RANTES release was effectively inhibited by pre-incubation of cells with CTRP-3. CTRP-3 also antagonized LPS-triggered induction of NOD1 gene expression in murine adipose tissue, whereas adipocyte CTRP-3 deficiency upregulated NOD1 expression in adipose tissue. CTRP-3 is an effective antagonist of peptidoglycan-induced, NOD1-mediated inflammation and of LPS-induced NOD1 expression. Since basal NOD1 expression is increased by adipocyte CTRP-3 deficiency, there have to be also inflammation-independent mechanisms of NOD1 expression regulation by CTRP-3.
Subject(s)
Adipocytes/metabolism , Adipokines/metabolism , Intra-Abdominal Fat/metabolism , Nod1 Signaling Adaptor Protein/metabolism , Systemic Inflammatory Response Syndrome/metabolism , 3T3-L1 Cells , Adipocytes/immunology , Adipokines/genetics , Animals , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Intra-Abdominal Fat/immunology , Lipopolysaccharides , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nod1 Signaling Adaptor Protein/genetics , Signal Transduction , Subcutaneous Fat/immunology , Subcutaneous Fat/metabolism , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/genetics , Systemic Inflammatory Response Syndrome/immunology , THP-1 CellsABSTRACT
Multisystem inflammatory syndrome in children has become a recognised syndrome, whereas a parallel syndrome in adults, multisystem inflammatory syndrome in adults (MIS-A), has not been well defined. Most cases occur several weeks following confirmed or suspected SARS-CoV-2 infection, but none have been reported in association with SARS-CoV-2 vaccines. Here we describe the case of a 22-year-old man, who received the inactivated SARS-CoV-2 vaccine 6 weeks following a mild COVID-19 infection. He presented after his second dose of the vaccine with a clinical picture of a multisystem inflammatory syndrome-like illness. Additionally, there was laboratory evidence of acute inflammation. The patient's condition markedly improved after initiation of steroids. Whether the vaccine augmented an already-primed immunity from the infection and contributed to the occurrence of MIS-A is difficult to prove. Understanding the pathogenesis of this condition will shed light on this question and entail major implications on treatment and prevention.
Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 , Systemic Inflammatory Response Syndrome/chemically induced , Humans , Male , Steroids/therapeutic use , Systemic Inflammatory Response Syndrome/drug therapy , Young AdultABSTRACT
Perioperative systemic inflammation induced by surgical stress elevates the risk of hematogenous cancer metastasis. This study investigated the anti-metastatic effects and mechanisms of methylprednisolone (MP) administration for surgical stress. We examined the effects of MP on the expression of adhesion molecules in human vascular endothelial cells and in a murine hepatic metastasis model under lipopolysaccharide (LPS) administration, which mimics systemic inflammation induced by surgical stress. Serum E-selectin level was measured in blood samples obtained from 32 gastric cancer patients who were randomly assigned to treat preoperatively with or without MP. The expression of E-selectin in LPS-induced vascular endothelial cells was suppressed by MP. An adhesion assay showed the number of LPS-induced adherent tumour cells was significantly lower following MP. In the in vivo study, LPS significantly elevated the number of hepatic metastases, but pretreatment with MP before LPS significantly inhibited this elevation. The LPS-induced expression of E-selectin in the vascular endothelium of the portal vein was suppressed by MP. In human clinical samples, serum E-selectin level was significantly decreased by preoperative MP. Suppression of surgically induced systemic inflammation by MP administration might prevent hematogenous cancer metastases by suppressing the induction of E-selectin expression in the vascular endothelium.
Subject(s)
Anticarcinogenic Agents/administration & dosage , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Endothelium, Vascular/drug effects , Human Umbilical Vein Endothelial Cells/drug effects , Liver Neoplasms/prevention & control , Liver Neoplasms/secondary , Methylprednisolone/administration & dosage , Postoperative Complications/prevention & control , Stomach Neoplasms/blood , Stomach Neoplasms/surgery , Systemic Inflammatory Response Syndrome/prevention & control , Animals , Cell Adhesion/drug effects , Cell Line, Tumor , Disease Models, Animal , E-Selectin/blood , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Intercellular Adhesion Molecule-1/metabolism , Lipopolysaccharides/adverse effects , Liver Neoplasms/chemically induced , Male , Mice , Mice, Inbred BALB C , Postoperative Complications/blood , Preoperative Care/methods , Signal Transduction/drug effects , Stomach Neoplasms/pathology , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/chemically induced , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
Nitrofurantoin is considered optimal treatment for acute uncomplicated cystitis by the Infectious Diseases Society of America and is being increasingly recommended due to microbial resistance to sulfamethoxazole/trimethoprim and various fluoroquinolone antibiotics. Adverse effects of nitrofurantoin are generally considered mild, with gastrointestinal complaints being the most common. However, there have been isolated case reports describing a more severe systemic inflammatory response syndrome-like reaction, which leads to diagnostic challenges and treatment complications. We report the case of a patient with repeat episodes of systemic inflammatory response syndrome secondary to nitrofurantoin, which was initially attributed to recurrent urinary tract infections.
Subject(s)
Cystitis , Urinary Tract Infections , Cystitis/chemically induced , Cystitis/drug therapy , Humans , Nitrofurantoin/adverse effects , Systemic Inflammatory Response Syndrome/chemically induced , Trimethoprim, Sulfamethoxazole Drug Combination , Urinary Tract Infections/drug therapyABSTRACT
Patients with chronic granulomatous disease (CGD) who have mutated phagocyte NADPH oxidase are susceptible to infections due to reduced reactive oxygen species production and exhibit autoimmune and inflammatory diseases in the absence of evident infection. Neutrophils and macrophages have been extensively studied since phagocyte NADPH oxidase is mainly found only in them, while the impact of its deficiency on lymphocyte cellularity is less well characterized. We showed herein a zymosan-induced systemic inflammation model that CGD mice deficient in the phagocyte NADPH oxidase gp91phox subunit (NOX2) exhibited more severe thymic atrophy associated with peripheral blood and splenic lymphopenia and reduced lymphopoiesis in the bone marrow in comparison with the wild-type mice. Conversely, the zymosan-exposed CGD mice suffered from more remarkable neutrophilic lung inflammation, circulating and splenic neutrophilia, and enhanced granulopoiesis compared with those in zymosan-exposed wild-type mice. Overall, this study provided evidence that NOX2 deficiency exhibits severe thymic atrophy and lymphopenia concomitant with enhanced neutrophilic inflammation in a zymosan-induced systemic inflammation model.
Subject(s)
Lymphopenia/metabolism , Lymphopoiesis/physiology , NADPH Oxidase 2/deficiency , Systemic Inflammatory Response Syndrome/metabolism , Thymus Gland/metabolism , Zymosan/toxicity , Animals , Atrophy , Disease Models, Animal , Dose-Response Relationship, Drug , Granulomatous Disease, Chronic/chemically induced , Granulomatous Disease, Chronic/metabolism , Granulomatous Disease, Chronic/pathology , Lymphopenia/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/pathology , Thymus Gland/drug effects , Thymus Gland/pathologyABSTRACT
The anemia of inflammation is related in part to abnormal erythropoiesis in bone marrow. G-CSF regulates granulopoiesis and is increased during systemic inflammation. Here, we have showed that high levels of G-CSF are associated with repression of bone marrow erythropoiesis and expansion of splenic erythropoiesis in Escherichia coli-infected mice and lipopolysaccharide-treated mice. Under lipopolysaccharide-induced systemic inflammatory conditions in mice, G-CSF neutralization with antibody alleviated the blockage of bone marrow erythropoiesis, prevented the enhancement of splenic erythropoiesis, ameliorated splenomegaly, and reduced the brittleness of spleen. We further demonstrated that after lipopolysaccharide treatment, TLR4-knockout mice display low levels of G-CSF, healthy bone marrow erythropoiesis, almost no stress erythropoiesis in the spleen, and normal size and toughness of spleen. In addition, we found HIF-mediated erythropoietin production is essential for splenic erythropoiesis in the setting of G-CSF-induced suppression of bone marrow erythropoiesis. Our findings identify G-CSF as a critical mediator of inflammation-associated erythropoiesis dysfunction in bone marrow and offer insight into the mechanism of G-CSF-induced splenic erythropoiesis. We provide experimentally significant dimension to the biology of G-CSF.
Subject(s)
Bone Marrow/metabolism , Erythropoiesis/drug effects , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/metabolism , Signal Transduction/drug effects , Spleen/metabolism , Systemic Inflammatory Response Syndrome/metabolism , Animals , Bone Marrow/drug effects , Erythropoiesis/genetics , Erythropoietin/biosynthesis , Escherichia coli , Escherichia coli Infections/metabolism , Escherichia coli Infections/microbiology , Injections, Subcutaneous , Lipopolysaccharides/adverse effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/genetics , Spleen/drug effects , Systemic Inflammatory Response Syndrome/chemically induced , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/geneticsABSTRACT
BACKGROUND Amiodarone, an anti-arrhythmic medication, has been associated with the development of multiple organ toxicities. Most of these toxicities develop insidiously. However, in rare cases, these toxicities manifest with more acute symptoms. We present an unusual case of amiodarone toxicity which manifested with multiorgan failure and systemic inflammatory response syndrome that mimicked sepsis. CASE REPORT A 73-year-old man who was being treated with chronic oral amiodarone for atrial fibrillation presented with flu-like symptoms and fever, pulmonary infiltrate, acute kidney injury, and thrombocytopenia. The patient did not improve with antibiotics and fluid resuscitation. The results of an extensive infectious and non-infectious workup were negative. His symptoms worsened during hospitalization, which correlated with the loading of intravenous amiodarone given for his acute worsening of atrial fibrillation. Amiodarone-induced drug toxicity was contemplated by the treating medical team. Amiodarone was stopped, and the patient was treated with steroids, which improved his symptoms and organ dysfunctions. Subsequent bronchoscopy with lung biopsy showed foamy macrophages with organizing pneumonia and fibrinoid changes. CONCLUSIONS This case highlights an atypical and rare presentation of a complication of chronic amiodarone use that presented with acute onset of fever, systemic inflammatory response syndrome, and multiorgan failure masquerading as sepsis. The patient's symptoms and organ dysfunctions improved with the discontinuation of amiodarone and institution of steroids.
Subject(s)
Amiodarone , Sepsis , Aged , Amiodarone/adverse effects , Anti-Arrhythmia Agents/adverse effects , Humans , Male , Multiple Organ Failure/chemically induced , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/diagnosisABSTRACT
BACKGROUND: Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases. METHODS: To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500 µg/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue. RESULTS: In the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task. CONCLUSIONS: These results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.
Subject(s)
Blood-Brain Barrier/metabolism , Capillary Permeability/physiology , DNA-Binding Proteins/biosynthesis , Leukocytes/metabolism , Neurodegenerative Diseases/metabolism , Systemic Inflammatory Response Syndrome/metabolism , Animals , Blood-Brain Barrier/pathology , Capillary Permeability/drug effects , Disease Models, Animal , Female , Humans , Leukocytes/pathology , Lipopolysaccharides/toxicity , Male , Mice , Neurodegenerative Diseases/chemically induced , Neurodegenerative Diseases/pathology , Systemic Inflammatory Response Syndrome/chemically induced , Systemic Inflammatory Response Syndrome/pathologyABSTRACT
Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.
Subject(s)
Drug Delivery Systems/methods , Endotoxemia/drug therapy , Nanoparticles/chemistry , Squalene/chemistry , Systemic Inflammatory Response Syndrome/drug therapy , Adenosine/administration & dosage , Adenosine/chemistry , Animals , Antioxidants/administration & dosage , Antioxidants/chemistry , Betacoronavirus , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Models, Animal , Endotoxemia/chemically induced , Female , Immunologic Factors/administration & dosage , Immunologic Factors/chemistry , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nanoparticles/administration & dosage , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Squalene/administration & dosage , Systemic Inflammatory Response Syndrome/chemically induced , Treatment Outcome , alpha-Tocopherol/administration & dosage , alpha-Tocopherol/chemistryABSTRACT
PURPOSE: To investigate the usefulness of clinicopathological systemic inflammatory response and nutritional biomarkers for predicting the efficacy of nivolumab in patients with advanced gastric cancer. METHODS: The subjects of this study were 29 patients who received nivolumab treatment for advanced gastric cancer at the Kochi Medical School between 2017 and 2019. Clinicopathological information, including systemic inflammatory response data, were obtained to investigate the associations between baseline cancer-related prognostic variables and survival outcomes. RESULTS: Immune-related adverse events (irAEs) of any grade were identified in 34.5% (10/29) of the patients. The median progression-free survival of patients with irAEs was significantly greater than that of patients without irAEs (5.8 months vs. 1.2 months, respectively; P = 0.028). The neutrophil to lymphocyte ratio (NLR) after 4 weeks of treatment in the complete response (CR) or partial response (PR) group was significantly lower than that in the stable disease (SD) or progression disease (PD) group (2.2 vs. 2.9, respectively; P = 0.044). The prognostic nutrition index (PNI) before treatment in the CR or PR group was significantly higher than that in the SD or PD group (37.1 vs. 32.1, respectively; P = 0.011). The PNI 8 weeks after treatment and the Glasgow prognostic score (GPS) before treatment were significantly associated with a poor outcome. CONCLUSION: The irAE, NLR, PNI, and GPS may be useful predictive markers for nivolumab efficacy in patients with advanced gastric cancer.