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BACKGROUND AND PURPOSE: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)-a recently discovered blood biomarker-to predict poststroke infections. METHODS: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. RESULTS: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16-1.79]; P=0.001) and in study B (adjusted odds ratio, 1.52 [1.05-2.22]; P=0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69-0.83) to 0.79 (0.72-0.86; P<0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70-0.81) to 0.76 (0.71-0.82; P<0.038). CONCLUSIONS: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00390962.
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Reglas de Decisión Clínica , Infección Hospitalaria/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Proteína Amiloide A Sérica/metabolismo , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Biomarcadores , Proteína C-Reactiva/metabolismo , Infección Hospitalaria/epidemiología , Trastornos de Deglución/fisiopatología , Femenino , Neumonía Asociada a la Atención Médica/epidemiología , Neumonía Asociada a la Atención Médica/metabolismo , Humanos , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/terapia , Recuento de Leucocitos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polipéptido alfa Relacionado con Calcitonina/metabolismo , Curva ROC , Reproducibilidad de los Resultados , Sepsis/metabolismo , Sepsis/fisiopatología , Sepsis/terapia , Infecciones Urinarias/metabolismo , Infecciones Urinarias/fisiopatología , Infecciones Urinarias/terapiaRESUMEN
OBJECTIVE: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. APPROACH AND RESULTS: We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager(-/-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of α-SMA. Ager transcript levels in the aorta were 6× higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA. CONCLUSIONS: Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager(-/-) animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE.
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Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína Amiloide A Sérica/metabolismo , Uremia/complicaciones , Animales , Antioxidantes/farmacología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/etiología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/etiología , Aterosclerosis/genética , Aterosclerosis/patología , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Nefrectomía , Estrés Oxidativo , Fenotipo , Fosforilación , Placa Aterosclerótica , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada/deficiencia , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal , Uremia/genética , Uremia/metabolismoRESUMEN
Here we report a pig with amyloid A (AA) amyloidosis associated with Streptococcus suis infection and identification of a unique amyloid sequence in the amyloid deposits in the tissue. Tissues from the 180-day-old underdeveloped pig contained foci of necrosis and suppurative inflammation associated with S. suis infection. Congo red stain, immunohistochemistry, and electron microscopy revealed intense AA deposition in the spleen and renal glomeruli. Mass spectrometric analysis of amyloid material extracted from the spleen showed serum AA 2 (SAA2) peptide as well as a unique peptide sequence previously reported in a pig with AA amyloidosis. The common detection of the unique amyloid sequence in the current and past cases of AA amyloidosis in pigs suggests that this amyloid sequence might play a key role in the development of porcine AA amyloidosis. An in vitro fibrillation assay demonstrated that the unique AA peptide formed typically rigid, long amyloid fibrils (10 nm wide) and the N-terminus peptide of SAA2 formed zigzagged, short fibers (7 nm wide). Moreover, the SAA2 peptide formed long, rigid amyloid fibrils in the presence of sonicated amyloid fibrils formed by the unique AA peptide. These findings indicate that the N-terminus of SAA2 as well as the AA peptide mediate the development of AA amyloidosis in pigs via cross-seeding polymerization.
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Amiloidosis/veterinaria , Proteína Amiloide A Sérica/genética , Infecciones Estreptocócicas/patología , Enfermedades de los Porcinos/patología , Amiloidosis/etiología , Amiloidosis/metabolismo , Amiloidosis/patología , Animales , Espectrometría de Masas/veterinaria , Microscopía Electrónica/veterinaria , Placa Amiloide/metabolismo , Placa Amiloide/patología , Placa Amiloide/veterinaria , Reacción en Cadena de la Polimerasa/veterinaria , Análisis de Secuencia de ADN/veterinaria , Bazo/patología , Infecciones Estreptocócicas/complicaciones , Streptococcus suis , PorcinosRESUMEN
BACKGROUND AND PURPOSE: Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. METHODS: In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. RESULTS: Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. CONCLUSIONS: Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.
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Isquemia Encefálica/diagnóstico , Proteína C-Reactiva/metabolismo , Enfermedades Arteriales Cerebrales/diagnóstico , Peroxidasa/sangre , Proteína Amiloide A Sérica/metabolismo , Accidente Cerebrovascular/diagnóstico , Factor de Necrosis Tumoral alfa/sangre , Adolescente , Biomarcadores/sangre , Isquemia Encefálica/sangre , Isquemia Encefálica/etiología , Enfermedades Arteriales Cerebrales/sangre , Enfermedades Arteriales Cerebrales/etiología , Niño , Preescolar , Femenino , Humanos , Masculino , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiologíaRESUMEN
OBJECTIVE: Rupture of abdominal aortic aneurysm (AAA), a major cause of death in the aged population, is characterized by vascular inflammation and matrix degradation. Serum amyloid A (SAA), an acute-phase reactant linked to inflammation and matrix metalloproteinase induction, correlates with aortic dimensions before aneurysm formation in humans. We investigated whether SAA deficiency in mice affects AAA formation during angiotensin II (Ang II) infusion. APPROACH AND RESULTS: Plasma SAA increased ≈60-fold in apoE(-/-) mice 24 hours after intraperitoneal Ang II injection (100 µg/kg; n=4) and ≈15-fold after chronic 28-day Ang II infusion (1000 ng/kg per minute; n=9). AAA incidence and severity after 28-day Ang II infusion was significantly reduced in apoE(-/-) mice lacking both acute-phase SAA isoforms (SAAKO; n=20) compared with apoE(-/-) mice (SAAWT; n=20) as assessed by in vivo ultrasound and ex vivo morphometric analyses, despite a significant increase in systolic blood pressure in SAAKO mice compared with SAAWT mice after Ang II infusion. Atherosclerotic lesion area of the aortic arch was similar in SAAKO and SAAWT mice after 28-day Ang II infusion. Immunostaining detected SAA in AAA tissues of Ang II-infused SAAWT mice that colocalized with macrophages, elastin breaks, and enhanced matrix metalloproteinase activity. Matrix metalloproteinase-2 activity was significantly lower in aortas of SAAKO mice compared with SAAWT mice after 10-day Ang II infusion. CONCLUSIONS: Lack of endogenous acute-phase SAA protects against experimental AAA through a mechanism that may involve reduced matrix metalloproteinase-2 activity.
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Angiotensina II/farmacología , Aneurisma de la Aorta Abdominal/prevención & control , Apolipoproteínas E/deficiencia , Metaloproteinasa 2 de la Matriz/metabolismo , Proteína Amiloide A Sérica/deficiencia , Animales , Aneurisma de la Aorta Abdominal/patología , Biomarcadores/sangre , Modelos Animales de Enfermedad , Elastina/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Distribución Aleatoria , Sensibilidad y Especificidad , Proteína Amiloide A Sérica/metabolismoRESUMEN
BACKGROUND: Chronic spontaneous urticaria (CSU) is an inflammatory skin disease with a complex physiopathology. Serum amyloid A (SAA), an acute-phase reactant, has been proposed as a potential biomarker in urticaria but has yet to be studied in a population with CSU or correlated with disease activity as indicated by the Urticaria Activity Score summed over 7 days (UAS7). OBJECTIVE: We sought to determine SAA-1 levels in patients with CSU and correlate them with its activity and control, as well as with clinical features of CSU and other potential blood biomarkers. METHODS: We conducted a retrospective multicenter study of 67 patients with CSU, from whom we obtained demographic and clinical data, UAS7 as an indicator of CSU activity, and blood and serum markers. RESULTS: SAA-1 levels positively correlated with UAS7 (rs = 0.47, P < .001). SAA-1 levels were higher in patients with noncontrolled (UAS7 > 6) CSU than in those with controlled (UAS ≤ 6) CSU (P < .001) and were also higher in patients with concomitant angioedema (P = .003) or delayed pressure urticaria (P = .003). CONCLUSION: We propose SAA-1 as a potential biomarker for activity in CSU. Further studies are required to evaluate its potential role as a biomarker for other CSU outcomes, such as response to treatment.
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Urticaria Crónica , Urticaria , Humanos , Proteína Amiloide A Sérica/uso terapéutico , Enfermedad Crónica , Urticaria/diagnóstico , BiomarcadoresRESUMEN
BACKGRUOUND: To date, consistent data have not been reported on the association between serum amyloid A (SAA) levels and type 2 diabetes mellitus (T2DM). The purpose of this study was to systematically summarize their relationship. METHODS: Databases including PubMed, Cochrane Library, Embase, Web of Science, and MEDLINE were searched until August 2021. Cross-sectional and case-control studies were included. RESULTS: Twenty-one studies with 1,780 cases and 2,070 controls were identified. SAA levels were significantly higher in T2DM patients than in healthy groups (standardized mean difference [SMD], 0.68; 95% confidence interval [CI], 0.39 to 0.98). A subgroup analysis showed that the mean age of participants and the continent that participants were from were related to differences in SAA levels between cases and controls. Furthermore, in T2DM patients, SAA levels were positively associated with body mass index (r=0.34; 95% CI, 0.03 to 0.66), triglycerides (r=0.12; 95% CI, 0.01 to 0.24), fasting plasma glucose (r=0.26; 95% CI, 0.07 to 0.45), hemoglobin A1c (r=0.24; 95% CI, 0.16 to 0.33), homeostasis model assessment for insulin resistance (r=0.22; 95% CI, 0.10 to 0.34), C-reactive protein (r=0.77; 95% CI, 0.62 to 0.91), and interleukin-6 (r=0.42; 95% CI, 0.31 to 0.54), but negatively linked with highdensity lipoprotein cholesterol (r=-0.23; 95% CI, -0.44 to -0.03). CONCLUSION: The meta-analysis suggests that high SAA levels may be associated with the presence of T2DM, as well as lipid metabolism homeostasis and the inflammatory response.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Proteína Amiloide A Sérica/análisis , Estudios Transversales , Hemoglobina GlucadaRESUMEN
Autoinflammatory diseases are innate immune-mediated inflammatory disorders, unlike autoimmune diseases, which are characterised by abnormalities in adoptive immunity, although autoimmune and autoinflammatory diseases have certain similar clinical features. Familial Mediterranean fever (FMF), the most common monogenic autoinflammatory disease, is associated with mutations in the MEFV gene that encodes pyrin, which results in inflammasome activation and uncontrolled production of interleukin (IL)-1ß. Regular use of colchicine, the primary drug for FMF treatment, prevents febrile attacks and reduces the long-term risk of subsequent complications of amyloid A (AA) amyloidosis. However, a minority of FMF patients develop colchicine resistance, and anti-IL-1ß treatment with canakinumab, which is a genetically modified human IgG subclass type 1 (IgG1) monoclonal antibody specific for human IL-1ß, was beneficial in inhibiting inflammation in such patients. Here, we present a patient with FMF associated with AA amyloidosis, who was treated with canakinumab and demonstrated down-regulated Th17 cells and activated Th17 cells (from 21.4% to 12.8%, and from 1.45% to 0.83%, respectively) in peripheral blood, as shown by immunophenotyping via multicolour flow cytometry and by disease activity and improved laboratory inflammatory surrogate markers-C-reactive protein (CRP) and serum AA protein (SAA). CRP had values within normal limits, but SAA did not (Spearman's rank correlation coefficient; ρ = 0.133). We report that SAA and IL-1ß may differentiate Th17 cells from CD4+-naïve T cells, and we discuss interactions between autoinflammation and autoimmunity as a model based on this case, through modes of action with IL-1ß and SAA. This report is the first demonstrating that an IL-1ß antagonist may reduce Th17 cells in FMF as a therapeutic option.
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Fiebre Mediterránea Familiar , Humanos , Fiebre Mediterránea Familiar/complicaciones , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Células Th17 , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Colchicina/uso terapéutico , PirinaRESUMEN
As the field of interventional pain management (IPM) grows, the risk of surgical site infections (SSIs) is increasing. SSI is defined as an infection of the incision or organ/space that occurs within one month after operation or three months after implantation. It is also common to find patients with suspected infection in an outpatient clinic. The most frequent IPM procedures are performed in the spine. Even though primary pyogenic spondylodiscitis via hematogenous spread is the most common type among spinal infections, secondary spinal infections from direct inoculation should be monitored after IPM procedures. Various preventive guidelines for SSI have been published. Cefazolin, followed by vancomycin, is the most commonly used surgical antibiotic prophylaxis in IPM. Diagnosis of SSI is confirmed by purulent discharge, isolation of causative organisms, pain/tenderness, swelling, redness, or heat, or diagnosis by a surgeon or attending physician. Inflammatory markers include traditional (C-reactive protein, erythrocyte sedimentation rate, and white blood cell count) and novel (procalcitonin, serum amyloid A, and presepsin) markers. Empirical antibiotic therapy is defined as the initial administration of antibiotics within at least 24 hours prior to the results of blood culture and antibiotic susceptibility testing. Definitive antibiotic therapy is initiated based on the above culture and testing. Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria infections appears to be superior to monotherapy in mortality with the risk of increasing antibiotic resistance rates. The never-ending war between bacterial resistance and new antibiotics is continuing. This article reviews prevention, diagnosis, and treatment of infection in pain medicine.
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AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.
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Amiloidosis , Fiebre Mediterránea Familiar , Insuficiencia Renal , Masculino , Humanos , Femenino , Proteína Amiloide A Sérica/metabolismo , Proteína Amiloide A Sérica/uso terapéutico , Amiloidosis/diagnóstico , Amiloidosis/etiología , Amiloidosis/terapia , Fiebre Mediterránea Familiar/complicaciones , Enfermedad Crónica , Insuficiencia Renal/complicacionesRESUMEN
Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.
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Amiloidosis , Fiebre Mediterránea Familiar , Insuficiencia Renal , Humanos , Niño , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/genética , Colchicina/uso terapéutico , Amiloidosis/complicaciones , Pirina/genética , Insuficiencia Renal/complicaciones , MutaciónRESUMEN
Secondary amyloidosis (AA) is an established consequence of many chronic inflammatory conditions. In the developed world, it is most often the result of rheumatological disease. However, the relative frequency of underlying causes may be different in indigenous populations. We present a case series of three remote-living, Indigenous Australians found to have pathologically confirmed amyloidosis and renal impairment at diagnosis. The presence of an underlying inflammatory condition was unclear in two cases. The remaining case had established bronchiectasis and suffered rapidly progressive renal impairment at a young age.
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Amiloidosis/etnología , Nativos de Hawái y Otras Islas del Pacífico , Adolescente , Adulto , Amiloidosis/etiología , Amiloidosis/metabolismo , Bronquiectasia/complicaciones , Comorbilidad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Inflamación/complicaciones , Fallo Renal Crónico/etnología , Fallo Renal Crónico/etiología , Fallo Renal Crónico/metabolismo , Masculino , Proteína Amiloide A Sérica/metabolismoRESUMEN
PURPOSE: We evaluated the role of serum amyloid A1 (SAA1) in the pathogenesis of airway inflammation according to the phenotype of asthma. METHODS: One hundred twenty-two asthmatic patients and 60 healthy control subjects (HCs) were enrolled to measure SAA1 levels. The production of SAA1 from airway epithelial cells (AECs) and its effects on macrophages and neutrophils were investigated in vitro and in vivo. RESULTS: The SAA1 levels were significantly higher in sera of asthmatic patients than in those of HCs (P = 0.014); among asthmatics, patients with neutrophilic asthma (NA) showed significantly higher SAA1 levels than those with non-NA (P < 0.001). In vitro, polyinosinic:polycytidylic acid (Poly I-C) treatment markedly enhanced the production of SAA1 from AECs, which was further augmented by neutrophils; SAA1 could induce the production of interleukin (IL)-6, IL-8, and S100 calcium-binding protein A9 from AECs. Additionally, SAA1 activated neutrophils and macrophages isolated from peripheral blood of asthmatics, releasing neutrophil extracellular traps (NETs) and secreting proinflammatory cytokines presenting M1 phenotype, respectively. In ovalbumin-induced asthma mice, Poly I-C treatment significantly increased SAA1 levels as well as IL-17A/interferon-gamma/IL-33 levels in bronchoalveolar lavage fluid (BALF), leading to airway hyperresponsiveness and inflammation. The highest levels of SAA1 and neutrophilia were noted in the BALF and sera of the NA mouse model, followed by the mixed granulocytic asthma (MA) model. Especially, SAA1 induced IL-17/retinoic acid receptor-related orphan receptor γt expression from activated CD4+ T lymphocytes in asthmatic mice. CONCLUSIONS: The results show that SAA1 could induce neutrophilic airway inflammation by activating neutrophils along with NET formation, M1 macrophages, and Th2/Th17 predominant cells, contributing to the phenotype of NA or MA.
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Serum amyloid A protein (AA) amyloidosis, also known as secondary amyloidosis, is a known consequence of chronic inflammation and results from several conditions including inflammatory arthritis, periodic fever syndromes, and chronic infection. AA amyloidosis can lead to multiorgan dysfunction, including changes in glomerular filtration rate and proteinuria. Definitive diagnosis requires tissue biopsy, and management of AA amyloid kidney disease is primarily focused on treating the underlying inflammatory condition to stabilize glomerular filtration rate, reduce proteinuria, and slow potential progression to kidney failure. In this narrative review, we describe the causes, pathophysiology, presentation, and pathologic diagnosis of AA amyloid kidney disease using an illustrative case of biopsy-proven AA amyloid kidney disease in a patient with long-standing rheumatoid arthritis who had a favorable response to interleukin 6 inhibition. We conclude the review with a description of established and more novel therapies for AA amyloidosis including published cases of use of tocilizumab (an interleukin 6 inhibitor) in biopsy-proven AA amyloid kidney disease.
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BACKGROUND: Autoinflammatory diseases are rare disorders of the innate immune system characterized by fever and other signs of inflammation. A feared complication of autoinflammatory diseases is the development of AA amyloidosis. AA amyloidosis is caused by extracellular deposition of soluble serum amyloid A (SAA) proteins as insoluble amyloid fibrils leading to organ damage. Prolonged high levels of SAA are a prerequisite to develop AA amyloidosis. Since measurement of SAA is relatively expensive and sometimes unavailable, C-reactive protein (CRP) is often used as a surrogacy marker to test for inflammation. OBJECTIVE: The aim of this research is to evaluate the possible relation between CRP and SAA. METHODS: A retrospective cohort of patients with autoinflammatory diseases (n = 99) where SAA and CRP blood testing was performed in the period between 2015 and 2021 in the University Medical Centre in Groningen was used to investigate the correlation between CRP and SAA. RESULTS: CRP and SAA have a high correlation (rho = 0.755, p < 0.001). A CRP value below 0.45 mg/L results in 100% sensitivity for SAA below 4 mg/L. CRP below 5 mg/L is a good predictor of SAA below 4 mg/L with 85.4% sensitivity and 83.6% specificity. Only prednisone and erythrocyte sedimentation rate (ESR) significantly influence the relation between CRP and log10SAA. CONCLUSION: There was a significant correlation between CRP and SAA in our retrospective cohort. CRP levels below 5 mg/L proved to be highly predictive of SAA levels below 4 mg/L. This may not be true for patients on steroids.
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Enfermedades Autoinflamatorias Hereditarias , Proteína Amiloide A Sérica , Humanos , Proteína Amiloide A Sérica/análisis , Proteína Amiloide A Sérica/metabolismo , Proteína C-Reactiva/metabolismo , Estudios Retrospectivos , Inflamación , Enfermedades Autoinflamatorias Hereditarias/diagnósticoRESUMEN
BACKGROUND AND PURPOSE: The constitutive androstane receptor (CAR), a known xenobiotic sensor, plays an important role in drug metabolism by regulating numerous genes. The polycyclic aromatic hydrocarbon pyrene, an environmental pollutant, is a CAR activator and induces mouse hepatotoxicity via CAR. Here, we investigate the molecular mechanisms of the inflammatory response in pyrene-caused mice liver injury. EXPERIMENTAL APPROACH: Effects of pyrene on the liver were investigated in wild-type and CAR knockout (KO) mice. Levels of pyrene and its urinary metabolite were analysed by high performance liquid chromatography (HPLC). Inflammatory responses were measured by qRT-PCR, western blotting, and ELISA for cytokines. KEY RESULTS: Serum amyloid A proteins (SAAs) were markedly increased in the liver and serum of pyrene-exposed wild-type mice. IL-17-producing helper T cells (Th17 cells) and IL-17 levels were increased in the liver of pyrene-exposed wild-type mice. Hepatic mRNA levels of inflammatory cytokines including IL-1ß, IL-6 and TNFα, and serum IL-6 levels were significantly elevated in pyrene-treated wild-type mice. However, these changes were not observed in CAR KO mice. CONCLUSION AND IMPLICATIONS: CAR plays a crucial role in pyrene-caused mice liver inflammatory response with increased SAAs and Th17 cells. Our results suggest that serum SAAs may be a convenient biomarker for early diagnosis of liver inflammatory response caused by polycyclic aromatic hydrocarbons, including pyrene. CAR and Th17 cells may be potential targets for novel therapeutic strategies for xenobiotic-induced liver inflammation.
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Receptor de Androstano Constitutivo , Pirenos , Animales , Ratones , Receptor de Androstano Constitutivo/metabolismo , Interleucina-17 , Interleucina-6 , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Pirenos/toxicidad , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína Amiloide A Sérica/metabolismo , Células Th17 , Xenobióticos/toxicidadRESUMEN
A pandemic designated as Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. Up to date, there is no efficient biomarker for the timely prediction of the disease progression in patients. To analyze the inflammatory profiles of COVID-19 patients and demonstrate their implications for the illness progression of COVID-19. Retrospective analysis of 3,265 confirmed COVID-19 cases hospitalized between 10 January 2020, and 26 March 2020 in three medical centers in Wuhan, China. Patients were diagnosed as COVID-19 and hospitalized in Leishenshan Hospital, Zhongnan Hospital of Wuhan University and The Seventh Hospital of Wuhan, China. Univariable and multivariable logistic regression models were used to determine the possible risk factors for disease progression. Moreover, cutoff values, the sensitivity and specificity of inflammatory parameters for disease progression were determined by MedCalc Version 19.2.0. Age (95%CI, 1.017 to 1.048; P < 0.001), serum amyloid A protein (SAA) (95%CI, 1.216 to 1.396; P < 0.001) and erythrocyte sedimentation rate (ESR) (95%CI, 1.006 to 1.045; P < 0.001) were likely the risk factors for the disease progression. The Area under the curve (AUC) of SAA for the progression of COVID-19 was 0.923, with the best predictive cutoff value of SAA of 12.4 mg/L, with a sensitivity of 83.9% and a specificity of 97.67%. SAA-containing parameters are novel promising ones for predicting disease progression in COVID-19.
Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/diagnóstico , Anciano , Área Bajo la Curva , Betacoronavirus/genética , Biomarcadores , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , COVID-19 , China , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Laringe/virología , Recuento de Leucocitos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pandemias , Valor Predictivo de las Pruebas , ARN Viral/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Sensibilidad y Especificidad , Proteína Amiloide A Sérica/análisisRESUMEN
BACKGROUND: Psoriasis is a chronic systemic inflammatory disease frequently associated with serious comorbidities. OBJECTIVES: To investigate the systemic inflammatory burden in psoriasis and to assess the correlation between traditional and novel inflammatory markers and the severity of the disease. METHODS: This cross-sectional study was conducted on 60 patients with psoriasis vulgaris and 50 healthy volunteers. Data including demographics, Psoriasis Area and Severity Index scores, and laboratory results were analyzed and compared. RESULTS: Compared with the control group, the psoriatic patients had significantly higher high sensitive C-reactive protein, serum amyloid A, erythrocyte sedimentation rate, leukocyte, neutrophil, neutrophil-to-lymphocyte ratio, monocyte to high density lipoprotein (HDL) cholesterol ratio, and aspartate aminotransferase levels, and significantly lower HDL cholesterol levels (pâ¯<â¯0.05). No significant difference was found in procalcitonin, lymphocyte, monocyte, hemoglobin, red blood cell distribution width, platelet, mean platelet volume, platelet distribution width, lymphocyte-to-monocyte ratio, anti-cyclic citrullinated peptide, glucose, alanine aminotransaminase, blood urea nitrogen, creatinine, triglyceride, total cholesterol, and LDL cholesterol levels between the two groups (pâ¯>â¯0.05). The Psoriasis Area and Severity Index score was positively correlated with high-sensitivity C-reactive protein, serum amyloid A, and monocyte to HDL cholesterol ratio, and negatively correlated with lymphocyte-to-monocyte ratio (pâ¯<â¯0.05). STUDY LIMITATIONS: This was a single-center study with relatively limited numbers of patients and controls. CONCLUSIONS: The data show that high sensitivity C-reactive protein, serum amyloid A, erythrocyte sedimentation rate, neutrophil-to-lymphocyte ratio, and monocyte to HDL cholesterol ratio can be used as markers of systemic inflammation in patients with psoriasis. Moreover, high sensitivity C-reactive protein, serum amyloid A, monocyte to HDL cholesterol ratio and lymphocyte-to-monocyte ratio are closely related to the Psoriasis Area and Severity Index score, and they may be regarded as objective indicators in determining the disease severity.
Asunto(s)
Monocitos , Psoriasis , Biomarcadores , HDL-Colesterol , Estudios Transversales , HumanosRESUMEN
There is limited epidemiological information on AA amyloidosis in Argentina, so the objective of this study was to describe the epidemiological characteristics of this disease in a tertiary hospital in our country. We designed a prospective clinical cohort of all consecutive patients with AA amyloidosis confirmed by immunohistochemistry in tissue from the Institutional Registry of Amyloidosis of the Hospital Italiano de Buenos Aires, in the period 04/01/2012- 12/31/2017. Of the 121 patients in the registry, 18 were included with AA for the analysis. Of the total included, 50% (9) were female, with a median age of 53.5 (interquartile range, RII 46-61) years. The 88.9% (16) of cohort presented renal compromise, all had proteinuria, and 6 required dialysis. Six had amyloid infiltration of the digestive system. The latency between the onset of the underlying disease and the diagnosis of AA had a median of 27 (RII 8-35) years. The underlying disease was of inflammatory origin in 6 cases. In 50% (9) of the patients the cause of AA amyloidosis was unknown. In the remaining 50%, these causes resemble those observed in developed countries. Furthermore, our results highlight the importance of their differential diagnosis to identify the most appropriate treatment or follow-up according to the situation presented by each patient.
La amiloidosis AA causa principalmente disfunción renal, lo que lleva a un elevado riesgo de mortalidad a mediano plazo. Existe escasa información epidemiológica sobre la amiloidosis AA en Argentina, por lo que el objetivo de este trabajo fue describir las características epidemiológicas de esta enfermedad en un hospital de tercer nivel en nuestro país. Se realizó una cohorte prospectiva de todos los pacientes consecutivos con evidencia de amiloidosis AA, por inmunohistoquímica de tejidos, incluidos en el Registro Institucional de Amiloidosis del Hospital Italiano de Buenos Aires, desde el 01/04/2012 hasta el 31/12/2017. De los 121 pacientes del registro, se incluyeron 18 con AA para el análisis. Del total incluido, 50% (9) eran mujeres, con una mediana de edad de 53.5 (rango intercuartil, RII 46-61) años. El 88.9% (16) presentó compromiso renal, todos tuvieron proteinuria, y 6 requirieron diálisis. Seis tuvieron infiltración amiloide del aparato digestivo. La latencia entre la aparición de la enfermedad subyacente y el diagnóstico de AA tuvo una mediana de 27 (RII 8-35) años. La enfermedad subyacente fue de origen inflamatorio en 6 casos. En el 50% (9) de los enfermos la causa de amiloidosis AA fue desconocida. En el restante 50% esas causas se asemejan a las de países desarrollados. A su vez, nuestros resultados resaltan la importancia de su diagnóstico diferencial para identificar el tratamiento o seguimiento más adecuado según el cuadro que presente cada paciente.
Asunto(s)
Amiloidosis/diagnóstico , Proteína Amiloide A Sérica/análisis , Adulto , Anciano , Argentina , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Acute phase protein (APP) concentrations can change due to inflammation and be used to monitor disease in the Iberian ibex (Capra pyrenaica). OBJECTIVES: This study aimed to validate Haptoglobin (Hp) and serum amyloid A (SAA) analytes, establish reference values, and characterize Hp and SAA responses in the Iberian ibex after experimentally induced inflammation and experimental bluetongue virus (BTV) infection. METHODS: Sera from 40 free-ranging box-trapped ibexes were used to establish Hp and SAA reference values. Six healthy ibexes were subcutaneously injected with 5 mL of turpentine, then, blood samples were taken, and clinical evaluations were performed on days 0, 1, 2, 3, 4, 7, and 14 postinjection. Another seven ibexes were challenged with BTV. Serum Hp and SAA concentrations were quantified using commercial assays following the manufacturer's instructions. RESULTS: Intra-assay precision and linearity were acceptable for both Hp and SAA. Intra-assay variation for high and low concentration of Hp and SAA were 9.74% and 17.31% and 16.49% and 12.89%, respectively. Inter-assay variation was higher for the low APP concentrations. Reference values for the healthy Iberian ibexes were (median, minimum, and maximum values) 0.2 (0.12-0.64) g/L for Hp and 4.74 (0.05-29.54) mg/L for SAA. Both Hp and SAA acted as a moderate and a major APP, respectively, and each could distinguish animals with turpentine-induced inflammation from those without. Hp and SAA did not change in asymptomatic BTV-infected animals. CONCLUSION: This study validated Hp and SAA analytes and provided basal reference values for these analytes in the Iberian ibex. Both APPs were able to discriminate between healthy and diseased Iberian ibexes animals during turpentine-induced inflammatory processes.