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1.
PLoS One ; 13(4): e0196455, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29694434

RESUMO

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. Plasma haptoglobin and hemopexin scavenge free hemoglobin and heme, respectively, but can be depleted in hemolytic states. Haptoglobin and hemopexin supplementation protect tissues, including the vasculature, liver and kidneys. It is widely assumed that these protective effects are due primarily to hemoglobin and heme clearance from the vasculature. However, this simple assumption does not account for the consequent cytoprotective adaptation seen in cells and organs. To further address the mechanism, we used a hyperhemolytic murine model (Townes-SS) of sickle cell disease to examine cellular responses to haptoglobin and hemopexin supplementation. A single infusion of haptoglobin or hemopexin (± equimolar hemoglobin) in SS-mice increased heme oxygenase-1 (HO-1) in the liver, kidney and skin several fold within 1 hour and decreased nuclear NF-ĸB phospho-p65, and vaso-occlusion for 48 hours after infusion. Plasma hemoglobin and heme levels were not significantly changed 1 hour after infusion of haptoglobin or hemopexin. Haptoglobin and hemopexin also inhibited hypoxia/reoxygenation and lipopolysaccharide-induced vaso-occlusion in SS-mice. Inhibition of HO-1 activity with tin protoporphyrin blocked the protections afforded by haptoglobin and hemopexin in SS-mice. The HO-1 reaction product carbon monoxide, fully restored the protection, in part by inhibiting Weibel-Palade body mobilization of P-selectin and von Willebrand factor to endothelial cell surfaces. Thus, the mechanism by which haptoglobin and hemopexin supplementation in hyperhemolytic SS-mice induces cytoprotective cellular responses is linked to increased HO-1 activity.


Assuntos
Anemia Falciforme/prevenção & controle , Haptoglobinas/uso terapêutico , Heme Oxigenase-1/metabolismo , Hemopexina/uso terapêutico , Inflamação/prevenção & controle , Aldeídos/análise , Anemia Falciforme/patologia , Animais , Monóxido de Carbono/farmacologia , Citocinas/análise , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Haptoglobinas/farmacologia , Hemopexina/farmacologia , Molécula 1 de Adesão Intercelular , Masculino , Metaloporfirinas/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Protoporfirinas/farmacologia , Pele/metabolismo , Pele/patologia , Fator de Transcrição RelA/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
2.
PLoS One ; 8(5): e63162, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23696796

RESUMO

Intravenous Immunoglobulin (IVIG) has been proposed as a potential therapeutic for Alzheimer's disease (AD) and its efficacy is currently being tested in mild-to-moderate AD. Earlier studies reported the presence of anti-amyloid beta (Aß) antibodies in IVIG. These observations led to clinical studies investigating the potential role of IVIG as a therapeutic agent in AD. Also, IVIG is known to mediate beneficial effects in chronic inflammatory and autoimmune conditions by interfering with various pathological processes. Therefore, we investigated the effects of IVIG and purified polyclonal Aß-specific antibodies (pAbs-Aß) on aggregation, toxicity and phagocytosis of Aß in vitro, thus elucidating some of the potential mechanisms of action of IVIG in AD patients. We report that both IVIG and pAbs-Aß specifically bound to Aß and inhibited its aggregation in a dose-dependent manner as measured by Thioflavin T assay. Additionally, IVIG and the purified pAbs-Aß inhibited Aß-induced neurotoxicity in the SH-SY5Y human neuroblastoma cell line and prevented Aß binding to rat primary cortical neurons. Interestingly, IVIG and pAbs-Aß also increased the number of phagocytosing cells as well as the amount of phagocytosed fibrillar Aß by BV-2 microglia. Phagocytosis of Aß depended on receptor-mediated endocytosis and was accompanied by upregulation of CD11b expression. Importantly, we could also show that Privigen dose-dependently reversed Aß-mediated LTP inhibition in mouse hippocampal slices. Therefore, our in vitro results suggest that IVIG may have an impact on different processes involved in AD pathogenesis, thereby promoting further understanding of the effects of IVIG observed in clinical studies.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Imunoglobulinas/metabolismo , Microglia/citologia , Microglia/metabolismo , Fagocitose/fisiologia , Peptídeos beta-Amiloides/genética , Animais , Antígeno CD11b/metabolismo , Linhagem Celular Tumoral , Cromatografia de Afinidade , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulinas/genética , Imuno-Histoquímica , Camundongos , Microscopia de Força Atômica
3.
J Biol Chem ; 288(6): 4085-94, 2013 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-23250751

RESUMO

Immunotherapy with monoclonal and polyclonal immunoglobulin is successfully applied to improve many clinical conditions, including infection, autoimmune diseases, or immunodeficiency. Most immunoglobulin products, recombinant or plasma-derived, are based on IgG antibodies, whereas to date, the use of IgA for therapeutic application has remained anecdotal. In particular, purification or production of large quantities of secretory IgA (SIgA) for potential mucosal application has not been achieved. In this work, we sought to investigate whether polymeric IgA (pIgA) recovered from human plasma is able to associate with secretory component (SC) to generate SIgA-like molecules. We found that ∼15% of plasma pIgA carried J chain and displayed selective SC binding capacity either in a mixture with monomeric IgA (mIgA) or after purification. The recombinant SC associated covalently in a 1:1 stoichiometry with pIgA and with similar efficacy as colostrum-derived SC. In comparison with pIgA, the association with SC delayed degradation of SIgA by intestinal proteases. Similar results were obtained with plasma-derived IgM. In vitro, plasma-derived IgA and SIgA neutralized Shigella flexneri used as a model pathogen, resulting in a delay of bacteria-induced damage targeted to polarized Caco-2 cell monolayers. The sum of these novel data demonstrates that association of plasma-derived IgA or IgM with recombinant/colostrum-derived SC is feasible and yields SIgA- and SIgM-like molecules with similar biochemical and functional characteristics as mucosa-derived immunoglobulins.


Assuntos
Anticorpos Antibacterianos/imunologia , Anticorpos Neutralizantes/imunologia , Cadeias J de Imunoglobulina/imunologia , Imunoglobulina M/imunologia , Plasma/imunologia , Componente Secretório/imunologia , Shigella flexneri/imunologia , Animais , Anticorpos Antibacterianos/química , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/isolamento & purificação , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/isolamento & purificação , Células COS , Chlorocebus aethiops , Humanos , Cadeias J de Imunoglobulina/química , Cadeias J de Imunoglobulina/genética , Cadeias J de Imunoglobulina/isolamento & purificação , Imunoglobulina M/química , Imunoglobulina M/genética , Imunoglobulina M/isolamento & purificação , Plasma/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Componente Secretório/química , Componente Secretório/genética , Componente Secretório/isolamento & purificação
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