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1.
Am J Physiol Gastrointest Liver Physiol ; 309(10): G841-54, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26381705

RESUMO

Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression.


Assuntos
Bilirrubina , Movimento Celular/efeitos dos fármacos , Colite/prevenção & controle , Óxido Nítrico Sintase Tipo II/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Bilirrubina/administração & dosagem , Bilirrubina/metabolismo , Colite/etiologia , Colite/metabolismo , Colo/metabolismo , Colo/patologia , Citotoxinas/farmacologia , Sulfato de Dextrana/farmacologia , Interleucina-5/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
J Am Heart Assoc ; 6(4)2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28365565

RESUMO

BACKGROUND: Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient (Ldlr-/- ) mice and elucidate the molecular processes underlying this effect. METHODS AND RESULTS: Bilirubin, at physiological concentrations (≤20 µmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to Ldlr-/- mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression. CONCLUSIONS: Bilirubin suppresses atherosclerotic plaque formation in Ldlr-/- mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin.


Assuntos
Antioxidantes/farmacologia , Bilirrubina/farmacologia , Movimento Celular/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Placa Aterosclerótica/genética , Receptores de LDL/genética , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Colágeno/metabolismo , Dieta Ocidental , Molécula 1 de Adesão Intercelular/metabolismo , Metabolismo dos Lipídeos , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-26925435

RESUMO

There is a growing body of evidence that bilirubin, which is generated during the physiological breakdown of heme, exerts potent anti-inflammatory effects. Previous work by our group suggests that bilirubin is able to suppress inflammatory responses by preventing the migration of leukocytes into target tissues through disruption of vascular cell adhesion molecule-1 (VCAM-1)-dependent cell signaling. As VCAM-1 is an important mediator of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. As anticipated, bilirubin-treated animals manifested significantly less colonic injury and reduced infiltration of inflammatory cells into colon tissues. We further observed that bilirubin administration was associated with a reduced number of eosinophils and monocytes in the small intestine, with a corresponding increase in peripheral blood eosinophilia, regardless of whether mice received DSS. These findings suggest that bilirubin impairs the normal migration of eosinophils into intestinal tissues, as supported by in vitro experiments showing that bilirubin blocks the VCAM-1-dependent movement of Jurkat cells across human endothelial cell monolayers. Taken together, our findings support that bilirubin ameliorates DSS-induced colitis and disrupts the physiological trafficking of leukocytes to the intestine by preventing transmigration across the vascular endothelium, potentially through the inhibition VCAM-1-mediated signaling. Our findings raise the possibility that bilirubin functions as an endogenous regulator of inflammatory responses.

4.
Sci Total Environ ; 562: 987-995, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27260619

RESUMO

An occurrence survey was conducted on selected pathogens in source and treated drinking water collected from 25 drinking water treatment plants (DWTPs) in the United States. Water samples were analyzed for the protozoa Giardia and Cryptosporidium (EPA Method 1623); the fungi Aspergillus fumigatus, Aspergillus niger and Aspergillus terreus (quantitative PCR [qPCR]); and the bacteria Legionella pneumophila (qPCR), Mycobacterium avium, M. avium subspecies paratuberculosis, and Mycobacterium intracellulare (qPCR and culture). Cryptosporidium and Giardia were detected in 25% and in 46% of the source water samples, respectively (treated waters were not tested). Aspergillus fumigatus was the most commonly detected fungus in source waters (48%) but none of the three fungi were detected in treated water. Legionella pneumophila was detected in 25% of the source water samples but in only 4% of treated water samples. M. avium and M. intracellulare were both detected in 25% of source water, while all three mycobacteria were detected in 36% of treated water samples. Five species of mycobacteria, Mycobacterium mucogenicum, Mycobacterium phocaicum, Mycobacterium triplex, Mycobacterium fortuitum, and Mycobacterium lentiflavum were cultured from treated water samples. Although these DWTPs represent a fraction of those in the U.S., the results suggest that many of these pathogens are widespread in source waters but that treatment is generally effective in reducing them to below detection limits. The one exception is the mycobacteria, which were commonly detected in treated water, even when not detected in source waters.


Assuntos
Água Potável/microbiologia , Microbiologia da Água , Purificação da Água/métodos , Humanos , Mycobacterium , Estados Unidos
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