osmotic-drug-delivery-to-ischemic-hindlimbs-perfusion-vasculature

Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging

Preclinical research in animal models of peripheral arterial disease plays a vital role in testing the efficacy of therapeutic agents designed to ...

The Texas Heart Institute at St. Luke's Episcopal Hospital

By means of observing the clinical development of asymptomatic chronic HBsAg carriers (AsC) to explore the clinical rule of development of chronic hepatitis B (CHB) to liver cirrhosis (LC) to hepatocellular carcinoma (HCC) and to seek effective method for blocking the procedure.

[A 16-year clinical observation on 217 chronic HBsAg carriers].

Au moyen d&#39;observer le d&eacute;veloppement clinique des porteurs asymptomatiques de l&#39;AgHBs chroniques (AsC) d&#39;explorer l&#39;&eacute;tat clinique de d&eacute;veloppement de l&#39;h&eacute;patite B chronique (CHB) &agrave; une cirrhose du foie (LC) pour carcinome h&eacute;patocellulaire (CHC) et &agrave; rechercher le moyen efficace pour bloquer la proc&eacute;dure.

[Une observation 16 ans clinique sur 217 porteurs chroniques d&#39;AgHBs].

Mezzo di osservare lo sviluppo clinico di portatori asintomatici di HBsAg croniche (AsC) per esplorare la regola clinica di sviluppo di epatite B cronica (CHB) di cirrosi epatica (LC) per il carcinoma epatocellulare (HCC) e a cercare un metodo efficacia per bloccare la procedura.

[Un 16 anni osservazione clinica su 217 portatori cronici di HBsAg].

Prostacyclin and its stable analogs play an important vascular protective role by promoting angiogenesis, but their role in arteriolar growth is unclear. Here, we examined the effect of prostacyclin stable analog carbaprostacyclin on arteriolar growth in mouse hindlimb ischemia. Using an osmotic-controlled release system to continuously deliver carbaprostacyclin or saline (control) to ischemic mouse hindlimbs for up to 14 days, we found that blood perfusion was significantly better at 7 and 14 days in carbaprostacyclin-treated mice than in saline-treated mice. Microscopic examination of the microvasculature showed more morphological signs of arteriolar formation in carbaprostacyclin- versus saline-treated legs. A double-blind, quantitative microcomputed tomography analysis indicated that carbaprostacyclin-treated legs had markedly increased vascular volume and small- to medium-sized vessel numbers that correspond to decreased vessel separation. A proteome profiler antibody array demonstrated that carbaprostacyclin-treated ischemic muscles secreted significantly higher amounts of acidic fibroblast growth factor and other chemokines. Conditioned media containing those secreted factors promoted smooth muscle cell growth and migration. Additionally, increased acidic fibroblast growth factor protein levels were detected in smooth muscle cells and skeletal myotubes at different time periods after carbaprostacyclin treatment. Furthermore, the selective peroxisome proliferation-activated receptor Î²/Î´ antagonist significantly suppressed carbaprostacyclin-induced acidic fibroblast growth factor protein production. Collectively, our data provide the first morphological and molecular evidence that local delivery of carbaprostacyclin promotes vascular growth in hindlimb ischemia, and that peroxisome proliferation-activated receptor Î²/Î´ signaling plays a critical role in inducing acidic fibroblast growth factor expression.

Targeted delivery of carbaprostacyclin to ischemic hindlimbs enhances adaptive remodeling of the microvascular network.

Prostacycline et ses analogues stables jouent un r&ocirc;le important de protection vasculaire en promouvant l&#39;angiogen&egrave;se, mais leur r&ocirc;le dans la croissance art&eacute;riolaire n&#39;est pas clair. Ici, nous avons examin&eacute; l&#39;effet de la prostacycline stable carbaprostacyclin analogiques sur croissance art&eacute;riolaire dans l&#39;isch&eacute;mie du membre post&eacute;rieur de la souris. Utilisez un syst&egrave;me osmotique-controlled release pour offrir continuellement carbaprostacyclin ou une solution saline (contr&ocirc;le) de souris isch&eacute;mique post&eacute;rieurs jusqu&#39;&agrave; 14 jours, nous avons constat&eacute; que la perfusion sanguine &eacute;tait significativement meilleure &agrave; 7 &agrave; 14 jours chez les souris trait&eacute;es carbaprostacyclin que chez les souris trait&eacute;es &agrave; une solution saline. L&#39;examen microscopique de la microcirculation a montr&eacute; plus de signes morphologiques de formation des art&eacute;rioles dans carbaprostacyclin et jambes impr&eacute;gn&eacute;es d&#39;une solution saline. Une analyse de tomographie quantitative en double-aveugle, microcomputed a indiqu&eacute; qu&#39;impr&eacute;gn&eacute;es de carbaprostacyclin jambes avaient nettement augment&eacute; de volume vasculaire et nombre de navires de petites &agrave; moyennes correspondant &agrave; une diminution s&eacute;paration de navire. Un tableau d&#39;anticorps de profileur proteome d&eacute;montr&eacute; que trait&eacute;s carbaprostacyclin isch&eacute;miques muscles s&eacute;cr&eacute;t&eacute;e des montants beaucoup plus &eacute;lev&eacute;s de facteur de croissance fibroblastique acides et autres chimiokines. Milieux conditionn&eacute;s contenant ces facteurs s&eacute;cr&eacute;t&eacute;s promu des migrations et la croissance des cellules musculaires lisses. En outre, taux de prot&eacute;ines de facteur de croissance fibroblastique acides accrue ont &eacute;t&eacute; d&eacute;tect&eacute;es dans les cellules musculaires lisses et des myotubes squelettiques &agrave; diff&eacute;rentes p&eacute;riodes de temps apr&egrave;s le traitement de carbaprostacyclin. En outre, l&#39;antagoniste &beta;/&delta; r&eacute;cepteur activ&eacute; par la prolif&eacute;ration des peroxysomes s&eacute;lective supprim&eacute;e significativement production de prot&eacute;ines pour le facteur de croissance fibroblastique acide induite par le carbaprostacyclin. Collectivement, nos r&eacute;sultats fournissent la premi&egrave;re preuve morphologique et mol&eacute;culaire que remise locale de carbaprostacyclin favorise la croissance vasculaire dans l&#39;isch&eacute;mie du membre post&eacute;rieur, et que ce r&eacute;cepteur activ&eacute; par la prolif&eacute;ration de peroxysomes &beta;/&delta; signalisation joue un r&ocirc;le crucial en induisant l&#39;expression du facteur de croissance fibroblastique acides.

CIBLEE de carbaprostacyclin aux membres post&eacute;rieurs isch&eacute;mique am&eacute;liore adaptative remodelage du r&eacute;seau microvasculaire.

Prostaciclina e suoi analoghi stabili giocano un importante ruolo protettivo vascolare promuovendo l&#39;angiogenesi, ma il loro ruolo nella crescita arteriolare &egrave; poco chiaro. Qui, abbiamo esaminato l&#39;effetto della prostaciclina stabile carbaprostacyclin analogico su arteriolare crescita nell&#39;ischemia arto posteriore del mouse. Utilizzando un sistema osmotico-controlled release per fornire continuamente carbaprostacyclin o soluzione salina (controllo) a posteriori ischemici del mouse fino a 14 giorni, abbiamo trovato che perfusione di sangue era significativamente migliore di 7 e 14 giorni nei topi trattati con carbaprostacyclin che nei topi trattati con soluzione fisiologica. L&#39;esame microscopico del microvasculature ha mostrato pi&ugrave; segni morfologici di formazione arteriolare in carbaprostacyclin-contro le gambe trattate con soluzione fisiologica. Un&#39;analisi di tomografia quantitativa in doppio cieco, microtomografia indicato che trattate con carbaprostacyclin gambe erano marcatamente aumentato volume vascolare e numeri vaso di piccole e medie dimensioni che corrispondono a diminuito separazione del vaso. Una matrice di anticorpo proteome profiler ha dimostrato che muscoli ischemici trattati carbaprostacyclin secernuto significativamente una maggiore quantit&agrave; di fattore di crescita dei fibroblasti acide e altre chemiochine. Media condizionata contenente quei fattori secrete promosso migrazione e crescita delle cellule muscolari lisce. Inoltre, livelli di proteina fattore di crescita del fibroblasto acida aumentata sono stati rilevati nelle cellule muscolari lisce e scheletriche myotubes a diversi periodi di tempo dopo il trattamento carbaprostacyclin. Inoltre, antagonista selettiva dei perossisomi attivato di proliferazione dei recettori &beta;/&delta; significativamente soppressa produzione di proteine del fattore di crescita dei fibroblasti acida indotta da carbaprostacyclin. Collettivamente, i nostri dati forniscono la prima prova morfologica e molecolare che consegna locale del carbaprostacyclin promuove la crescita vascolare nell&#39;ischemia arto posteriore, e quello dei perossisomi attivato di proliferazione recettori &beta;/&delta; segnalazione svolge un ruolo critico nell&#39;indurre l&#39;espressione di fattore di crescita dei fibroblasti acide.

Consegna mirata di carbaprostacyclin a posteriori ischemico migliora il rimodellamento adattativo della rete microvascolare.

Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injury-induced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury.

L&eacute;sion pulmonaire aigu&euml; (ALI) survient souvent apr&egrave;s une greffe du foie et de la chirurgie h&eacute;patique majeure. M&eacute;diateurs pro-inflammatoires sortis endommag&eacute; foie apr&egrave;s isch&eacute;mie/reperfusion du foie (je / R) blessures pourraient contribuer &agrave; cette forme d&#39;ALI, mais les m&eacute;canismes sous-jacents n&#39;ont pas &eacute;t&eacute; bien caract&eacute;ris&eacute;es. Prot&eacute;ine de box haute mobilit&eacute; Groupe 1 (HMGB1), une cytokine pro-inflammatoire r&eacute;cemment identifi&eacute;, s&#39;est av&eacute;r&eacute;e pour &ecirc;tre significativement plus &eacute;lev&eacute; dans le s&eacute;rum apr&egrave;s foie j&#39;ai / blessure de R. Cette &eacute;tude examine si HMGB1 participait comme un facteur stimulant, et si son aval Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK) et activator protein-1 (AP-1) voies de signalisation agir comme m&eacute;diateurs dans le d&eacute;veloppement du foie j&#39;ai / R ALI la blessure induite. Vaste inflammations pulmonaires et ALI sont induite dans un mod&egrave;le de rat de foie j&#39;ai / blessure de R. S&eacute;rum HMGB1 &eacute;tait significativement plus &eacute;lev&eacute; apr&egrave;s foie j&#39;ai / R blessures et plus important encore, l&#39;expression des ARNm de HMGB1 et prot&eacute;ines dans les tissus pulmonaires a &eacute;galement consid&eacute;rablement augment&eacute;. Nous avons trouv&eacute; plus loin que foie j&#39;ai / renforcement des blessures R l&#39;expression des ARNm de TLR4 et prot&eacute;ine et l&#39;activit&eacute; de p38MAPK et AP-1 dans le tissu pulmonaire. Inhibition de l&#39;expression de TLR4 dans les tissus pulmonaires par l&#39;infection avec pGCSIL-GFP-lentivirus exprimant petite &eacute;pingle RNAs ciblant le g&egrave;ne TLR4 (TLR4-shARN lentivirus) significativement att&eacute;nu&eacute; ALI, inflammation des poumons et l&#39;activit&eacute; de p38MAPK et AP-1 dans le tissu pulmonaire. Ces r&eacute;sultats indiquent que HMGB1 pourraient contribuer au m&eacute;canisme sous-jacent pour le foie je / R ALI la blessure induite et que son aval TLR4, p38MAPK et voies de signalisation AP-1 sont des m&eacute;diateurs potentiellement importants dans le d&eacute;veloppement d&#39;ALI.

TLR4 comme r&eacute;cepteur de m&eacute;diation HMGB1 acute lung injury apr&egrave;s isch&eacute;mie/reperfusion du foie.

Acute lung injury (ALI) is considered to be the major cause of respiratory failure in critically ill patients. Clinical studies have found that in patients with sepsis and after hemorrhage, the elevated level of high mobility group box-1(HMGB-1) in their circulation is highly associated with ALI, but the underlying mechanism remains unclear. Extracellular HMGB-1 has cytokine-like properties and can bind to Toll-like Receptor-4 (TLR4), which was reported to play an important role in the pathogenesis of ALI. The aim of this study was to determine whether HMGB-1 directly contributes to ALI and whether TLR4 signaling pathway is involved in this process.

Toll-like receptor 4 mediates acute lung injury induced by high mobility group box-1.

L&eacute;sion pulmonaire aigu&euml; (ALI) est consid&eacute;r&eacute; comme la cause majeure d&#39;insuffisance respiratoire chez les patients gravement malades. Des &eacute;tudes cliniques ont constat&eacute; que chez les patients pr&eacute;sentant une infection et apr&egrave;s l&#39;h&eacute;morragie, le niveau &eacute;lev&eacute; de haute mobilit&eacute; Groupe box-1(HMGB-1) dans leur circulation est fortement associ&eacute; &agrave; ALI, mais ne sait pas le m&eacute;canisme sous-jacent. Extracellulaire BHGM-1 a des propri&eacute;t&eacute;s de type cytokines et peut lier &agrave; Toll-like Receptor-4 (TLR4), qui a &eacute;t&eacute; signal&eacute; &agrave; jouer un r&ocirc;le important dans la pathogen&egrave;se de l&#39;ALI. Le but de cette &eacute;tude &eacute;tait de d&eacute;terminer si les BHGM-1 contribue directement &agrave; ALI et si la voie de signalisation de TLR4 est impliqu&eacute; dans ce processus.

Zhongwei Yang

The Texas Heart Institute at St. Luke's Episcopal Hospital

Osmotic Drug Delivery to Ischemic Hindlimbs and Perfusion of Vasculature with Microfil for Micro-Computed Tomography Imaging