Intravenous immunoglobulins prevent the breakdown of the blood-brain barrier in experimentally induced sepsis

Esen, Figen; Şentürk, Evren; Özcan, Perihan Ergin; Ahıshalı, Bülent; Arıcan, Nadir; Orhan, Nurcan; Ekizoğlu, Oğuzhan; Küçük, Mutlu; Kaya, Mehmet

doi:10.1097/ccm.0b013e31823779ca

Cited by 39 publications

(37 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous work suggested that hIgG could saturate the recycling receptor FcRn on endothelial cells and decrease the half-life of pathogenic antibodies in blood (Li et al, 2005). A previous study demonstrated that hIgG reduced blood-brain barrier disruption in a cecal puncture model of sepsis (Esen et al, 2012), though it is difficult to establish whether this was a direct effect or a secondary effect due to a global antiinflammatory response. Here, we found comparable albumin extravasation, a measure of blood-brain barrier integrity, in control and hIgG-treated rats.…”

Section: Discussionmentioning

confidence: 99%

Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

Ratelade

Smith

Verkman

2014

Experimental Neurology

View full text Add to dashboard Cite

Neuromyelitis optica (NMO) pathogenesis involves binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) present in serum to AQP4 on astrocytes, which causes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Human immunoglobulin G (hIgG) is effective for treatment of humorally mediated neurological autoimmune diseases and has been reported to improve disease outcome in a limited number of NMO patients. Here, we investigated hIgG actions on NMO-IgG pathogenicity using an in vivo rat model of NMO and in vitro assays. In rats administered NMO-IgG by intracerebral injection, the size of neuroinflammatory demyelinating lesions was reduced by ∼ 50 % when hIgG was administered by intraperitoneal injection to reach levels of 10-25 mg/mL in rat serum, comparable with human therapeutic levels. In vitro, hIgG at 10 mg/mL reduced by 90 % NMO-IgG-mediated CDC following addition of NMO-IgG and human complement to AQP4-expressing cells. The hIgG effect was mainly on the classical complement pathway. hIgG at 10 mg/mL also reduced by up to 90 % NMO-IgG-mediated ADCC as assayed with human natural killer cells as effector cells. However, hIgG at up to 40 mg/mL did not affect AQP4 cell surface expression or its supramolecular assembly in orthogonal arrays of particles, nor did it affect NMO-IgG binding to AQP4. We conclude that hIgG reduces NMO-IgG pathogenicity by inhibition of CDC and ADCC, providing a mechanistic basis to support further clinical evaluation of its therapeutic efficacy in NMO.

show abstract

Section: Discussionmentioning

confidence: 99%

Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

Ratelade

Smith

Verkman

2014

Experimental Neurology

View full text Add to dashboard Cite

show abstract

“…IVIg could, therefore, prevent the loss of tight junction integrity in the brain and consequently protect the BBB whose breakdown contributes to a large part of stroke-induced injury. A recent study investigating the effect of IVIg on BBB integrity in a sepsis model suggested that immunoglobulin G, A, or M improved the integrity of the BBB and inhibited symptoms of sickness in rats [14]. We previously reported that IVIg crosses the BBB and exerts protective effects in a mouse model of stroke [2,3].…”

Section: Discussionmentioning

confidence: 99%

Intravenous immunoglobulin (IVIg) provides protection against endothelial cell dysfunction and death in ischemic stroke

Widiapradja

Santro

Bašta

et al. 2014

Exp & Trans Stroke Med

View full text Add to dashboard Cite

BackgroundThe brain endothelium is a key component of the blood brain barrier which is compromised following ischemia, allowing infiltration of damaging immune cells and other inflammatory molecules into the brain. Intravenous immunoglobulin (IVIg) is known to reduce infarct size in a mouse model of experimental stroke.FindingsFlow cytometry analysis showed that the protective effect of IVIg in ischemia and reperfusion injury in vivo is associated with reduced leukocyte infiltration, suggesting an involvement of the endothelium. In an in vitro model of ischemia, permeability analysis of the mouse brain endothelial cell line bEnd.3 revealed that IVIg prevented the loss of permeability caused by oxygen and glucose deprivation (OGD). In addition, western blot analysis of these brain endothelial cells showed that IVIg prevented the down-regulation of tight junction proteins claudin 5 and occludin and the decline in anti-apoptotic proteins Bcl-2 and Bcl-XL caused by OGD.ConclusionIVIg protects endothelial cells from ischemic insult. These studies support the use of IVIg as a pharmacological intervention for stroke therapy.

show abstract

“…Therefore, regulation of caveolae formation and paracellular junction to prevent microvascular hyperpermeability has become a potential new strategy for septicemia therapy. However, few clinical drugs are available that direct at hyperpermeability in endotoxemia therapy, although preclinical experiments for some new agents have been undertaken to test their roles in endothelial barrier protection (7,25).…”

mentioning

confidence: 99%

Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans- and paracellular pathway

Sun

Liu

Zhang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

. Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans-and paracellular pathway. Am J Physiol Gastrointest Liver Physiol 306: G289-G300, 2014. First published December 19, 2013; doi:10.1152/ajpgi.00168.2013 is one of the common pathogens that causes mesentery hyperpermeability-and intestinal edema-related diseases. This study evaluated whether ginsenoside Rb1 (Rb1), an ingredient of a Chinese medicine Panax ginseng, has beneficial effects on mesentery microvascular hyperpermeability induced by LPS and the underlying mechanisms. Male Wistar rats were continuously infused with LPS (5 mg·kg Ϫ1 ·h Ϫ1 ) via the left jugular vein for 90 min. In some rats, Rb1 (5 mg·kg Ϫ1 ·h Ϫ1 ) was administrated through the left jugular vein 30 min after LPS infusion. The dynamics of fluorescein isothiocynatelabeled albumin leakage from mesentery venules was assessed by intravital microscopy. Intestinal tissue edema was evaluated by hematoxylin and eosin staining. The number of caveolae in endothelial cells of microvessels was examined by electron microscopy. Confocal microscopy and Western blotting were applied to detect caveolin-1 (Cav-1) expression and phosphorylation, junction-related proteins, and concerning signaling proteins in intestinal tissues and human umbilical vein endothelial cells. LPS infusion evoked an increased albumin leakage from mesentery venules that was significantly ameliorated by Rb1 posttreatment. Mortality and intestinal edema around microvessels were also reduced by Rb1. Rb1 decreased caveolae number in endothelial cells of microvessels. Cav-1 expression and phosphorylation, VE-Cadherin phosphorylation, ZO-1 degradation, nuclear factor-B (NF-B) activation, and Src kinase phosphorylation were inhibited by Rb1. Rb1 ameliorated microvascular hyperpermeability after the onset of endotoxemia and improved intestinal edema through inhibiting caveolae formation and junction disruption, which was correlated to suppression of NF-B and Src activation.hyperpermeability; caveolin-1; nuclear factor-B; Src; Panax ginseng LIPOPOLYSACCHARIDE (LPS) is one of the common pathogens that causes mesentery hyperpermeability-and intestinal edema-related diseases [diarrhea, cirrhosis with ascites, inflammatory bowel disease, etc. (1, 2, 31)]. Shedding of LPS from gram-negative bacteria into the circulation results in endotox-

show abstract

Intravenous immunoglobulins prevent the breakdown of the blood-brain barrier in experimentally induced sepsis

Abstract: Our study suggests that immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M improve the integrity of the blood-brain barrier and inhibits cecal ligation and perforation-induced symptoms of sickness behavior in rats.

Cited by 39 publications

References 26 publications

Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

Human immunoglobulin G reduces the pathogenicity of aquaporin-4 autoantibodies in neuromyelitis optica

Intravenous immunoglobulin (IVIg) provides protection against endothelial cell dysfunction and death in ischemic stroke

Ginsenoside Rb1 ameliorates lipopolysaccharide-induced albumin leakage from rat mesenteric venules by intervening in both trans- and paracellular pathway

Contact Info

Product

Resources

About