scholarly journals Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

2004 ◽  
Vol 77 (2) ◽  
pp. 117-125 ◽  
Author(s):  
Venkatasubramaniam S. Kalambur ◽  
Hemchandra Mahaseth ◽  
John C. Bischof ◽  
Miroslaw C. Kielbik ◽  
Thomas E. Welch ◽  
...  
Keyword(s):  
Blood Flow ◽  
Intravital Microscopy ◽  
Microvascular Blood Flow ◽  
Dorsal Skin ◽  
Skin Fold ◽  
Dorsal Skin Fold Chamber

scholarly journals MEK Inhibitors, Novel Anti-Adhesive Molecules, Reverse Sickle Red Blood Cell Adhesion and Vaso-Occlusion in Vivo

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 739-739
Author(s):  
Rahima Zennadi
Keyword(s):  
Blood Flow ◽  
Nude Mice ◽  
Vascular Endothelium ◽  
Intravital Microscopy ◽  
Dorsal Skin ◽  
Skin Fold ◽  
Normal Blood Flow ◽  
Window Chamber

In sickle cell disease (SCD), painful vaso-occlusive crises and end-organ damage are caused by obstruction of the vessels due in large part to sickle erythrocyte (SSRBC) adherence to both the endothelium and leukocytes. Despite the contribution of SSRBC adhesiveness to vaso-occlusion, we lack treatments that specifically target intracellular signaling mechanisms critical for SSRBC cell-cell interactions. We have previously shown that the mitogen-activated protein (MAP) kinase ERK1/2 is aberrantly activated in SSRBCs. ERK1/2 signaling activation is critical for SSRBC interactions with the vascular endothelium and leukocytes. We have now evaluated the anti-adhesive properties of RDEA119, an inhibitor of MEK1/2, the kinase that activates the MAP kinase ERK1/2, in in vitro adhesion assays and in vivo in both nude mouse and humanized models of vaso-occlusion analyzed by intravital microscopy. We used RDEA119 because this dryg has previously been developed for human use. We found that RDEA119 caused a dose-dependent inhibition of human SSRBC adhesion to cultured TNFα-activated human micro-vascular endothelial cells (HMVECs) in vitro with a half-maximum inhibitory concentration (IC50) < 2 nmol/L. This suggests that RDEA119 would be effective at very low doses in reducing SSRBC adhesion and vaso-occlusion in vivo. To determine if RDEA119 prevents vaso-occlusion in nude mice, animals were injected with TNFα followed by infusion of RDEA119 (or placebo control), and then human SSRBCs. Intravital microscopy observations of enflamed vessels visible through dorsal skin-fold window chamber implants immediately after human SSRBC infusion showed persistent human SSRBC adhesion to both small and large vessels, with mean diameter of 29±3.5 μm, and vaso-occlusion in placebo-treated nude mice for at least 2 h, promoting blood stasis. However, treatment of nude mice with either 0.2 mg/kg or 2 mg/kg RDEA119 markedly reduced human SSRBC adhesion and mitigated vaso-occlusion. While human SSRBC adhered to 68.5±4.6% of total vessels recorded in placebo-treated animals, SSRBCs occupied only 33 ± 6.6% (p<0.0001) and 25 ± 3.7% (p<0.0001) of vessels in 0.2 and 2 mg/kg RDEA119-treated nude mice, respectively. As a result, normal blood flow was restored in 95±3.5% and 76±6.2% of vessels in 0.2 and 2 mg/kg RDEA119-treated animals, respectively, compared to 43±5.8% of vessels with normal blood flow in placebo-treated mice (p<0.001). Nude mice treated with 0.2 mg/kg RDEA119 also exhibited reduced human SSRBC trapping in the lungs, liver and spleen (p<0.0001), and an increased number of human SSRBCs remaining in circulation. RDEA119 was also administered to nude mice after onset of vaso-occlusion for a more clinically relevant outcome. Infusion of a single dose of 1 mg/kg RDEA119 to nude mice reduced human SSRBC adhesion and vaso-occlusion within 5 min of RDEA119 administration, and adhesion progressively decreased thereafter compared to SSRBC adhesion and vaso-occlusion in these same vessel segments prior to drug administration (p<0.0001). RDEA119 led to a 72% reduction in the percentage of vessels occupied by adherent human SSRBCs (p<0.001) and improvement in blood flow in 89±2.4% of vessels (p<0.001). Similar therapeutic benefits were obtained when RDEA119 was administered after the inflammatory trigger of TNFα to induce vaso-occlusion in transgenic sickle mice. RDEA119 resulted in a significant decrease in adherent sickle cells in enflamed vessels of sickle mice treated with only one dose of RDEA119 at 0.1, 0.05 or 0.025 mg/kg (p<0.001). RDEA119 at 0.1, 0.05 or 0.025 mg/kg also significantly reduced adhesion of leukocytes to the vascular endothelium compared with placebo-treated sickle mice (p<0.001). The effect of RDEA119 on both sickle RBCs and leukocyte adhesion was rapid, because a reduction in adhesion of the cells was already detectable within the first 15 minutes after drug infusion, and adhesion further decreased thereafter. In contrast, adherence of leukocytes increased progressively over time in placebo-treated sickle mice. Treatment of sickle mice with RDEA119 led to improved microcirculatory blood flow in enflamed vessels visible through the dorsal skin-fold window chamber and improved survival. These results suggest that RDEA119 may represent a valuable novel therapeutic intervention for acute pain crises that should be further evaluated in humans with SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Tissue Engineered Skin Substitutes Created by Laser-Assisted Bioprinting Form Skin-Like Structures in the Dorsal Skin Fold Chamber in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e57741 ◽  
Author(s):  
Stefanie Michael ◽  
Heiko Sorg ◽  
Claas-Tido Peck ◽  
Lothar Koch ◽  
Andrea Deiwick ◽  
...  
Keyword(s):  
Dorsal Skin ◽  
Skin Substitutes ◽  
Skin Fold ◽  
Engineered Skin Substitutes ◽  
Dorsal Skin Fold Chamber

Irreversible Electroporation: An In Vivo Study with Dorsal Skin Fold Chamber

2012 ◽  
Vol 41 (3) ◽  
pp. 619-629 ◽  
Author(s):  
Zhenpeng Qin ◽  
Jing Jiang ◽  
Gary Long ◽  
Bruce Lindgren ◽  
John C. Bischof
Keyword(s):  
Irreversible Electroporation ◽  
In Vivo Study ◽  
Dorsal Skin ◽  
Skin Fold ◽  
Dorsal Skin Fold Chamber

scholarly journals Dorsal Skin Fold Chamber for High Resolution Multiphoton Imaging

2005 ◽  
Vol 37 (13-15) ◽  
pp. 1439-1445 ◽  
Author(s):  
Feng-Chieh Li ◽  
Chun-Chin Wang ◽  
Sung-Jan Lin ◽  
Shiou-Hwa Jee ◽  
Wen Lo ◽  
...  
Keyword(s):  
High Resolution ◽  
Dorsal Skin ◽  
Multiphoton Imaging ◽  
Skin Fold ◽  
Dorsal Skin Fold Chamber

scholarly journals Intravital insights in skin wound healing using the mouse dorsal skin fold chamber

2007 ◽  
Vol 211 (6) ◽  
pp. 810-818 ◽  
Author(s):  
Heiko Sorg ◽  
Christian Krueger ◽  
Brigitte Vollmar
Keyword(s):  
Wound Healing ◽  
Skin Wound ◽  
Dorsal Skin ◽  
Skin Wound Healing ◽  
Skin Fold ◽  
Dorsal Skin Fold Chamber

The mouse dorsal skin fold chamber as a means for the analysis of tissue engineered skin

Burns ◽  
2013 ◽  
Vol 39 (1) ◽  
pp. 82-88 ◽  
Author(s):  
Stefanie Michael ◽  
Heiko Sorg ◽  
Claas-Tido Peck ◽  
Kerstin Reimers ◽  
Peter M. Vogt
Keyword(s):  
Dorsal Skin ◽  
Skin Fold ◽  
Dorsal Skin Fold Chamber
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