Abstract:AimsEndothelial hyperpermeability exacerbates multiple organ damage during inflammation or infection. The endothelial glycocalyx, a protective matrix covering the luminal surface of endothelial cells (ECs), undergoes enzymatic shedding during inflammation, contributing to barrier hyperpermeability. A disintegrin and metalloproteinase 15 (ADAM15) is a sheddase capable of cleaving the ectodomains of membrane-bound molecules. Herein, we tested whether and how ADAM15 is involved in glycocalyx shedding and vascular… Show more
“…After anesthesia, mice were intravenously injected with 1% Evans blue dye (100 mg/kg). After 30 min, the lungs were perfused with lactated ringer's solution to remove intravascular Evans blue dye (14). The entire right lobes were homogenized in 0.5 mL of PBS, incubated with 1 mL of formamide (Fisher Scientific, BP227-500) at 60 • C for 18 h to extract Evans blue, and centrifuged at 5,000 g for 30 min to collect the supernatant.…”
Gut ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidities that result from systemic inflammation and remote organ dysfunction, typically acute lung injury. The mechanisms underlying the dissemination of gut-derived harmful mediators into the circulation are poorly understood. The objective of our study was to determine the role of mesenteric lymphatic circulation in the systemic and pulmonary inflammatory response to gut I/R. Using a murine intestinal I/R model, we evaluated whether and how blocking mesenteric lymph flow affects the inflammatory response in local tissues (gut) and remote organs (lungs). We further explored the mechanisms of post-I/R lymph-induced systemic inflammation by examining neutrophil activity and interaction with endothelial cells in vitro. Mice subjected to intestinal I/R displayed a significant inflammatory response in local tissues, evidenced by neutrophil infiltration into mucosal areas, as well as lung inflammation, evidenced by increased myeloperoxidase levels, neutrophil infiltration, and elevated microvascular permeability in the lungs. Mesenteric lymph duct ligation (MLDL) had no effect on gut injury per se, but effectively attenuated lung injury following gut I/R. Cell experiments showed that lymph fluid from post-I/R animals, but not pre-I/R, increased neutrophil surface CD11b expression and their ability to migrate across vascular endothelial monolayers. Moreover, post-I/R lymph upregulated neutrophil expression of pro-inflammatory cytokines and chemokines, which was mediated by a mechanism involving nuclear factor (NF)-κB signaling. Consistently, gut I/R activated NF-κB in lung neutrophils, which was alleviated by MLDL. In conclusion, all these data indicate that mesenteric lymph circulation contributes to neutrophil activation and lung inflammation following gut I/R injury partly through activating NF-κB.
“…After anesthesia, mice were intravenously injected with 1% Evans blue dye (100 mg/kg). After 30 min, the lungs were perfused with lactated ringer's solution to remove intravascular Evans blue dye (14). The entire right lobes were homogenized in 0.5 mL of PBS, incubated with 1 mL of formamide (Fisher Scientific, BP227-500) at 60 • C for 18 h to extract Evans blue, and centrifuged at 5,000 g for 30 min to collect the supernatant.…”
Gut ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidities that result from systemic inflammation and remote organ dysfunction, typically acute lung injury. The mechanisms underlying the dissemination of gut-derived harmful mediators into the circulation are poorly understood. The objective of our study was to determine the role of mesenteric lymphatic circulation in the systemic and pulmonary inflammatory response to gut I/R. Using a murine intestinal I/R model, we evaluated whether and how blocking mesenteric lymph flow affects the inflammatory response in local tissues (gut) and remote organs (lungs). We further explored the mechanisms of post-I/R lymph-induced systemic inflammation by examining neutrophil activity and interaction with endothelial cells in vitro. Mice subjected to intestinal I/R displayed a significant inflammatory response in local tissues, evidenced by neutrophil infiltration into mucosal areas, as well as lung inflammation, evidenced by increased myeloperoxidase levels, neutrophil infiltration, and elevated microvascular permeability in the lungs. Mesenteric lymph duct ligation (MLDL) had no effect on gut injury per se, but effectively attenuated lung injury following gut I/R. Cell experiments showed that lymph fluid from post-I/R animals, but not pre-I/R, increased neutrophil surface CD11b expression and their ability to migrate across vascular endothelial monolayers. Moreover, post-I/R lymph upregulated neutrophil expression of pro-inflammatory cytokines and chemokines, which was mediated by a mechanism involving nuclear factor (NF)-κB signaling. Consistently, gut I/R activated NF-κB in lung neutrophils, which was alleviated by MLDL. In conclusion, all these data indicate that mesenteric lymph circulation contributes to neutrophil activation and lung inflammation following gut I/R injury partly through activating NF-κB.
“…Soluble CD44 is not only regulated by HA but also other factors, such as cytokines and shedding from immune cells. 27 The metabolism of soluble CD44 in STEMI patients needs further investigation.…”
Background
The metabolism of hyaluronan (HA) is widely known to be involved in the process of acute coronary syndrome, but it is unknown how circulating HA levels change in ST-Segment–Elevation Myocardial Infarction (STEMI) patients and whether HA is associated with plaque morphology, including rupture and erosion.
Objectives
This study focused on the changes in the plasma levels of HA and CD44 in STEMI patients and their relationship with plaque morphology evaluated by optical coherence tomography (OCT).
Methods
We prospectively enrolled 3 cohorts in this study, including 162 patients with STEMI, 34 patients with stable coronary artery disease (SCAD) and 50 healthy controls. Plaque morphology was detected by OCT analysis, and the plasma levels of HA and CD44 were examined by enzyme-linked immunosorbent assay (ELISA). We compared HA and CD44 expression among STEMI patients, SCAD patients and healthy controls, as well as in plaque rupture and plaque erosion.
Results
The plasma levels of HA and CD44 were significantly lower in STEMI patients than in healthy controls (p = 0.009 and p < 0.001, respectively). In addition, plasma HA expression in plaque erosion was significantly lower than that in plaque rupture (p = 0.021), whereas no differences were found in soluble CD44 expression between plaque rupture and erosion.
Conclusions
Low levels of circulating HA and CD44 were independently correlated with STEMI, and low levels of HA were associated with plaque erosion compared with rupture. Moreover, plasma HA might be a useful biomarker for identifying plaque erosion to improve the risk stratification and management of STEMI patients.
“… 149 Therefore, multiple circulating biomarkers of GCX shedding have been studied in humans as markers of sepsis, including SDC1, HS and HA. 15 , 36 , 118 , 227 Figure 13 Representative STORM-acquired images of anti-HS labeled EG and vWF-labeled WPBs distribution in control and 10 min post-LPS. The left panel shows 2D images of a region of ~ 40 µ m x 40 µ m at the apical surface of cultured mouse brain microvascular endothelial cell (EC).…”
Section: Part B: the Role Of The Glycocalyx In Vascular Related Diseamentioning
confidence: 99%
“… 137 In addition to turning TNF-α into a soluble form, ADAM 17 cleaves SDC4 while ADAM 10 sheds SDC1 and ADAM15 cleaves CD44. 227 MMPs induced in sepsis activate TNF-α, interfere in CD44-HA binding and shed HS, CS, and the SDC1 ectodomain. 244 …”
Section: Part B: the Role Of The Glycocalyx In Vascular Related Diseamentioning
Purpose
In 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121–167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper.
Methods
A literature search mainly focusing on the role of the glycocalyx in the two major areas described above was performed using electronic databases.
Results
In part (A) of this review, the new formulation of the century old Starling principle, now referred to as the Michel–Weinbaum glycoclayx model or revised Starling hypothesis, is described including new subtleties and physiological ramifications. New insights into mechanotransduction and release of nitric oxide due to fluid shear stress sensed by the glycocalyx are elaborated. Major advances in understanding the organization and function of glycocalyx components, and new techniques for measuring both its thickness and spatio-chemical organization based on super resolution, stochastic optical reconstruction microscopy (STORM) are presented. As discussed in part (B) of this review, it is now recognized that artery wall stiffness associated with hypertension and aging induces glycocalyx degradation, endothelial dysfunction and vascular disease. In addition to atherosclerosis and cardiovascular diseases, the glycocalyx plays an important role in lifestyle related diseases (e.g., diabetes) and cancer. Infectious diseases including sepsis, Dengue, Zika and Corona viruses, and malaria also involve the glycocalyx. Because of increasing recognition of the role of the glycocalyx in a wide range of diseases, there has been a vigorous search for methods to protect the glycocalyx from degradation or to enhance its synthesis in disease environments.
Conclusion
As we have seen in this review, many important developments in our basic understanding of GCX structure, function and role in diseases have been described since the 2007 paper. The future is wide open for continued GCX research.
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