Loss of Syndecan-1 Abrogates the Pulmonary Protective Phenotype Induced by Plasma After Hemorrhagic Shock

Abstract

Syndecan-1 is considered a biomarker of injury to the endothelial glycocalyx following hemorrhagic shock, with shedding of sdc1 deleterious. Resuscitation with fresh frozen plasma (FFP) has been correlated with restitution of pulmonary sdc1 and reduction of lung injury, but the precise contribution of sdc1 to FFPs protection in the lung remains unclear. Human lung endothelial cells were used to assess the time and dose dependent effect of FFP on sdc1 expression and the effect of sdc1 silencing on in vitro endothelial cell permeability and actin stress fiber formation. Wild-type (WT) and syndecan-1−/− mice were subjected to hemorrhagic shock followed by resuscitation with lactated ringers (LR) or FFP and compared to shock alone and shams. Lungs were harvested after 3 hours for analysis of permeability, histology, and inflammation and for measurement of syndecan- 2 and 4 expression. In vitro, FFP enhanced pulmonary endothelial sdc1 expression in time- and dose-dependent manners and loss of sdc1 in pulmonary endothelial cells worsened permeability and stress fiber formation by FFP. Loss of sdc1 in vivo lead to equivalency between LR and FFP in restoring pulmonary injury, inflammation, and permeability after shock. Lastly, sdc1 −/− mice demonstrated a significant increase in pulmonary syndecan 4 expression after hemorrhagic shock and FFP based resuscitation. Taken together, our findings support a key role for sdc1 in modulating pulmonary protection by FFP after hemorrhagic shock. Our results also suggest that other members of the syndecan family may at least be contributing to FFP’s effects on the endothelium, an area that warrants further investigation.

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“…[30][31][32] Trauma-induced disruption of glycocalyx has been reported to increase the permeability of the blood-brain barrier. 33,34 In addition, the RGD sequence in lactadherin binds the integrins avb 3 and avb 5 to promote cell adhesion, 16,19,34,35 through integrin-mediated intracellular signaling, 36 to repair injured endothelial barriers. This lactadherin-integrin interaction may also promote phagocytosis of BDMVs by endothelial cells, which have been shown to have a phagocytic activity, 37 as lactadherin also protects the endothelial barrier independent of monocytes ( Figure 5A).…”

Trauma‐induced coagulopathy: The past, present, and future

“…Emerging literature describes a conglomeration of sterile inflammatory and immune responses that center around the endothelium and that are related but unique to biochemical coagulopathies of TIC . The injury response establishes a cascade of inflammatory and immune dysfunction resulting in single and multiple organ failure (acute kidney injury, acute respiratory distress syndrome, and hepatic dysfunction) and a higher susceptibility to infection . Much work has been performed in sepsis models, but, more recently, bridging work has been performed between coagulation and inflammation in trauma.…”

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“…Endothelial function HDIVC decreases circulating thrombomodulin, an endothelial membrane protein receptor for thrombin that converts thrombin to an anticoagulant capable of activating protein C [95]. Decreases plasma Syndecan-1 levels, a by-product of endothelial glycocalyx shedding [96][97][98][99][100][101][102][103][104][105][106][107][108].…”