TREATMENT STRATEGIES FOR THE ENDOTHELIOPATHY OF TRAUMA

Transcription

1 TREATMENT STRATEGIES FOR THE ENDOTHELIOPATHY OF TRAUMA Rosemary Kozar, MD, PhD Professor of Surgery University of Texas- Houston Shock- Trauma; University of Maryland

2 Trauma Hemostasis and Oxygena on Research Posi on Paper on RDCR: Defini ons, Current Prac ce, and Knowledge Gaps SHOCK 2014:41S, 3-12 Endotheliopathy of trauma : result of systemic endothelial injury caused by trauma and hemorrhage leading to disturbances in: Coagula on Inflamma on Blood- organ endothelial barrier integrity Vasoregula on

3 SYNDECAN- 1 (sdc- 1) Syndecan- 1 is a heparan sulfate cell surface proteoglycan that forms the structural backbone of a protec ve network of soluble plasma components referred to as the glycocalyx

4 SYNDECAN- 1 (sdc- 1) Syndecan- 1 is a Heparan sulfate cell surface proteoglycan that forms the structural backbone of a protec ve network of soluble plasma components referred to as the glycocalyx Glycocalyx projects from the cell surface and shields receptors from being exposed to proinflammatory mediators and adhesion ligands.

5 SYNDECAN- 1 (sdc- 1) Disrup on of the sdc- 1 backbone by shedding of its ectodomain is thought to result in vascular hyperpermeability and breakdown of the endothelial barrier

6 Hypothesis: Hemorrhagic shock induces shedding of sdc- 1 from the endothelium Sdc- 1 shedding leads to vascular instability and organ injury FFP based resuscita on is protec ve by restoring the endothelial glycocalyx

7 Modulation of Syndecan-1 Shedding after Hemorrhagic Shock and Resuscitation PLoS ONE 6:2011 Ricky J. Haywood-Watson, John B. Holcomb, Ernest A. Gonzalez, Zhanglong Peng, Shibani Pati Pyong Woo Park, WeiWei Wang, Ana Maria Zaske, Tyler Menge, Rosemary A. Kozar Survivors vs nonsurvivors Prospec ve pilot study of 32 severely injured pa ents

8 Prospec ve cohort study of 75 trauma pa ents 3 fold increase in mortality in pa ents with high circula ng syndecan- 1 levels

9 Cytokines that correlated with syndecan shedding

10 In vitro: endothelial cell permeability HUVECs underwent hypoxia/reoxygena on and IL- 1β then incuba on in 5% LR or FFP

11 VE- cadherin immunoreac vity in enhanced by FFP in an in vitro model of endothelial injury

12 Endothelial ultrastructure is restored by FFP Atomic Force Microscope A. Normoxic controls: no gap B. LR: gap 6.5 ± 1.1 um C. FFP gap: 2.4 ± 0.2 um

13 Cell surface syndecan is enhanced by FFP

14 Proposed model of sydnecan- 1 interac on with inflammatory cytokines a er shock and resuscita on with FFP

15 Plasma Restoration of Endothelial Glycocalyx in a Rodent Model of Hemorrhagic Shock Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, Ko T, Paredes A Anesth Analg :1289

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18 Pulmonary syndecan- 1 is restored by plasma

19 J Trauma 75:5 2013

20 Glycocalyx thickness

21 FRESH FROZEN PLASMA LESSENS PULMONARY ENDOTHELIAL INFLAMMATION AND HYPERPERMEABILITY AFTER HEMORRHAGIC SHOCK AND IS ASSOCIATED WITH LOSS OF SYNDECAN 1 Zhanglong Peng, Shibani Pati, Daniel Potter, Ryan Brown, John B. Holcomb, Raymond Grill, Kathryn Wataha, Pyong Woo Park, Hasen Xue, and Rosemary A. Kozar Shock (3):

22 Effect of resuscita on fluids on MAP LR FFP

23 Pulmonary syndecan- 1 is restored by FFP

24 Pulmonary inflamma on is lessen by FFP

25 FFP is being used in the prehospital se ng in some civilian trauma centers We have been examining the use of lyophilized plasma and comparing its effects to fresh frozen plasma

26 Ques on When using a rodent model of hemorrhagic shock, should we be tes ng rodent plasma or human plasma?????? Tested mouse FFP, human FFP, and human LP

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28 Lung Injury: histopathology Lung histologic score mouse human LP No significant differences between groups

29 Lung permeability: Evan s Blue dye extravasa on 7 Lung permeability (arbitary unit) mouse human LP No significant differences between groups

30 Lung Edema: wet/dry weight ra o 4 Lung wet/dry weight ra o mouse human LP No difference between groups

31 Lung Inflamma on: Neutrophil staining 30 p<0.01 p< Neutrophile (cells/ 1050X1050 pixels area) mouse human LP Mouse and human LP were similar but a significant increase in human FFP

32 Conclusion: Mouse vs human plasma There is an adverse early effect of human plasma on systemic perfusion

33 Conclusion: Mouse vs human plasma There is an adverse early effect of human plasma on systemic perfusion This does not seem to translate into significant effects on end organ (lung) injury, permeability, or edema but does increase inflamma on

34 Conclusion: Mouse vs human plasma There is an adverse early effect of human plasma on systemic perfusion This does not seem to translate into significant effects on end organ (lung) injury, permeability, or edema but does increase inflamma on Lung inflamma on was s ll reduced by human plasma compared to LR

35 Conclusion: Mouse vs human plasma There is an adverse early effect of human plasma on systemic perfusion This does not seem to translate into significant effects on end organ (lung) injury, permeability, or edema but does increase inflamma on Lung inflamma on was s ll reduced by human plasma compared to LR The protec ve effects of plasma may be slightly masked by using human plasma in animal experiments

36 S ll Lots to Do Determine the effect of syndecan- 1 silencing Determine the effect of endothelial specific syndecan- 1: syndecan- 1 is found on both endothelial and epithelial cells What are the mechanisms by which syndecan- 1 is shed a er hemorrhagic shock

37 What is the effect of syndecan- 1 silencing?? Syndecan- 1 null mice have a worse survival compared to WT Preliminary data in KO mice demonstrate that FFP loses it protec ve effects in the small intes ne

38 Examine endothelial specific sdc- 1 VE cadherin- tta/tre

39 Mechanisms: Determine the effect of HS on sdc- 1 sheddases and sheddase inhibitors Pro- TNFα 7 TACE ADAM- 17 Ac ve TNFα Plasma ADAM17 (ng/ml) Sham Sham- TXA Shock Shock- TXA

40 Summary HS adversely affects endothelial integrety Leads to hyperpermeability and organ damage Associated with syndecan- 1 shedding Plasma recons tutes the syndecan- 1 ectodomain. This may represent one mechanism by which plasma restores the endothiopathy of trauma

41 Targe ng the injured endothelium may represent a future area of research Certain frac ons of FFP Inhibitors of sheddases: TIMP3 Slit- 2