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. 2015 Nov;44(5):452-7.
doi: 10.1097/SHK.0000000000000452.

Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1-/- Mice

Kechen Ban  1 , Zhanglong Peng, Shibani Pati, Richard B Witkov, Pyong Woo Park, Rosemary A Kozar
Affiliations

Plasma-Mediated Gut Protection After Hemorrhagic Shock is Lessened in Syndecan-1-/- Mice

Kechen Ban et al. Shock. 2015 Nov.

Abstract

We have shown in a rodent model of hemorrhagic shock (HS) that fresh frozen plasma (FFP) reduces lung inflammation and injury that are correlated with restitution of syndecan-1. As the gut is believed to contribute to distant organ injury and inflammation after shock, the current study sought to determine if the protective effects of plasma would extend to the gut and to elucidate the contribution of syndecan-1 to this protective effect. We also examined the potential role of TNFα, and a disintegrin and metalloproteinase (ADAM)-17, both intestinal sheddases of syndecan-1. Wild-type (WT) and syndecan-1 (KO) mice were subjected to HS followed by resuscitation with lactated Ringer's (LR) or FFP and compared with shock alone and shams. Small bowel and blood were obtained after 3 h for analysis of mucosal injury and inflammation and TNFα and ADAM-17 protein expression and activity. After HS, gut injury and inflammation were significantly increased compared with shams. Resuscitation with LR decreased both injury and inflammation that were further lessened by FFP. KO mice displayed worsened gut injury and inflammation after HS compared with WT mice, and LR and FFP equivalently inhibited injury and inflammation. Both systemic and intestinal TNFα and ADAM-17 followed similar trends, with increases after HS, reduction by LR, and a further decrease by FFP in WT but not KO mice. In conclusion, FFP decreased gut injury and inflammation after hemorrhagic shock, an effect that was abrogated in syndecan-1 mice. Plasma also decreased TNFα and ADAM-17, representing a potential mechanistic link to its protection via syndecan-1.

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Figures

Figure 1
Figure 1. Plasma mitigates gut injury in wild type but not syndecan-1 null mice
Wild-type and syndecan-1 null mice underwent laparotomy and hemorrhagic shock followed by resuscitation with either lactated Ringers or fresh frozen plasma. After three hours small bowel was harvested and histopathologic injury assessed. Representative images from WT mice are shown for each group: (A) WT shams, (B) WT shock (C) WT LR and (D) WT FFP. The percentage of injured villi are shown in the graph. Data are expressed as mean±SEM, n=8/group with significance indicated by lines over the respective groups. WT= wild type; LR= lactated ringers, FFP= fresh frozen plasma
Figure 2
Figure 2. Plasma mitigates inflammation in wild type but not syndecan-1 null mice
Wild-type and syndecan-1 null mice underwent laparotomy and hemorrhagic shock followed by resuscitation with either lactated Ringers or fresh frozen plasma. After three hours small bowel was harvested for assessment of inflammation by quantifying neutrophilic infiltration. Data are expressed as mean±SEM, n=8/group with significance indicated by lines over the respective groups.
Figure 3
Figure 3. Plasma lessens systemic TNFα and ADAM-17 protein in wild type but not syndecan-1 KO mice
Wild-type and syndecan-1 KO mice underwent laparotomy and hemorrhagic shock followed by resuscitation with either lactated Ringers or fresh frozen plasma. After three hours animals were euthanized and blood obtained for measurement of TNFα and ADAM-17 protein by ELISA. Data are expressed as mean±SEM, n=8/group with significance indicated by lines over the respective groups.
Figure 3
Figure 3. Plasma lessens systemic TNFα and ADAM-17 protein in wild type but not syndecan-1 KO mice
Wild-type and syndecan-1 KO mice underwent laparotomy and hemorrhagic shock followed by resuscitation with either lactated Ringers or fresh frozen plasma. After three hours animals were euthanized and blood obtained for measurement of TNFα and ADAM-17 protein by ELISA. Data are expressed as mean±SEM, n=8/group with significance indicated by lines over the respective groups.
Figure 4
Figure 4. ADAM-17 activity in wild type and syndecan-1 null mice
Wild-type and syndecan-1 null mice underwent laparotomy and hemorrhagic shock followed by resuscitation with either lactated Ringers or fresh frozen plasma. After three hours animals were euthanized and small bowel and blood obtained for measurement of ADAM-17 activity. Data are expressed as mean±SEM, n=8/group with significance indicated by lines over the respective groups.
Figure 4
Figure 4. ADAM-17 activity in wild type and syndecan-1 null mice
Wild-type and syndecan-1 null mice underwent laparotomy and hemorrhagic shock followed by resuscitation with either lactated Ringers or fresh frozen plasma. After three hours animals were euthanized and small bowel and blood obtained for measurement of ADAM-17 activity. Data are expressed as mean±SEM, n=8/group with significance indicated by lines over the respective groups.
Figure 5
Figure 5. Proposed pathway of fresh frozen plasma's protection after hemorrhagic shock
After hemorrhagic shock, ADAM-17 is increased. ADAM-17 is a known sheddase of both TNFα and syndecan-1. Additionally, TNFα is a potent sheddase of syndecan-1. Fresh frozen plasma (FFP) may directly interact with ADAM-17 to reduce its activity and/or interact with syndecan-1 to reconstitute gut epithelial cell syndecan-1 and reduce systemic syndecan-1 shedding.
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