The Role of Arginine Vasopressin Receptor 2 in Microvascular Hyperpermeability During Severe Sepsis and Septic Shock

dc.contributor.advisorEnkhbaatar, Perenlei
dc.contributor.advisor
dc.contributor.committeeMemberBarral, Jose M.
dc.contributor.committeeMemberPrough, Donald S.
dc.contributor.committeeMemberCox, Robert A.
dc.contributor.committeeMemberLee, Jae-Woo
dc.creatorLopez, Ernesto
dc.date.accessioned2019-03-13T20:52:07Z
dc.date.available2019-03-13T20:52:07Z
dc.date.created2015-12
dc.date.submittedDecember 2015
dc.date.updated2019-03-13T20:52:07Z
dc.description.abstractSepsis compromises more than 18 million lives worldwide every year. Moreover, methicillin-resistant Staphylococcus aureus (MRSA) sepsis is one of the most severe types. Despite efforts to provide novel therapies for sepsis, the mortality has not decreased in several decades. Sepsis often leads to vascular leakage, and although the hemodynamic management of this condition targets hypotension, currently no specific treatment is available for vascular leakage. Thus, the overall goal of the current study was to investigate the most important mechanisms of vascular leakage during severe sepsis and propose a novel therapeutic strategy for this condition. Arginine vasopressin (AVP), a hypothalamic hormone, has been used exogenously in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1R). However, recent evidence suggests that an increased fluid retention may be associated when AVP receptor 2 (V2R) is simultaneously activated. Hence, we hypothesized that V2R activation induces vascular hyperpermeability. The hypothesis was tested using a well-characterized ovine model of MRSA sepsis and various in vitro cell-based assays with human lung microvascular endothelial cells (HMVECs). Results demonstrated that the treatment of septic sheep with tolvaptan, an FDA-approved V2R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected or augmented by the treatment with V2R agonist desmopressin (DDAVP). Furthermore, the incubation of cultured HMVECs with DDAVP significantly increased the paracellular permeability. Moreover, endothelial cells subjected to MRSA also augmented the endothelial permeability. Finally, both the DDAVP and MRSA induced elevated hyperpermeability were significantly attenuated by the V2R antagonist tolvaptan (TLVP). Subsequent protein and gene assays determined that the V2R-induce increase in permeability is mediated by phospholipase C beta 4 (PLCĪ²-4) and the potent permeability factor angiopoietin-2. In conclusion, the results of the present work show that endothelial V2R activation increases vascular permeability during sepsis and perhaps its closer modulation could improve the outcome of these critically ill patients. The results from this clinically relevant animal study might be translated into clinical practice in the near future.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2152.3/11213
dc.subjectvasopressin receptor 2, tolvaptan, vascular leakage, sepsis, angiopoietin-2, microvascular endothelial cells, microvascular hyperpermeability, methicillin-resistant Staphylococcus aureus
dc.titleThe Role of Arginine Vasopressin Receptor 2 in Microvascular Hyperpermeability During Severe Sepsis and Septic Shock
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentNeuroscience
thesis.degree.grantorThe University of Texas Medical Branch at Galveston
thesis.degree.levelDoctoral
thesis.degree.nameNeuroscience (Doctoral)

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
LOPEZ-DISSERTATIONDOCTORAL-2015.pdf
Size:
6.53 MB
Format:
Adobe Portable Document Format

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
LICENSE.txt
Size:
1.84 KB
Format:
Plain Text
Description: