Methicillin-resistant Staphylococcus aureus (MRSA) infection has become a serious health problem both in the community and in hospitals. ~20,000 people die annually in the U.S. because of MRSA, the rate is greater than those die from AIDS. The goal of the present proposal is to characterize novel mechanistic aspects of microvascular hyper-permeability during MRSA pneumonia/sepsis and offer novel and efficient therapeutic options that will reduce morbidity and mortality. Our general hypothesis is that stimulation of arginine vasopressin V1a receptors (V1aR) will mitigate MRSA sepsis-induced vascular hyper-permeability and reverse the hypotension, whereas the stimulation of the arginine vasopressin V2 receptors (V2R) will augment the vascular hyper- permeability and will not affect the hypotension. We propose to elucidate the downstream mechanisms, focusing on the interaction between V1aR, V2R, reactive nitrogen species (RNS), and potent angiogenic growth factors such as angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF).
Aim 1 : In an ovine MRSA sepsis model, establish mechanisms of severe vascular hyper-permeability, focusing on opposing effects of V1aR and V2R on release of potent permeability factor Ang-2 and microvascular hyper- permeability. Hypotheses: 1) V1aR activation reduces vascular hyper-permeability by inhibiting Ang-2 release;2) V2R stimulation increases vascular hyper-permeability by promoting Ang-2 release;3) a selective V1aR agonist is superior to a mixed V1aR/V2R agonist arginine vasopressin (AVP) for preventing cardiovascular collapse.
Aim 2 : In an ovine MRSA sepsis model, determine that novel and selective V1aR agonist will mitigate severe vascular leakage by preventing RNS formation through inhibiting excessive nitric oxide production. The down- stream mechanisms of how RNS cause vascular leakage will be also determined. Hypotheses: 1) The vascular hyper-permeability caused by RNS is mediated by Ang-2 release and VEGF expression;3) RNS cause hypo- reactivity of V1aR: 3) V1aR agonist reduces RNS formation by inhibiting excessive nitric oxide production.
Aim 3 : In human cell culture studies, determine the molecular mechanisms of MRSA-induced severe vascular hyper-permeability with especial reference to downstream mechanisms of how V2R activation causes, and of how V1aR agonist inhibits, vascular hyper-permeability in MRSA sepsis. Hypotheses: 1) V2R stimulation pro- motes Ang-2 release in a MAPK-dependent pathway;2) The V1aR agonist suppresses V2R and thus prevents Ang-2 release;3) V1aR agonist modulates interaction of Ang-2 with Tie-2 receptors, most probably by sup- pressing the Tie-2 activation;4) VEGF promotes Ang-2 release by its direct action or via V2R stimulation;5) V2R activation in MRSA sepsis is mediated by RNS;6) V1aR is oxidized/nitrated by RNS. To achieve the aims, the study will utilize a novel ovine model of MRSA sepsis and sophisticated cell culture techniques. We are particularly optimistic about the possibility that the proposed research will lead to translational clinical studies for agonists of the selective V1aR and peroxynitrite modulators.

Public Health Relevance

Sepsis and septic shock are the most common cause of death in intensive care units, accounting for mortality rates of up to 70%. Methicillin-resistant Staphylococcus aureus is a frequent source of sepsis associated with high mortality because it is resistant to most of the conventional antibiotics. This study investigates the pathophysiology of sepsis/septic shock induced by methicillinresistant Staphylococcus aureus and offers novel treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM097480-01A1
Application #
8239374
Study Section
Special Emphasis Panel (ZRG1-SBIB-Q (02))
Program Officer
Dunsmore, Sarah
Project Start
2012-06-01
Project End
2017-02-28
Budget Start
2012-06-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$288,477
Indirect Cost
$98,477
Name
University of Texas Medical Br Galveston
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Maybauer, Marc O; Maybauer, Dirk M; Enkhbaatar, Perenlei et al. (2014) The selective vasopressin type 1a receptor agonist selepressin (FE 202158) blocks vascular leak in ovine severe sepsis*. Crit Care Med 42:e525-33
Asmussen, Sven; Ito, Hiroshi; Traber, Daniel L et al. (2014) Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax 69:819-25
Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda E et al. (2014) Advantages and pitfalls of combining intravenous antithrombin with nebulized heparin and tissue plasminogen activator in acute respiratory distress syndrome. J Trauma Acute Care Surg 76:126-33
Lange, Matthias; Cox, Robert A; Traber, Daniel L et al. (2013) Time course of early histopathological lung changes in an ovine model of acute lung injury and pulmonary infection. Exp Lung Res 39:201-6