Blockade of Endothelial Growth Factor, Angiopoietin-2, Reduces Indices of Ards and Mortality in Mice Resulting from the Dual-Insults of Hemorrhagic Shock and Sepsis :

Abstract

<p class="first" id="P1">We have demonstrated hemorrhagic shock “priming” for the development of indirect (i)ARDS in mice following subsequent septic challenge and show pathology characteristic of patients with iARDS, including increased lung micro-vascular permeability and arterial PO ₂/FI0 ₂ reduced to levels comparable to mild/moderate ARDS during the 48 hours following hemorrhage. Loss of endothelial cell (EC) barrier function is a major component in the development of iARDS. EC growth factors, Angiopoietin (Ang)-1 &amp; 2, maintain vascular homeostasis via tightly regulated competitive interaction with tyrosine kinase receptor, Tie2, expressed on ECs. Ang-2/Tie2 binding, in contrast to Ang-1, is believed to produce vessel destabilization, pulmonary leakage and inflammation. Recent clinical findings from our trauma/surgical intensive care units and others have reported elevated Ang-2 in the plasma from patients that develop ARDS. We have previously described similarly elevated Ang-2 in plasma and lung tissue in our shock/sepsis model for the development of iARDS and demonstrated effective reduction in indices of inflammation and lung tissue injury following siRNA inhibition of Ang-2 protein synthesis. In this study we show that Ang-2 in lung tissue and plasma spikes following hemorrhage (priming) and remain elevated at sepsis induction. Also, that transient inhibition of Ang-2 function immediately following hemorrhage, suppressing priming, but not following sepsis, impacts the development of iARDS in our model. Our data demonstrates that selective temporal blockade of Ang-2 function following hemorrhagic shock priming, significantly improved PO ₂/FIO ₂, decreased lung protein leak and indices of inflammation, and improved 10-day survival in our murine model for the development iARDS. </p>