Microthrombus Formation Triggers Lung Injury in Sepsis
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Project Summary:
Septic Lung injury is an often-fatal complication of numerous clinical conditions that affects a significant percentage of the VA patient population.
This injury is characterized by gross cellular damage of the lung endothelium and epithelium, and degradation of the barrier that separates the capillaries from the alveolar air space. The result is that blood components, including re cells and plasma, enter the alveolar air space. The presence of these materials in the air space is associated with the development SIRS/ARDS, and with the subsequent development of interstitial fibrosis, type-II cell proliferation and hyaline membrane disease. Septic lung injury is known to be associated with the sequestration of activated neutrophils into the pulmonary circulation, and it is widely believed that cytotoxic agents released by these cells are responsible for the injury to the capillaries and alveoli that characterize this disease. However, the specific trigger for sepsis-induced neutrophil invasion of the lung is not known, and is the subject of our proposed studies. We hypothesize that agents that prevent microthrombus formation (low molecular weight heparin or recombinant activated protein C) may prevent the subsequent neutrophil invasion, and therefore minimize the lung injury associated with sepsis.
Specific Aim 1: Measure thrombus formation within lung microvessels early in sepsis, and measure their effects on the distribution of microvascular perfusion. We will induce sepsis using our intra-abdominal live bacteria model, and assess thrombin formation using immunoflourescence and Western blot analysis. We will also perform these studies in rats depleted of neutrophils.
Specific Aim 2: Show that neutrophil sequestration into the lung occurs only after microthrombus formation. We will use immunoflourescence to label both microthrombi and neutrophils within lung microvessels of rats at various times after the induction of sepsis. We hope to show that thrombus formation precedes the appearance of neutrophils.
Specific Aim 3: Show that prevention of thrombus formation prevents neutrophil sequestration, and prevents lung injury. We will use recombinant activated Protein C (Drotrecogin alpha), low molecular weight heparin and recombinant hirudin to determine in septic rats if: 1) thrombin formation can be reduced or prevented, 2) neutrophil sequestration within the lung can also be prevented due to inhibition of thrombus formation, 3) alveolar perfusion man-distribution can be prevented due to prevention of thrombus formation and neutrophil sequestration.
Specific Aim 4: Determine the role of thromboxane in the control of lung mircovascular perfusion during sepsis. We have shown that thromboxane alters the distribution of microvascular perfusion in isolated lungs perfused with cell-free perfusate. Thromboxane is also known to be secreted by neutrophils. We will also conduct additional studies using a thromboxane receptor antagonist to further explore the role of thromboxane in sepsis.
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General Surgery
University of Wisconsin Department of Surgery
First published: 07/15/02 Last updated: 11/24/09 webmaster@surgery.wisc.edu
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