VAP is the most common nosocomial infection in ICU patients. Trauma patients are more susceptible to develop VAP than other ICU patients. Among trauma patients, those with severe tissue hypoperfusion have a significantly higher incidence of VAP, although the mechanisms are not well understood. Results from our recent clinical studies and preliminary data from our mouse model of trauma-hemorrhage indicate that this acute hypocoagulation is primarily caused by the activation of the anticoagulant protein C pathway. Several hours later, there is the development of a procoagulant activity associated with (a) low plasma levels of aPC and (b) an inhibition of the fibrinolysis caused by elevated plasma levels of PAI-1. These coagulation abnormalities have previously been associated with an abnormal host response to lung infection induced by nosocomial bacteria, such as P. aeruginosa, the most common gram-negative bacteria associated with VAP, although the mechanistic link between these abnormalities and the development of VAP is unknown. Thus, we will test in this grant proposal the central hypothesis that increased susceptibility to P. aeruginosa pneumonia following severe tissue hypoperfusion is mediated in part by these posttraumatic coagulation abnormalities within the airspaces of the lung. Specifically, we will first examine the in vitro mechanisms by which PAI-1 increases P. aeruginosa-induced lung endothelial permeability by activating RhoA and unligating the 1v23 integrin from its extracellular ligand vitronectin (aim 1). Second, we will examine the mechanisms by which activated protein C inhibits the P. aeruginosa-induced activation of the RhoA signaling pathway in lung endothelial cells (aim 2). Third, we will determine the in vivo relevance of the mechanisms by which PAI-1 and activated protein C modulate the increase in lung vascular permeability induced by airspace P. aeruginosa following severe trauma/hemorrhage in mice.
(aim 3). The information obtained from the in vitro experiments and our clinically relevant mouse model of trauma-hemorrhage and subsequent P. aeruginosa pneumonia will have important therapeutic significance in humans. Indeed, understanding the molecular mechanisms by which nosocomial bacteria manipulate coagulation proteins may provide new avenues for causal therapy for VAP in trauma patients, such as using pharmacologic PAI-1 or non-anticoagulant aPC that have been shown to be safe in humans.
Project Narrative: We have previously identified a new mechanism that explains why trauma patients with major bleeding develop early abnormalities in their coagulation system that are characterized by an inability to coagulate normally. We found that the activation of the protein C pathway is critical for the development of these early coagulation abnormalities. As the posttraumatic inflammation develops, it then activates the coagulation system by decreasing the activity of these natural anticoagulants, such as the protein C, and by inhibiting the fibrinolysis. Because it has been shown that the downregulation of these anticoagulant pathways not only promotes thrombosis, but also amplifies the inflammatory process, we will test in this grant proposal the hypothesis that these posttraumatic coagulation abnormalities increase the lung injury caused by a virulent bacterium, Pseudomonas aeruginosa, that often infects the lungs of severely traumatized patients.
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|Wagener, Brant M; Roux, JÃ©rÃ©mie; Carles, Michel et al. (2015) Synergistic Inhibition of Î²2-adrenergic Receptor-mediated Alveolar Epithelial Fluid Transport by Interleukin-8 and Transforming Growth Factor-Î². Anesthesiology 122:1084-92|
|Simmons, Jeffrey W; Pittet, Jean-Francois (2015) Revealing the real risks of perioperative transfusion: rise of the machines! Anesthesiology 122:1-2|
|Simmons, Jeff; Sikorski, Robert A; Pittet, Jean-Francois (2015) Tranexamic acid: from trauma to routine perioperative use. Curr Opin Anaesthesiol 28:191-200|
|Simmons, Jeff; Pittet, Jean-Francois (2015) The coagulopathy of acute sepsis. Curr Opin Anaesthesiol 28:227-36|
|Pierce, Albert; Pittet, Jean-FranÃ§ois (2014) Inflammatory response to trauma: implications for coagulation and resuscitation. Curr Opin Anaesthesiol 27:246-52|
|Smith, Jeremy B; Pittet, Jean-Francois; Pierce, Albert (2014) Hypotensive Resuscitation. Curr Anesthesiol Rep 4:209-215|
|Wagener, Brant M; Pittet, Jean-Francois (2014) A more clinically relevant model of ventilator-associated pneumonia? Anesthesiology 120:1075-7|
|Pierce, Albert; Pittet, Jean-Francois (2014) Practical understanding of hemostasis and approach to the bleeding patient in the OR. Adv Anesth 32:1-21|
|Simmons, Jeffrey W; Pittet, Jean-Francois; Pierce, Bert (2014) Trauma-Induced Coagulopathy. Curr Anesthesiol Rep 4:189-199|
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