Traumatic brain injury (TBI) is the leading cause of injury related death in patients from ages 1-44 (REF). Survivors of initial brain injury suffer from numerous extracranial complications including secondary end-organ injury and infection. These morbidities are a major determinant of survival and long-term outcomes in the most productive years of their lives. Importantly, coagulation abnormalities associated with TBI lead to a substantial increase in mortality. Post-TBI activation of the coagulation depends on two major mechanisms; Tissue Factor (TF) pathway-mediated activation of the extrinsic pathway caused by extravascular tissue injury and release of von Willebrand Factor (vWF) secondary to endothelial injury causing consumption of ADAMTS13 (A13), platelet activation and formation of microthrombi. Although imbalance of the A13/vWF pathway has been reported post-TBI in rodents and humans, its importance in causing sex-dependent coagulation abnormalities, brain and secondary organ injury directly or via the activation of the complement is less clear.

Based on our preliminary data and our published clinical results, we propose the central hypothesis that sex-dependent alterations in the A13/vWF relationship play a mechanistic role in coagulation abnormalities, severity of brain damage and development of acute kidney injury secondary to TBI. We are testing this hypothesis in patients with isolated TBI as well as in a mouse model of well controlled TBI.

A recently published NHBLI working group report emphasized the importance of two erroneous paradigms that have limited our understanding of the role of bacterial pneumonia on health and have compromised the research agenda on pneumonia. The first erroneous paradigm is that pneumonia is a localized disease. In fact, pneumonia causes end-organ injury by mechanisms that are poorly understood. The second erroneous paradigm is that pneumonia is an acute disease. Clinical manifestations present during the acute episode persist long after resolution of the primary infection, such as, but not limited to delirium, coagulation abnormalities, skeletal muscle weakness or acute kidney injury leading to chronic kidney disease.

Clinical studies have reported a significant association between bacterial pneumonia and subsequent development of coagulation abnormalities in mechanically ventilated ICU patients. We are particularly interested to understand how the decrease of plasma ADAMTS13 activity associated with a significant increase in VWF antigen binding to collagen causes the development of a procoagulant phenotype in these patients. Furthermore, our collaborative efforts with Dr. Troy Stevens research laboratory at the University of South Alabama in Mobile AL, are in progress to explore in preclinical and clinical studies the mechanisms by which cytotoxic prions that contain high molecular weight tau, and beta-amyloids produced by bacterial infection (Pseudomonas aeruginosa, Staph. aureus, Klebsiella pneumoniae, Pneumococcus) cause coagulation abnormalities and end-organ dysfunction. This exciting endeavor is likely to define a new form of bacterial toxicity that may in part explain the end-organ injury associated with bacterial infection in surgical patients.

Thus, based on our preliminary data and our published preclinical and clinical results, we hypothesize that circulating cytotoxic prions contribute to a strong association between bacterial pneumonia and a systemic procoagulant phenotype that can cause the development of systemic microvascular thrombosis and end-organ injury. Future studies may include the administration of recombinant ADAMTS13 to correct the deficit in circulating ADAMTS13 in these patients. Importantly, recombinant ADAMTS13 is not an anticoagulant, as systemic anticoagulation may cause serious complications in these patients.

Proposed studies are focused on the mechanisms of trauma-related immune deficiency that is associated  with the development of secondary bacterial infections. Our long-term collaborative work with Dr. Zmijewski, Professor of Medicine at UAB, has provided expertise and strong publication records of impactful research in lung injury, trauma and sepsis-related immunosuppression. Recent preliminary clinical data revealed that plasma from patients with severe trauma have significant metabolic alterations, as evidenced by metabolomics and bioenergetic profiling that can be corrected by activators of the AMP kinase. We linked these alterations with immunosuppressive effects of plasma on innate immune responses.  

Scientific premise of proposed studies is that AMPK activators, including repurpose of metformin (FDA approved drug for Type II diabetes), will effectively protect against the development of secondary bacterial pneumonia in severely traumatized patients that has been associated with poor outcome in that patient population. Fifty million people take metformin daily; toxicity is very rare. Metformin has no adverse effects in healthy individuals, and even reduces mortality (~30%) in polymicrobial sepsis, despite high lactic acidosis. Finally, several clinical trials have been initiated to determine anti-aging effects of metformin.

Based on our preliminary data and our published preclinical and clinical results, we hypothesize that severe trauma promotes metabolic maladaptation characterized by mitochondrial dysfunction and plasma-mediated inhibition of immune responses, thereby causes an increased risk of secondary bacterial infections, end-organ injury and death. We further hypothesize that Metformin, an AMP kinase activator, significantly decreases the risk of secondary bacterial infections and associated end-organ injury. We are testing this hypothesis in patients with severe trauma as well as in a mouse model of polytrauma followed 24h later by the onset of bacterial pneumonia caused by Pseudomonas aeruginosa.

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