The purpose of this proposal is to cultivate the scientific and professional development of Dr. Julie Bastarache so that she may become an independent investigator. She is currently developing her research career in the Center for Lung Research at Vanderbilt University Medical Center. Under the guidance of Drs. Lorraine Ware and Timothy Blackwell, Dr. Bastarache will design and perform experiments that will enhance her knowledge and research skills in the pathobiology of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). Through laboratory experience, formal coursework, and the peer review process she will gain expertise in experimental design and execution, laboratory techniques, data analysis, and manuscript preparation. These skills will provide the foundation for Dr. Bastarache to pursue an independent career in lung research. Despite progress in understanding the basic pathogenic mechanisms of ALI/ARDS, fundamental questions remain unanswered and disease specific treatments are lacking. Experimental studies have established that intra-alveolar thrombin formation and fibrin deposition as a consequence of a pro-coagulant intra-alveolar environment are detrimental however, the specific mechanisms that regulate fibrin deposition in the airspaces and link lung inflammation and coagulation are unknown. Our preliminary data identifies the alveolar epithelium as a potential source of tissue factor (TF), the major pro-coagulant stimulus in the alveolar compartment. As a result we have formed the following hypothesis: Local production of tissue factor in the airspace in response to pro-inflammatory stimuli perpetuates inflammation and leads to lung injury. Inhibition of TF in the lungs will reduce fibrin formation, decrease cytokine production and limit lung injury. To test this hypothesis we will:1) determine the factors that regulate TF activity, thrombin formation, and fibrin deposition in the acutely injured lung. 2) define the impact of attenuating intra-alveolar TF activity on ongoing inflammation and injury in the acutely injured lung. 3) determine the mechanisms of TF upregulation and activation in the alveolar epithelium. Completion of these studies will provide critical information about the pathogenesis of ARDS that could lead to novel therapeutic strategies.

Public Health Relevance

The Acute Respiratory Distress Syndrome (ARDS) is a common disorder with a high mortality rate with no specific drug treatments. New data suggests critical links between two important pathways involved in lung injury: inflammation and coagulation. This proposal will use unique animal models to define the specific mechanisms that link these two independent pathways and will help to identify key targets for new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL090785-05
Application #
8423338
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$125,739
Indirect Cost
$9,314
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Shaver, Ciara M; Upchurch, Cameron P; Janz, David R et al. (2016) Cell-free hemoglobin: a novel mediator of acute lung injury. Am J Physiol Lung Cell Mol Physiol 310:L532-41
Shaver, Ciara M; Grove, Brandon S; Clune, Jennifer K et al. (2016) Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury. Sci Rep 6:22249
Rondina, Matthew T; Tatsumi, Kohei; Bastarache, Julie A et al. (2016) Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection. Crit Care Med 44:e574-8
Janz, David R; Bastarache, Julie A; Rice, Todd W et al. (2015) Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial. Crit Care Med 43:534-41
Shaver, Ciara M; Grove, Brandon S; Putz, Nathan D et al. (2015) Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor. Am J Respir Cell Mol Biol 53:719-27
Shaver, Ciara M; Chen, Wei; Janz, David R et al. (2015) Atrial Fibrillation Is an Independent Predictor of Mortality in Critically Ill Patients. Crit Care Med 43:2104-11
Shaver, Ciara M; Bastarache, Julie A (2014) Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury. Clin Chest Med 35:639-53
Bastarache, J A; Koyama, T; Wickersham, N E et al. (2014) Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples. J Immunol Methods 408:13-23
Janz, David R; Bastarache, Julie A; Peterson, Josh F et al. (2013) Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study. Crit Care Med 41:784-90
Janz, David R; Bastarache, Julie A; Sills, Gillian et al. (2013) Association between haptoglobin, hemopexin and mortality in adults with sepsis. Crit Care 17:R272

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