Despite progress in the last decade in understanding the basic pathogenetic mechanisms of acute lung injury and the acute respiratory distress syndrome (ALVARDS), fundamental questions remain unanswered and disease specific treatments are lacking. Experimental and clinical studies have established that intact alveolar fluid clearance is important to the resolution of ALI/ARDS. However, preliminary clinical studies indicate that less than half of ALI/ARDS patients have intact alveolar fluid clearance. The overall goal of the proposal is to study the mechanisms that regulate alveolar fluid clearance in ALVARDS. Strial samples of plasma and pulmonary edema fluid will be obtained from 375 patients with ALVARDS and 125 control patients with hydrostatic pulmonary edema. The rate of alveolar epithelial fluid clearance will be calculated from the rise in protein concentration in pulmonary edema fluid over time. The first goal (Aim 1) is to determine the mechanisms that impair alveolar fluid clearance in ALI/ARDS by measuring biological markers of lung epithelial and endothelial injury in the pulmonary edema fluid. Markers of specific mediators of injury such as reactive nitrogen-oxygen species will also be measured. Since the relative contributions of alveolar epithelial and lung endothelial injury to the overall severity of acute lung injury are not well understood, the prognostic value of these markers will also be investigated. The second goal (Aim 2) is to study soluble factors in the pulmonary edema fluid that can alter the rate of alveolar fluid clearance in the in situ mouse lung and the ex vivo human lung in the absence of alveolar epithelial injury. The studies proposed in this application will provide new and valuable insights into the pathogenesis of clinical acute lung injury, by applying innovative methods to the study of alveolar epithelial integrity and function and focusing on determinants of the resolution of acute lung injury, a potential new therapeutic target. In addition, the proposed studies will prepare the principal investigator for a career as an independent investigator in academic medicine. The training outlined in this proposal includes excellent mentoring, a rich scientific environment, and a curriculum of formal coursework in biostatistics, study design and scientific writing. The studies proposed are innovative, novel and hypothesis-driven and are designed to develop an independent research focus for the trainee. Combined with a compelling research project, the training will -provide the skills necessary for a successful career in biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL070521-04
Application #
6666829
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2001-09-01
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$121,770
Indirect Cost
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
Katayama, Masahiko; Ishizaka, Akitoshi; Sakamoto, Michiie et al. (2010) Laminin gamma2 fragments are increased in the circulation of patients with early phase acute lung injury. Intensive Care Med 36:479-86
White, Kimberly E; Ding, Qiang; Moore, Bethany B et al. (2008) Prostaglandin E2 mediates IL-1beta-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors. J Immunol 180:637-46
Ware, Lorraine B; Matthay, Michael A; Parsons, Polly E et al. (2007) Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 35:1821-8
Rice, Todd W; Wheeler, Arthur P; Bernard, Gordon R et al. (2007) Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 132:410-7
Bastarache, Julie A; Wang, Ling; Geiser, Thomas et al. (2007) The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax 62:608-16
Flori, Heidi R; Ware, Lorraine B; Milet, Meredith et al. (2007) Early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury is associated with an increased risk of death and prolonged mechanical ventilation. Pediatr Crit Care Med 8:96-101
McClintock, Dana E; Ware, Lorraine B; Eisner, Mark D et al. (2007) Higher urine nitric oxide is associated with improved outcomes in patients with acute lung injury. Am J Respir Crit Care Med 175:256-62
Wang, Ling; Bastarache, Julie A; Wickersham, Nancy et al. (2007) Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation. Am J Respir Cell Mol Biol 36:497-503
Ganter, Michael T; Ware, Lorraine B; Howard, Marybeth et al. (2006) Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. Am J Physiol Lung Cell Mol Physiol 291:L354-61
Sakuma, Tsutomu; Gu, Xiu; Wang, Zheng et al. (2006) Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine. Crit Care Med 34:676-81

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