) Overall objectives: Develop an animal model for the sickle acute chest syndrome (ACS), a life-threatening complication of human sickle cell disease, in order to study pathophysiology and test therapy. The applicant, who is trained in pediatric hematology-oncology, proposes to learn methods in pulmonary research and endothelial cell adhesion research under the mentorship of a pulmonologist and a hematologist. The study hypothesis is that pathophysiology of ACS includes erythrocyte (RBC) sickling and adhesion, neutrophils, and monocytes. Mice will be used to examine the effects of hydroxyurea, which has shown therapeutic benefit in preventing ACS, in relation to RBC and leukocytes. Using the murine models of sickle cell disease currently available to the applicant, plethysmographic measures of pulmonary function will complement the histopathologic studies of structure. The applicant will extend the studies as collaborations make other mice available during the course of the project. The Georgia-NIH Comprehensive Sickle Cell Center (co-sponsor James Eckman), the Lung Biology Group in Atlanta VA Medical Center (co-sponsor Samuel Aguayo), active groups in endothelial cell adhesions at Georgia Institute of Technology and Emory University, and microcirculation group at the Morehouse School of Medicine. Hypothesis: Transgenic mice expressing human sickle hemoglobin are more susceptible than normal mice to acute lung injury from oleic acid injection, due to abnormal interactions of blood cells and endothelium.
Specific aims are to examine the roles of different blood cells in increased susceptibility to acute lung injury. 1. Abnormal RBC - (a) sickling, (b) adhesion; 2. Neutrophils - (a) numbers, (b) adhesion/retention, (c) activation; 3. Monocytes - (a) numbers, (b) adhesion/retention, (c) activation; 4. Examine effects hydroxyurea on RBC, neutrophils, and monocytes in acute lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL003811-01
Application #
2596295
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F1))
Project Start
1998-07-10
Project End
2002-06-30
Budget Start
1998-07-10
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Holtzclaw, J David; Jack, Daniel; Aguayo, Samuel M et al. (2004) Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice. Am J Respir Crit Care Med 169:687-95
Fryer, R M; Schultz, J E; Hsu, A K et al. (1999) Importance of PKC and tyrosine kinase in single or multiple cycles of preconditioning in rat hearts. Am J Physiol 276:H1229-35