My main career goal is to become an independent investigator performing translational and integrative research in the field of acute lung injury. Acute lung injury (ALI) is characterized by severe neutrophilic alvelitis and extensive injury to the alveolar epithelium, both of unclear cause. My main scientific goal is to determine the specific contributions of the pro-apoptotic and pro-inflammatory functions of the Fas/FasL system to the pathogenesis of ALI. The main hypothesis is that early in the course of ALI, activated alveolar macrophages (AM) and bronchial epithelial cells release soluble Fas-ligand (sFasL). Binding of sFasL to Fas (CD95) in alveolar epithelial cells results in apoptosis and epithelial damage. In contrast, activation of Fas in AM does not result in apoptosis, but instead leads to release of inflammatory cytokines. This hypothesis is derived from our preliminary data and the literature.
Aim 1 investigates the cellular sources of sFasLin the airspaces of the lung and the mechanisms that control its release.
Aim 2 investigates the specific role of the proapoptotic function of Fas in the development of alveolar permeability changes during bacterial pneumonia.
Aim 3 investigates the specific role of the pro-inflammatory function of Fas, by generating chimeric mice lacking either Fas or FasL in key target cells, then evaluating the inflammatory response to either intratracheal FasL or aerosolized LPS. Clarifying the role of the Fas/FasL system in the pathogenesis of ALI is important because it could lead to the development of therapeutic strategies for the Acute Respiratory Distress Syndrome (ARDS). These studies will be performed at the laboratory of Dr. Thomas R. Martin at the University of Washington (UW). This career development proposal includes a customized training program consisting of an advisory committee composed of six experts in the field, a didactic component including several graduate courses at the UW, and active participation in the Respiratory Cell and Molecular Biology Study Group at the Pulmonary Division of the UW. The proposed studies will allow for the acquisition of new techniques and further scientific development of the trainee into an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL070840-01
Application #
6521602
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2002-08-06
Project End
2007-06-30
Budget Start
2002-08-06
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$128,169
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bem, R A; Farnand, A W; Wong, V et al. (2008) Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice. Am J Physiol Lung Cell Mol Physiol 295:L314-25
Matute-Bello, Gustavo; Wurfel, Mark M; Lee, Janet S et al. (2007) Essential role of MMP-12 in Fas-induced lung fibrosis. Am J Respir Cell Mol Biol 37:210-21
Lee, Janet S; Wurfel, Mark M; Matute-Bello, Gustavo et al. (2006) The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation. J Immunol 177:8086-94
O'Mahony, D Shane; Liles, W Conrad; Altemeier, William A et al. (2006) Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction. Crit Care 10:R136
Matute-Bello, Gustavo; Liles, W Conrad; Frevert, Charles W et al. (2005) Blockade of the Fas/FasL system improves pneumococcal clearance from the lungs without preventing dissemination of bacteria to the spleen. J Infect Dis 191:596-606
Lee, Janet S; Frevert, Charles W; Matute-Bello, Gustavo et al. (2005) TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia. Am J Physiol Lung Cell Mol Physiol 289:L731-8
Matute-Bello, Gustavo; Lee, Janet S; Liles, W Conrad et al. (2005) Fas-mediated acute lung injury requires fas expression on nonmyeloid cells of the lung. J Immunol 175:4069-75
Matute-Bello, Gustavo; Lee, Janet S; Frevert, Charles W et al. (2004) Optimal timing to repopulation of resident alveolar macrophages with donor cells following total body irradiation and bone marrow transplantation in mice. J Immunol Methods 292:25-34
Nakamura, Morio; Matute-Bello, Gustavo; Liles, W Conrad et al. (2004) Differential response of human lung epithelial cells to fas-induced apoptosis. Am J Pathol 164:1949-58
Matute-Bello, Gustavo; Winn, Robert K; Martin, Thomas R et al. (2004) Sustained lipopolysaccharide-induced lung inflammation in mice is attenuated by functional deficiency of the Fas/Fas ligand system. Clin Diagn Lab Immunol 11:358-61

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