The objective of this SCOR proposal is to further understand the pathogenesis of ARDS as it relates to multiple organ dysfunction. The central hypothesis of this proposal is the pathogenesis of sepsis-induced ARDS is due to the persistence of an imbalance of over-expression of pro- inflammatory/pro-angiogenic mediators, as compared to anti- inflammatory/anti-angiogenic factors. This paradigm predicts that perpetuation of inflammation, angiogenesis, and fibrosis in ARDS, ultimately results in impaired host defense and intra-alveolar fibrosis. An in-depth understanding of the molecular and cellular pathogenesis of ARDS is necessary in order to develop novel treatment strategies. The project hypothesis of this SCOR proposal are as follows: 1. The pathogenesis of intra-alveolar angiogenesis/fibrosis, as compared to angiostatic members of the CXC chemokine family. This paradigm of biological imbalance will favor net angiogenesis leading to intra-alveolar fibrosis and impaired lung function of ARDS patients. 2. The sepsis-induced suppression of lung antibacterial host defense is a result of altered expression of important pro- and anti-inflammatory cytokines; favoring the expression of detrimental Th2-, rather than protective Th1-phenotype cytokines. 3. The cytokine networks established during the pathogenesis of sepsis- shock result in the expression of specific chemokines which can exert either inflammatory or immunoregulatory effects. 4. Acute lung injury occurs during a variety of systemic insults, and that complement activation and chemokine production trigger an inflammatory reaction that injuries the lung. Furthermore, it is postulated that complement products cause synergistic production of chemokines by stimulated alveolar macrophages. This SCOR will utilize a multi-disciplinary approach to test these hypotheses. This expertise consists of investigators trained in Critical Care Medicine, Pathology, Cell and Molecular Biology, and Biostatistics. The strength of this proposal are the investigators, who have a long track-record of collaborative/investigative interests in mechanisms of lung injury. The exceptional institutional resources for biomedical research, the proven commitment to collaborative interaction by both clinicians and basic scientists, and the access to a large population ARDS patients will assure that the studies designed in this proposal will come to fruition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL060289-05
Application #
6625278
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Harabin, Andrea L
Project Start
1998-12-01
Project End
2003-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$904,799
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bosmann, Markus; Grailer, Jamison J; Ruemmler, Robert et al. (2013) Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. FASEB J 27:5010-21
Moss, Marc; Standiford, Theodore J (2011) Leptin in fibroproliferative acute respiratory distress syndrome: not just a satiety factor. Am J Respir Crit Care Med 183:1443-4
Smith, Monica R; Gangireddy, Srinivasa R; Narala, Venkata R et al. (2010) Curcumin inhibits fibrosis-related effects in IPF fibroblasts and in mice following bleomycin-induced lung injury. Am J Physiol Lung Cell Mol Physiol 298:L616-25
Keshamouni, Venkateshwar G; Jagtap, Pratik; Michailidis, George et al. (2009) Temporal quantitative proteomics by iTRAQ 2D-LC-MS/MS and corresponding mRNA expression analysis identify post-transcriptional modulation of actin-cytoskeleton regulators during TGF-beta-Induced epithelial-mesenchymal transition. J Proteome Res 8:35-47
Reddy, Raju C; Srirangam, Anjaiah; Reddy, Kaunteya et al. (2008) Chemotherapeutic drugs induce PPAR-gamma expression and show sequence-specific synergy with PPAR-gamma ligands in inhibition of non-small cell lung cancer. Neoplasia 10:597-603
Reddy, Raju C; Narala, Venkata R; Keshamouni, Venkateshwar G et al. (2008) Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-{gamma}. Blood 112:4250-8
Milam, Jami E; Keshamouni, Venkateshwar G; Phan, Sem H et al. (2008) PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 294:L891-901
Gomperts, Brigitte N; Belperio, John A; Fishbein, Michael C et al. (2007) Keratinocyte growth factor improves repair in the injured tracheal epithelium. Am J Respir Cell Mol Biol 37:48-56
Keshamouni, Venkateshwar G; Michailidis, George; Grasso, Catherine S et al. (2006) Differential protein expression profiling by iTRAQ-2DLC-MS/MS of lung cancer cells undergoing epithelial-mesenchymal transition reveals a migratory/invasive phenotype. J Proteome Res 5:1143-54
Gomperts, Brigitte N; Belperio, John A; Rao, P Nagesh et al. (2006) Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury. J Immunol 176:1916-27

Showing the most recent 10 out of 88 publications