Abstract

Bacterial endotoxins (LPS) are recognized as potential initiators of acute lung injury or ARDS. This laboratory's efforts have identified CD14 as a principal component of the mammalian system for recognizing the presence of LPS and initiating host defenses thereto. Two similar but distinct roles for CD134 have been identified. As a soluble plasma glycoprotein sCD14 in complex with LPS, i.e. LPS-sCD14, is an agonist for many LPS responsive cells such as endothelial, epithelial, smooth muscle, and mast cells. As a membrane bound surface glycoprotein of myeloid cells,, LPS-mCD14 complexes also initiate cellular activation, but in this context LPS-sCD14 complexes are not required another plasma LPS binding protein (LBP) has been identified which facilitates the formation of LPS-CD14 complexes. This project seeks to understand more about the mechanism by which LPS-sCD14 complexes initiative activation of endothelial and epithelial cells as cells of particular relevance to the lung.
The specific aims are designed to test the hypotheses that: (1) EC have two receptors for LPS; (2) LPS-SCD14 complexes contribute to pulmonary injury; (4) hypoxia inducible factor HIF) could be an intracellular regulator of LPS and cytokine induced injury; and (5) lung surfactant could be an important modulator of the effectiveness of LPS- sCD14's ability to activate EC.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL023584-22
Application #
6302125
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
22
Fiscal Year
2000
Total Cost
$148,366
Indirect Cost

  Institution

Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Kerr, Kim M; Auger, William R; Marsh, James J et al. (2012) Efficacy of methylprednisolone in preventing lung injury following pulmonary thromboendarterectomy. Chest 141:27-35
Spragg, Roger G; Ponganis, Paul J; Marsh, James J et al. (2004) Surfactant from diving aquatic mammals. J Appl Physiol 96:1626-32
Dunzendorfer, Stefan; Lee, Hyun-Ku; Soldau, Katrin et al. (2004) TLR4 is the signaling but not the lipopolysaccharide uptake receptor. J Immunol 173:1166-70
Dunzendorfer, Stefan; Lee, Hyun-Ku; Soldau, Katrin et al. (2004) Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: roles of LBP and sCD14 in mediating LPS responses. FASEB J 18:1117-9
Lee, Hyun-Ku; Dunzendorfer, Stefan; Tobias, Peter S (2004) Cytoplasmic domain-mediated dimerizations of toll-like receptor 4 observed by beta-lactamase enzyme fragment complementation. J Biol Chem 279:10564-74
Spragg, Roger G; Lewis, James F; Wurst, Wilhelm et al. (2003) Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant. Am J Respir Crit Care Med 167:1562-6
Thompson, Patricia A; Tobias, Peter S; Viriyakosol, Suganya et al. (2003) Lipopolysaccharide (LPS)-binding protein inhibits responses to cell-bound LPS. J Biol Chem 278:28367-71
Tapping, Richard I; Tobias, Peter S (2003) Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling. J Endotoxin Res 9:264-8
Bussolati, Benedetta; David, Salvatore; Cambi, Vincenzo et al. (2002) Urinary soluble CD14 mediates human proximal tubular epithelial cell injury induced by LPS. Int J Mol Med 10:441-9
Li, Jiali; Marsh, James J; Spragg, Roger G (2002) Effect of CTP:phosphocholine cytidylyltransferase overexpression on the mouse lung surfactant system. Am J Respir Cell Mol Biol 26:709-15

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