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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4071-4079.
Prepublished online as a Blood First Edition Paper on August 24, 2004; DOI 10.1182/blood-2003-04-1290.
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IMMUNOBIOLOGY
Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock
Jérôme Pugin,
Sabine Stern-Voeffray,
Bruno Daubeuf,
Michael A. Matthay,
Greg Elson, and
Irène Dunn-Siegrist
From the Laboratory of the Division of Medical Intensive Care, Departments of Internal Medicine, Microbiology, and Molecular Medicine, University Hospital of Geneva, Geneva, Switzerland; the Faculty of Medicine, University Hospital of Geneva, Geneva, Switzerland; NovImmune S.A., Geneva, Switzerland; and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA.
In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis. (Blood. 2004;104:4071-4079)
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