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Published on: June 24, 2019
Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock
Jérôme Pugin1, Sabine Stern-Voeffray, Bruno Daubeuf
1Laboratory of the Division of Intensive Care, Department of Internal Medicine, University Hospital of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. jerome.pugin@medecine.unige.ch
Abstract:
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.
Insights
Plasma from septic patients, unlike normal plasma, activates epithelial cells via lipopolysaccharide (LPS) and Toll-like receptor 4 (TLR4). Soluble myeloid differentiation protein-2 (MD-2) in septic plasma is key for this LPS-TLR4 activation, mediating organ inflammation.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Severe sepsis and septic shock involve complex inflammatory responses.
- Lipopolysaccharide (LPS) is a key trigger for sepsis-associated inflammation via Toll-like receptor 4 (TLR4).
- The precise mechanisms mediating TLR4 activation in epithelial cells during sepsis are not fully understood.
Purpose of the Study:
- To investigate the role of plasma components in LPS-induced activation of epithelial cells expressing TLR4.
- To identify the specific factor responsible for enhanced LPS-TLR4 activation in septic plasma.
- To explore the potential involvement of this factor in sepsis-induced organ inflammation.
Main Methods:
- Comparing LPS activation of epithelial cells using plasma from septic patients versus healthy controls.
- Assessing the effect of recombinant soluble myeloid differentiation protein-2 (MD-2) on LPS-TLR4 activation.
- Analyzing MD-2 activity in biological fluids like urine and lung edema fluid.
- Evaluating the impact of LPS-binding protein (LBP) and soluble CD14.
- Using an anti-MD-2 monoclonal antibody to block LPS-TLR4 activation.
Main Results:
- Septic plasma, but not normal plasma, supported LPS activation of TLR4-expressing epithelial cells.
- Recombinant soluble MD-2 restored LPS-TLR4 activation in normal plasma and MD-2-depleted septic plasma.
- "MD-2 activity" was detected in septic urine and ARDS lung edema fluid.
- LBP and soluble CD14 enhanced LPS sensitivity but required MD-2 for activation.
- Anti-MD-2 antibody blocked LPS-TLR4 activation in the presence of septic plasma or urine.
Conclusions:
- Soluble MD-2 in septic plasma and other bodily fluids is crucial for LPS activation of TLR4-expressing epithelial cells.
- Leaked soluble MD-2 in the extravascular space likely contributes to organ inflammation during sepsis.
- Soluble MD-2 is proposed as a significant mediator of organ inflammation in sepsis.