Sepsis is a profoundly morbid and life-threatening condition, and an increasingly alarming burden on modern healthcare economies. Patients with septic shock exhibit persistent hypotension despite adequate volume resuscitation requiring pharmacological vasoconstrictors, but the molecular mechanisms of this phenomenon remain unclear. The accumulation of misfolded proteins is linked to numerous diseases, and it has been observed that soluble oligomeric protein intermediates are the primary cytotoxic species in these conditions. Oligomeric protein assemblies have been shown to bind and activate a variety of pattern recognition receptors (PRRs) including formyl peptide receptor (FPR). While inhibition of endoplasmic reticulum (ER) stress and stabilization of protein homeostasis have been promising lines of inquiry regarding sepsis therapy, little attention has been given to the potential effects that the accumulation of misfolded proteins may have in driving sepsis pathogenesis. Here we propose that in sepsis, there is an accumulation of toxic misfolded proteins in the form of soluble protein oligomers (SPOs) that contribute to the inflammation and vascular dysfunction observed in sepsis via the activation of one or more PRRs including FPR. Our laboratory has shown increased levels of SPOs in the heart and intrarenal arteries of septic mice. We have also observed that exposure of resistance arteries and vascular smooth muscle cells to SPOs is associated with increased mitogen-activated protein kinase (MAPK) signaling including phosphorylated extracellular signal-regulated kinase (p-ERK) and p-P38 MAPK pathways, and that this response is abolished with the knockout of FPR. This hypothesis has promising clinical implications as it proposes a novel mechanism that can be exploited as a therapeutic target in sepsis.
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July 2018
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Cover Image
The 3D structure of recombinant human deoxyribonuclease I. The N-terminal leucine shown in yellow at the top of the structure was selected for PEGylation of the protein. The amino acids shown in yellow towards the bottom of the protein are those interacting with globular actin, a potent inhibitor of human deoxyribonuclease I; for details, see pages 1439–1452.
Hypothesis|
July 18 2018
Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis
Amel Komic;
1Department of Surgery, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
2Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
Correspondence: Amel Komic (akomic@augusta.edu) or Camilla F. Wenceslau (Camilla.Wenceslau@Utoledo.Edu)
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Patricia Martinez-Quinones;
Patricia Martinez-Quinones
1Department of Surgery, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
2Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
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Cameron G. McCarthy;
Cameron G. McCarthy
2Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
3Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, U.S.A.
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R. Clinton Webb;
R. Clinton Webb
2Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
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Camilla F. Wenceslau
2Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, U.S.A.
3Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, U.S.A.
Correspondence: Amel Komic (akomic@augusta.edu) or Camilla F. Wenceslau (Camilla.Wenceslau@Utoledo.Edu)
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Publisher: Portland Press Ltd
Received:
May 01 2018
Revision Received:
June 25 2018
Accepted:
June 26 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (13): 1433–1438.
Article history
Received:
May 01 2018
Revision Received:
June 25 2018
Accepted:
June 26 2018
Citation
Amel Komic, Patricia Martinez-Quinones, Cameron G. McCarthy, R. Clinton Webb, Camilla F. Wenceslau; Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis. Clin Sci (Lond) 18 July 2018; 132 (13): 1433–1438. doi: https://doi.org/10.1042/CS20180368
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