Increase in soluble protein oligomers triggers the innate immune system promoting inflammation and vascular dysfunction in the pathogenesis of sepsis.

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.

Targeting Endothelial Barrier Dysfunction Caused by Circulating Bacterial and Mitochondrial N-Formyl Peptides With Deformylase.

Despite recent advances in our understanding of the mechanisms underlying systemic inflammatory response syndrome (SIRS) and sepsis, the current therapeutic approach to these critically ill patients is centered around supportive care including fluid resuscitation, vasopressors and source control. The incidence of SIRS and sepsis continues to increase in the United States and patients die due to failure to respond to the traditional therapies of nitric oxide blockade, adrenergic agonists, etc. Bacterial and mitochondrial N-formyl peptides (NFPs) act as damage-associated molecular patterns and activate the innate immune system through formyl peptide receptors (FPR) located in immune and non-immune cells, including the vascular endothelium. The resulting inflammatory response manifests as capillary leak, tissue hypoperfusion and vasoplegia, partially due to endothelium barrier breakdown. Potential strategies to prevent this response include decreasing NFP release, breakdown of NFPs, and blocking NFPs from binding FPR. We propose the use of deformylase, the degrading enzyme for NFPs, as potential therapeutic approach to prevent the deleterious effects of NFPs in SIRS and sepsis.

Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall.

Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted.