Abstract
The major pathophysiological characteristic of systemic inflammatory response syndrome (SIRS) and sepsis is the loss of control of vascular tone and endothelial barrier dysfunction. These changes are attributed to pro-inflammatory mediators. It has been proposed that in patients and rats without infection, cell components from damaged tissue are the primary instigators of vascular damage. Mitochondria share several characteristics with bacteria, and when fragments of mitochondria are released into the circulation after injury, they are recognized by the innate immune system. N-Formyl peptides are common molecular signatures of bacteria and mitochondria and are known to play a role in the initiation of inflammation by activating the formyl peptide receptor (FPR). We have demonstrated that infusion of mitochondrial N-formyl peptides (F-MIT) leads to sepsis-like symptoms, including vascular leakage. We have also observed that F-MIT, via FPR activation, elicits changes in cytoskeleton-regulating proteins in endothelial cells. Therefore, we hypothesize that these FPR-mediated changes in cytoskeleton can cause endothelial cell contraction and, consequently vascular leakage. Here, we propose that endothelial FPR is a key contributor to impaired barrier function in SIRS and sepsis patients following trauma.
Highlights
Systemic inflammatory response syndrome (SIRS) and sepsis are the principal causes of death in intensive care units, with mortality rates between 30 and 70% [1,2,3] The diagnosis of sepsis requires confirmation of bacterial growth in blood cultures, as well as the presence of two or more of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea, and leukocytopenia or leukocytosis [1, 2]
It has been observed that other molecules released during acute inflammation such as bradykinin, thrombin, VEGF, and histamine result in endothelial activation and massive increases in glycocalyx expression of endothelial leukocyte adhesion molecule 1, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) [9]
Because formyl peptide receptor (FPR) is present in endothelial cells and because we observed that F-MIT induces vascular leakage due to FPR activation [22], we questioned if F-MIT via FPR activation could lead to changes in cytoskeleton-regulating proteins in primary cultures of human aortic endothelial cells (HAEC)
Summary
Systemic inflammatory response syndrome (SIRS) and sepsis are the principal causes of death in intensive care units, with mortality rates between 30 and 70% [1,2,3] The diagnosis of sepsis requires confirmation of bacterial growth in blood cultures, as well as the presence of two or more of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea, and leukocytopenia or leukocytosis [1, 2]. Supporting these data, it has been shown that transfection of constitutively active MLCK induces MLC phosphorylation associated with increase in permeability in endothelial cells [13]. It has previously shown that p38 MAPK kinase leads to reorganization of the actin cytoskeleton to form stress fibers and increase in vascular permeability [19].
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