Circulating Endothelial Cells From Septic Shock Patients Convert to Fibroblasts Are Associated With the Resuscitation Fluid Dose and Are Biomarkers for Survival Prediction

Abstract

Objectives: To determine whether circulating endothelial cells from septic shock patients and from nonseptic shock patients are transformed in activated fibroblast by changing the expression level of endothelial and fibrotic proteins, whether the level of the protein expression change is associated with the amount of administered resuscitation fluid, and whether this circulating endothelial cell protein expression change is a biomarker to predict sepsis survival. Design: Prospective study. Setting: Medical-surgical ICUs in a tertiary care hospital. Patients: Forty-three patients admitted in ICU and 22 healthy volunteers. Interventions: None. Measurements and Main Results: Circulating mature endothelial cells and circulating endothelial progenitor cells from septic shock and nonseptic shock patients showed evidence of endothelial fibrosis by changing the endothelial protein expression pattern. The endothelial proteins were downregulated, whereas fibroblast-specific markers were increased. The magnitude of the expression change in endothelial and fibrotic proteins was higher in the septic shock nonsurvivors patients but not in nonseptic shock. Interestingly, the decrease in the endothelial protein expression was correlated with the administered resuscitation fluid better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in the septic shock nonsurvivors patients but not in nonseptic shock. Notably, the significant difference between endothelial and fibrotic protein expression indicated a nonsurvival outcome in septic shock but not in nonseptic shock patients. Remarkably, area under the receiver operating characteristic curve analysis showed that endothelial protein expression levels predicted the survival outcome better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in septic shock but not in nonseptic shock patients. Conclusions: Circulating endothelial cells from septic shock patients are acutely converted into fibroblasts. Endothelial and fibrotic protein expression level are associated with resuscitation fluid administration magnitude and can be used as biomarkers for an early survival diagnosis of sepsis.

Six-gene Signature Based on Metabolism Is Closely Related to the Prognosis and Immune Infiltration of Patients With Sepsis

“…In addition, the proportion of myeloid dendritic cells, endothelial cells and fibroblasts was higher in the high-risk group. Among the three types of cells, the role of myeloid dendritic cells in sepsis has been poorly studied, and the functions of endothelial cells [45,46] and fibroblasts [47] have only been partially explored. Therefore, the changes in the proportion of these immune cells in different prognostic septic patient need to be further explored.…”

Oxidized High-Density Lipoprotein Induces Endothelial Fibrosis Promoting Hyperpermeability, Hypotension, and Increased Mortality

“…The collection of blood samples and the isolation of cells and their analysis were carried out by two personnel who were blinded to the patient information, as well as to the clinical characteristics or further outcome of the patients. The CMECs and CEPCs were isolated by magnetic bead-based immunoseparation, as described previously [ 30 , 38 ]. Briefly, after the blood samples were obtained, the total mononuclear blood cell fraction was isolated from the blood by Ficoll-Histopaque (Sigma Chemical Co, St Louis, MO, USA) gradient separation.…”

“…Notably, vascular permeability is maintained by the expression of adhesion proteins, including VE۔cadherin, which bind ECs to each other, preventing vascular leaks [ 26 , 27 , 28 ]. Thus, because of endothelial fibrosis, decreased VE-cadherin expression, together with α-SMA and FN upregulation, mediates EC shape disruption, impairing the endothelial monolayer and leading to an increased endothelial permeability that ultimately promotes hypotension, hypoperfusion, organ dysfunction, and increased mortality [ 25 , 29 , 30 ].…”

Mechanisms of Post-critical Illness Cardiovascular Disease

“…Furthermore, the use of resuscitative fluid therapy leads to atrial stretch and natriuretic peptide induced endothelial dysfunction, which may contribute to further acute organ dysfunction, and persists to some degree during convalescence (321,322). TLR4 agonists such as endotoxin and resuscitation fluid volume have also been shown to induce (or associate with) the transformation of mature and progenitor endothelial cells to a fibroblast-like form, in keeping with the process of endothelial-to-mesenchymal transition (EMT) (323,324). This important process which also involves TGF-β signaling is suspected to be centrally involved in multiple cardiovascular pathologies including atherosclerosis, leading weight to the idea that acute severe disease transitions to chronic (325).…”