Omics of endothelial cell dysfunction in sepsis

Abstract

During sepsis, defined as life-threatening organ dysfunction due to dysregulated host response to infection, systemic inflammation activates endothelial cells and initiates a multifaceted cascade of pro-inflammatory signaling events, resulting in increased permeability and excessive recruitment of leukocytes. Vascular endothelial cells share many common properties but have organ-specific phenotypes with unique structure and function. Thus, therapies directed against endothelial cell phenotypes are needed to address organ-specific endothelial cell dysfunction. Omics allow for the study of expressed genes, proteins and/or metabolites in biological systems and provide insight on temporal and spatial evolution of signals during normal and diseased conditions. Proteomics quantifies protein expression, identifies protein–protein interactions and can reveal mechanistic changes in endothelial cells that would not be possible to study via reductionist methods alone. In this review, we provide an overview of how sepsis pathophysiology impacts omics with a focus on proteomic analysis of mouse endothelial cells during sepsis/inflammation and its relationship with the more clinically relevant omics of human endothelial cells. We discuss how omics has been used to define septic endotype signatures in different populations with a focus on proteomic analysis in organ-specific microvascular endothelial cells during sepsis or septic-like inflammation. We believe that studies defining septic endotypes based on proteomic expression in endothelial cell phenotypes are urgently needed to complement omic profiling of whole blood and better define sepsis subphenotypes. Lastly, we provide a discussion of how in silico modeling can be used to leverage the large volume of omics data to map response pathways in sepsis.

Molecular Framework of Mouse Endothelial Cell Dysfunction during Inflammation: A Proteomics Approach

“…The proteins, such as Selp and Vcam-1 (adhesion molecules), thrombomodulin, Prox1, Foxc2 and endothelial protein c receptor (all involved in coagulation) were evaluated in this study, with Selp, Vcam-1 and Foxc2 being upregulated in ECs. The proteome of the human ECs under inflammatory conditions exhibit responses that are similar to the findings reported in this study for mouse ECs [ 15 , 44 ]. For example, during the cytokine-induced changes as observed in sepsis, IL-1β (which was part of the cytomix cocktail to stimulate the mouse ECs in our study) is released and adhesion molecules (such as VCAM-1 and SELP) are upregulated from human ECs during inflammation.…”

“…Zbp1 regulates the host defense against pathogens by sensing viral nucleic acids [ 32 ]. Cebpb (CCAAT Enhancer Binding Protein Beta) and H2-k1 (Histocompatibility 2, K1, K region) are two proteins that play critical roles in regulating the cytokine-induced changes as observed during sepsis, and were significantly higher in the lung compared to the liver and kidney [ 15 , 33 ]. Rsad2 (Radical S-adenosyl methionine domain containing 2) is found to be responsive to interferon and again is found to be associated with the cytokine-induced changes as observed during sepsis [ 34 ].…”

“…For example, during the cytokine-induced changes as observed in sepsis, IL-1β (which was part of the cytomix cocktail to stimulate the mouse ECs in our study) is released and adhesion molecules (such as VCAM-1 and SELP) are upregulated from human ECs during inflammation. Furthermore, in human ECs, the proteins, such as Prox1 and Foxc2, are downregulated during inflammation which, in turn, decrease thrombomodulin and endothelial protein c receptor expression (both involved in controlling coagulation), initiating leukocyte adhesion and migration [ 15 ]. Thus, inflammatory-related pathways and BPs are dysregulated in human ECs, similar to what was observed in this study using mouse ECs.…”

“…As inflammation is a highly dynamic process, the level of protein alterations may vary during the different stages of disease [ 13 ]. Compared with genetic analyses, which often provide indirect clues about cell function, proteomic analysis can give direct insight into the protein expression in organ-specific ECs and help bridge the genotype–phenotype gap [ 14 , 15 ]. Nonetheless, few previous studies have identified the possible protein regulation patterns or evaluated the interaction and differential expression among various proteins in organs, such as the lungs, liver and kidneys during inflammation [ 16 , 17 ].…”

P53 in endothelial function and unfolded protein response regulation

“…The endothelial cells form a semipermeable barrier that regulates blood fluidity and controls vessel permeability to regulate the passage of solutes and small molecules (Couto et al, 2020). In several states of human disease (e.g., sepsis, acute respiratory distress syndrome [ARDS]) the impaired endothelial function contributes in disease progression due to hyperpermeability (Langston et al, 2022). The consequent endothelial leakage, as well as the infiltration of activated leukocytes into the interstitium, results to lung edema and respiratory failure (Kubra & Barabutis, 2021; Kubra et al, 2022).…”