Abstract
Lung endothelial cell dysfunction plays a central role in septic-induced lung injury. We hypothesized that endothelial cell subsets, capillary endothelial cells (capEC) and post capillary venules (PCV), might play different roles in regulating important pathophysiology in sepsis. In order to reveal global transcriptomic changes in endothelial cell subsets during sepsis, we induced sepsis in C57BL/6 mice by cecal ligation and puncture (CLP). We confirmed that CLP induced systemic and lung inflammation in our model. Endothelial cells (ECs) from lung capillary and PCV were isolated by cell sorting and transcriptomic changes were analyzed by bioinformatic tools. Our analysis revealed that lung capEC are transcriptionally different than PCV. Comparison of top differentially expressed genes (DEGs) of capEC and PCV revealed that capEC responses are different than PCV during sepsis. It was found that capEC are more enriched with genes related to regulation of coagulation, vascular permeability, wound healing and lipid metabolic processes after sepsis. In contrast, PCV are more enriched with genes related to chemotaxis, cell–cell adhesion by integrins, chemokine biosynthesis, regulation of actin filament process and neutrophil homeostasis after sepsis. In addition, we predicted some transcription factor targets that regulate a significant number of DEGs in sepsis. We proposed that targeting certain DEGs or transcriptional factors would be useful in protecting against sepsis-induced lung damage.
Highlights
Sepsis is a dominating cause of hospital-related mortality all over the world [1]
The capillary endothelial cells (capEC) subset was identified as CD31+Icam1+Vcam1- and post capillary venules (PCV) subset was identified as CD31+Icam1+Vcam1+ (Figure 1A)
Flow cytometry analysis revealed that CD63, a tetraspanin protein linked to leukocyte adhesion and recruitment [18], was low on capEC but high on PCV
Summary
The management of sepsis patients is largely confined to supportive care which is partly due to an incomplete understanding of the pathophysiology [2]. One pathophysiological hallmark of sepsis is excessive tissue infiltration of leukocytes and disruption of gaseous exchange [6,7]. We and others have previously shown that leukocyte recruitment into the lung tissue is a multistep process, involving tethering, rolling, firm adhesion and extravascular migration, mediated by specific adhesion molecules expressed on leukocytes and ECs [8,9]. The selectin family of adhesion molecules, including P, E- and L-selectin, supports leukocyte tethering and rolling on vascular ECs in an organ-specific manner [10]
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