Abstract
Acute lung injury (ALI) is the leading cause of death in sepsis patients. Exosomes participate in the occurrence and development of ALI by regulating endothelial cell inflammatory response, oxidative stress and apoptosis, causing serious pulmonary vascular leakage and interstitial edema. The current study investigated the effect of exosomal miRNAs on endothelial cells during sepsis. We found a significant increase in miR-1-3p expression in cecal ligation and puncture (CLP) rats exosomes sequencing and sepsis patients’ exosomes, and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) in vitro. However, the specific biological function of miR-1-3p in ALI remains unknown. Therefore, mimics or inhibitors of miR-1-3p were transfected to modulate its expression in HUVECs. Cell proliferation, apoptosis, contraction, permeability, and membrane injury were examined via cell counting kit-8 (CCK-8), flow cytometry, phalloidin staining, Transwell assay, lactate dehydrogenase (LDH) activity, and Western blotting. The miR-1-3p target gene was predicted with miRNA-related databases and validated by luciferase reporter. Target gene expression was blocked by siRNA to explore the underlying mechanisms. The results illustrated increased miR-1-3p and decreased stress-associated endoplasmic reticulum protein 1 (SERP1) expression both in vivo and in vitro. SERP1 was a direct target gene of miR-1-3p. Up-regulated miR-1-3p inhibits cell proliferation, promotes apoptosis and cytoskeleton contraction, increases monolayer endothelial cell permeability and membrane injury by targeting SERP1, which leads to dysfunction of endothelial cells and weakens vascular barrier function involved in the development of ALI. MiR-1-3p and SERP1 may be promising therapeutic candidates for sepsis-induced lung injury.
Highlights
Sepsis is a common complication in patients with serious burns, trauma, or infection that causes life-threatening multiple organ dysfunction syndrome (MODS), including coagulopathy, acute lung injury (ALI), liver damage, and renal failure [1]
The results demonstrated that overexpressed miR-1-3p inhibited proliferation and promoted apoptosis as well as inflammatory response of human umbilical vein endothelial cell (HUVEC), which can be reversed by down-regulating the expression of miR-1-3p
lactate dehydrogenase (LDH) activity increased in the supernatant of si-stress-associated endoplasmic reticulum protein 1 (SERP1) group (Figure 6C). These results revealed that SERP1 inhibition caused increased cell contraction, inflammatory response, monolayer endothelial cell permeability and membrane damage, which demonstrated a similar effect on the miR-1-3p mimics on HUVECs dysfunction
Summary
Sepsis is a common complication in patients with serious burns, trauma, or infection that causes life-threatening multiple organ dysfunction syndrome (MODS), including coagulopathy, acute lung injury (ALI), liver damage, and renal failure [1]. Increasing studies have revealed that exosomes are involved in sepsis, which circulates along with body fluid to deliver messages between neighboring and distant cell communication [5]. MiRNA-1246 mediates LPS-induced endothelial cell apoptosis through targeting angiotensin-converting enzyme 2 (ACE-2); elimination of miR-1246 relieves inflammation and neutrophil infiltration in lung tissue [13]. MiR-539-5p was reported to attenuate apoptosis and pro-inflammatory cytokine production during ALI by down-regulating the expression of Rho-associated protein kinase 1 (ROCK1) in pulmonary microvascular endothelial cells [14]. Many studies have verified that miRNAs play a key role in homeostasis of vascular endothelial cells by regulating cell stress or inflammatory response
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