Acute Respiratory Distress Syndrome (ARDS) Clinical Trial
Official title:
the Mechanism of the Downregulation of R-spondin3 in Sepsis Induced Lung Injury
Sepsis is the most frequent risk factor for ALI/ARDS. Meanwhile, Pulmonary is the most
vulnerable organ to fail in response to sepsis, vascular endothelial dysfunction is a central
event in the pathophysiology of sepsis. An improved understanding of endothelial response and
associated biomarkers may lead to strategies to more accurately predict outcome and develop
novel endothelium-directed therapies in sepsis.
The human and mouse R-spondins encode a family of proteins that includes four paralogs
(R-spo1-4). R-spondins are secreted proteins found primarily in the extracellular region and
are known to promote β-catenin signaling. Among them, the embryonic lethal vascular
remodeling phenotype of R-spondin3 (Rspo3) mutant mice suggests a role of EC derived Rspo3 in
angiogenesis. Rspo3 protects tissues against mesenteric I/R by tightening endothelial cell
junction and improving vascular intergrity. However, the role of Rspo3 in sepsis-induced
pulmonary endothelial dysfunction remains unclear. Thus, it is worthwhile to explore the
relationship between Rspo3 and sepsis-induced lung injury, which will be helpful for
prevention and treatment of sepsis-induced lung injury and endothelial dysfunction.
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), is a clinical problem
induced by acute and excessive pulmonary inflammation. Sepsis is the most frequent risk
factor for ALI/ARDS. Meanwhile, Pulmonary is the most vulnerable organ to fail in response to
sepsis, and a major cause of death for sepsis patients is respiratory failure. Despite modern
clinical practices in critical care medicine, there still remains a mortality rate as high as
45%. In addition, Vascular endothelial dysfunction is a central event in the pathophysiology
of sepsis. Endothelial cell activation is associated with sepsis severity, organ dysfunction
and mortality. An improved understanding of endothelial response and associated biomarkers
may lead to strategies to more accurately predict outcome and develop novel
endothelium-directed therapies in sepsis.
The human and mouse R-spondins encode a family of proteins that includes four paralogs
(R-spo1-4). R-spondins are secreted proteins found primarily in the extracellular region and
are known to promote β-catenin signaling. Among them, the embryonic lethal vascular
remodeling phenotype of R-spondin3 (Rspo3) mutant mice suggests a role of EC derived Rspo3 in
angiogenesis. Former studies demonstrated that endothelial Rspo3 enhances cell autonomous
non-canonical Wnt signaling, thereby preventing retinal and tumor blood vessel regression and
EC apoptosis. The mid-gestational lethality of Rspo3-ECKO mice indicated a role of EC-derived
RSPO3 in controlling blood vessel remodeling. Furthermore, Rspo3 protects tissues against
mesenteric I/R by tightening endothelial cell junction and improving vascular intergrity.
However, the role of Rspo3 in sepsis-induced pulmonary endothelial dysfunction remains
unclear. Thus, it is worthwhile to explore the relationship between Rspo3 and sepsis-induced
lung injury.
In the present study, the investigators will analyze the expression of Rspo3 in septic
patients and sepsis-induced lung injury models and explore whether Rspo3 could protect
sepsis-associated lung injury, which will be helpful for prevention and treatment of
sepsis-induced lung injury and endothelial dysfunction.
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