As novel agonists of Wnt/β-catenin signaling pathway, R-spondin proteins constitute a class of ligands, including R-spondin 1/2/3/4, functioning through their receptors leucine-rich repeat-containing G-protein coupled receptor (LGR)4/5/6 to enhance Wnt/β-catenin activity. Since Wnt signaling plays pivotal roles in the regulation of many life processes involved in embryogenesis and adulthood, R-spondin proteins also take part in cell proliferation, differentiation and morphogenesis.For example, in the formation of respiratory system，R-spondin 2 is required for normal laryngeal-tracheal and lung morphogenesis，and the lack of R-spondin 1 expression results in the absence of duct side-branching development and subsequent alveolar formation. In addition, R-spondins show protective effect in tissue injury and diseases. R-spondin 1 and R-spondin 3 have been reported to prevent chemotherapy- or radiotherapy-induced mucous membrane lesion. R-spondin 1 attenuates oral mucositis contributed by radiotherapy in mouse models and R-spondin 3 potentiates intestinal regeneration elicited via gastrointestinal toxic effect of chemoradiotherapy treatment. However, whether R-spondin proteins exert salient influence on acute lung injury especially induced by mechanical ventilation is deficient. Therefore, this study aims to ascertain the implication of R-spondin proteins in the pathology of mechanical ventilation induced lung injury through detecting human plasma concentration change of R-spondin 1/2/3/4 after mechanical ventilation and interference effects in mouse model, which is helpful for prevention and treatment of ventilation induced lung injury.
Mechanical ventilation is a critical intervention for patients with acute respiratory failure. However, lung overdistension induced by mechanical ventilation also causes pulmonary endothelial dysfunction. The injurious effect of mechanical stretch on pulmonary endothelium has been implicated in the development of ventilator-induced lung injury, which is characterized by pulmonary inflammation and particularly increased vascular permeability. In addition, the investigators and others have previously shown that mechanical stretch increases cultured lung endothelial monolayer permeability in vitro and promotes lung vascular permeability in mice Thus, elucidating the mechanisms underlying the mechanical stretch-induced lung endothelial barrier dysfunction may provide a novel clinical therapeutic target against ventilator-induced lung injury. As novel agonists of Wnt/β-catenin signaling pathway, R-spondin proteins constitute a class of ligands, including R-spondin 1/2/3/4, functioning through their receptors leucine-rich repeat-containing G-protein coupled receptor (LGR)4/5/6 to enhance Wnt/β-catenin activity. Since Wnt signaling plays pivotal roles in the regulation of many life processes involved in embryogenesis and adulthood, R-spondin proteins also take part in cell proliferation, differentiation and morphogenesis. For example, in the formation of respiratory system，R-spondin 2 is required for normal laryngeal-tracheal and lung morphogenesis，and the lack of R-spondin 1 expression results in the absence of duct side-branching development and subsequent alveolar formation. In addition, R-spondins show protective effect in tissue injury and diseases. R-spondin 1 and R-spondin 3 have been reported to prevent chemotherapy- or radiotherapy-induced mucous membrane lesion. R-spondin 1 attenuates oral mucositis contributed by radiotherapy in mouse models and R-spondin 3 potentiates intestinal regeneration elicited via gastrointestinal toxic effect of chemoradiotherapy treatment. However, whether R-spondin proteins exert salient influence on acute lung injury especially induced by mechanical ventilation is deficient. Therefore, this study aims to ascertain the implication of R-spondin proteins in the pathology of mechanical ventilation induced lung injury through detecting human plasma concentration change of R-spondin 1/2/3/4 after mechanical ventilation and interference effects in mouse model, which is helpful for prevention and treatment of ventilation induced lung injury.
Study Type
OBSERVATIONAL
Enrollment
52
mechanical ventilation protocol: tidal volume 6-8 ml/kg, positive end-expiratory pressure 5 cm H2O, oxygen concentration 40%; respiratory rate 10-15/min, inspiratory/expiratory ratio 1:1.5.
Department of Anesthesia, Shanghai Xinhua hospital
Shanghai, Shanghai Municipality, China
Change in Plasma Concentration of R-spondin 1
The venous blood samples were collected twice for each patient that the first time was around the onset of the mechanical ventilation and the second was 3rd hour after the onset of the mechanical ventilation, which were named as sample A and sample B relatively. Then, plasmids were separated by centrifugation and detected for R-spondin1 concentration. And the outcome was calculated by subtracting the R-spondin1 plasmid concentration of sample A from the R-spondin1 plasmid concentration of sample B, which was the change in plasma concentration of R-spondin1.
Time frame: 3 hours
Change in Plasma Concentration of R-spondin 2
The venous blood samples were collected twice for each patient that the first time was around the onset of the mechanical ventilation and the second was 3rd hour after the onset of the mechanical ventilation, which were named as sample A and sample B relatively. Then, plasmids were separated by centrifugation and detected for R-spondin2 concentration. And the outcome was calculated by subtracting the R-spondin2 plasmid concentration of sample A from the R-spondin2 plasmid concentration of sample B, which was the change in plasma concentration of R-spondin2.
Time frame: 3 hours
Change in Plasma Concentration of R-spondin3
The venous blood samples were collected twice for each patient that the first time was around the onset of the mechanical ventilation and the second was 3rd hour after the onset of the mechanical ventilation, which were named as sample A and sample B relatively. Then, plasmids were separated by centrifugation and detected for R-spondin3 concentration. And the outcome was calculated by subtracting the R-spondin3 plasmid concentration of sample A from the R-spondin3 plasmid concentration of sample B, which was the change in plasma concentration of R-spondin3.
Time frame: 3 hours
Change in Plasma Concentration of R-spondin4
The venous blood samples were collected twice for each patient that the first time was around the onset of the mechanical ventilation and the second was 3rd hour after the onset of the mechanical ventilation, which were named as sample A and sample B relatively. Then, plasmids were separated by centrifugation and detected for R-spondin4 concentration. And the outcome was calculated by subtracting the R-spondin4 plasmid concentration of sample A from the R-spondin4 plasmid concentration of sample B, which was the change in plasma concentration of R-spondin4.
Time frame: 3 hours
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