Abstract
BackgroundVentilator-induced lung injury (VILI) is a common complication in the treatment of respiratory diseases with high morbidity and mortality. ETS-domain containing protein (Elk1) and Matrix metalloproteinase (MMP) 9 are involved in VILI, but the roles have not been fully elucidated. This study examined the mechanisms of the activation of MMP-9 and Elk1 regulating barrier function in VILI in vitro and in vivo.MethodsFor the in vitro study, Mouse lung epithelial cells (MLE-12) were pre-treated with Elk1 siRNA or MMP-9 siRNA for 48 h prior to cyclic stretch at 20% for 4 h. For the in vivo study, C57BL/6 mice were pre-treated with Elk1 siRNA or MMP-9 siRNA for 72 h prior to 4 h of mechanical ventilation. The expressions of Elk1, MMP-9, Tissue inhibitor of metalloproteinase 1 (TIMP-1), E-cadherin, and occludin were measured by Western blotting. The intracellular distribution of E-cadherin and occludin was shown by immunofluorescence. The degree of pulmonary edema and lung injury were evaluated by Hematoxylin–eosin (HE) staining, lung injury scores, Wet/Dry (W/D) weight ratio, total cell counts, and Evans blue dye.Results20% cyclic stretch and high tidal volume increases the expressions of Elk1, MMP-9, and TIMP-1, increases the ratio of MMP-9/TIMP-1, decreases the E-cadherin and occludin level. Elk1 siRNA or MMP-9 siRNA reverses the degradations of E-cadherin, occludin, and the ratio of MMP-9/TIMP-1 caused by cyclic stretch. Elk1 siRNA decreases the MMP-9 level with or not 20% cyclic stretch and high tidal volume.ConclusionsThe results demonstrate mechanical stretch damages the tight junctions and aggravates the permeability in VILI, Elk1 plays an important role in affecting the tight junctions and permeability by regulating the balance of MMP-9 and TIMP-1, thus indicating the therapeutic potential of Elk1 to treat VILI.
Highlights
Ventilator-induced lung injury (VILI) is a common complication in the treatment of respiratory diseases with high morbidity and mortality
In vivo and in vitro VILI models present the activation of ETS-domain containing protein (Elk1) and Matrix metalloproteinase (MMP)‐9 and loss of E‐cadherin and occludin In vivo, mice were treated with a high tidal volume (20 mL/kg) for 0, 2, and 4 h, while in vitro, MLE-12 cells were treated with a 20% cyclic stretch for 0, 2 and 4 h
Elk1 or MMP‐9 knockdown regulated the loss of E‐cadherin and occludin in VILI In vitro, MLE-12 cells were pre-treated with si-Elk1 or si-Matrix metalloproteinase 9 (MMP-9) and subjected to a 20% cyclic stretch for 4 h
Summary
Ventilator-induced lung injury (VILI) is a common complication in the treatment of respiratory diseases with high morbidity and mortality. ETS-domain containing protein (Elk1) and Matrix metalloproteinase (MMP) 9 are involved in VILI, but the roles have not been fully elucidated. This study examined the mechanisms of the activation of MMP-9 and Elk regulating barrier function in VILI in vitro and in vivo. In this regard, tight junctions, which connect adjacent cells through tight protein particles, play an important role in alveolar permeability [9,10,11]. Tao et al Respir Res (2021) 22:233 can decrease the expressions of tight junctions E-cadherin and occludin, increasing alveolar permeability [12, 13]. We aimed to identify the activation mechanism of E-cadherin and occludin in VILI
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