The Elk1/MMP-9 Axis Regulates E-Cadherin and Occludin in Ventilator-Induced Lung Injury

Abstract Background: Ventilator-induced lung injury (VILI) is a common complication in the treatment of respiratory diseases with high morbidity and mortality. Matrix metalloprotein (MMP) 9 and Elk1 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.Methods: For the in vitro study, MLE-12 cells 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 4h of mechanical ventilation. The expressions of Elk1, MMP-9, E-cadherin, and occludin were measured by Western blotting. The intracellular distribution of E-cadherin and occluding was shown by immunofluorescence. The degree of pulmonary edema and lung injury were evaluated by HE staining, lung injury scores, W/D weight ratio, total cell counts, and Evans blue dye.Results: 20% cyclic stretch and high tidal volume could increase the expressions of Elk1 and MMP-9, decrease the E-cadherin and occludin level. Elk1 siRNA or MMP-9 siRNA could reverse the degradations of E-cadherin and occludin caused by cyclic stretch. Elk1 siRNA could decrease the MMP-9 level with or not 20% cyclic stretch and high tidal volume. Conclusions: This study demonstrated that mechanical stretch could lead to the transcriptional activation of Elk1, enhance the expression of MMP-9 and mediate the loss of E-cadherin and occludin in VILI, thus indicating the therapeutic potential of Elk1 to treat VILI.