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.

Remifentanil modulates the TLR4‑mediated MMP‑9/TIMP1 balance and NF‑κB/STAT3 signaling in LPS‑induced A549 cells

“…Reactive oxidants and free radicals can directly obstruct cell function, causing proteases, such as MMP-9, to be released. MMP-9 serves a role in various physiological processes, including extracellular matrix degradation and lung tissue remodeling (42)(43)(44), both of which have been reported to be associated with the occurrence of various lung diseases including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (42)(43)(44). MMP9 activity is regulated by the specific endogenous inhibitor TIMP1 (45).…”

Comprehensive analysis of next-generation sequencing data in COVID-19 and its secondary complications

“…SREBF1 [747], ELF5 [748], TP53 [749], EGR1 [750], E2F6 [751] and STAT3 [752] have been demonstrated to function in cardiovascular diseases, but these genes might be involved in the progression of COVID-19. ELK1 [753], EGR1 [754] and STAT3 [755] plays a key role in the development of the lung diseases, but these genes might be involved in the progression of COVID-19. Previous studies have reported that EGR1 [756], FOXL1 [757] and STAT3 [758] exhibit significant associations with liver injury, but these genes might be involved in the progression of COVID-19.…”