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    • Introduction Ventilator induced lung injury VILI is the

    2022-06-07

    Introduction Ventilator-induced lung injury(VILI) is the most common complication in the mechanical ventilation in clinic. Repetitive opening and closing of sodium channel at high pressures during artificial ventilation would generate shear stress and then lead to the damage of cell junction and dysregulation of signal pathway in alveoli epithelial and the pulmonary capillary endothelial cells. Many factors and signal pathways, such as NF-KB, Akt, IL6, IL8, etc, are involved in the pathogenesis of VILI [1]. The SRY related High Mobility Group box group-F family member protein family(Sox) includes many members, of which Sox11 is reported to be involved in epithelial-mesenchymal interactions, and particularly involved in acute lung injury. For example, Sox11 overexpression is identified in pulmonary fibrosis [2], small cell lung cancer [3]. However, it is little known about the event of Sox11 in VILI. The focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase and regulated by Sox11. The activated FAK forms a complex with Src family kinases, and then phosphorylates other proteins to regulate various cell events, such as migration, immune response, cell differentiation and apoptosis. It is reported that decreased FAK expression induced barrier deterioration and increased vascular permeability in ischemic lung injury [4], while activation of FAK pathway improved the pulmonary microvascular hyperpermeability [5,6] and then decreased the protein content in bronchoalveolar lavage fluid and cell death induced by acute lung injury and fibrosis in mice [7]. Therefore, Sox11 and FAK have been focused as a therapeutic target in pulmonary diseases [2,6]. In the present study, we investigated the changes of Sox11 and FAK in the pathogenesis of VILI, and particularly the role of their upregulation in the improvement of VILI using a hyper-mechanical ventilation (HMV) mouse model.
    Material and methods
    Results
    Discussion In this study, we presented compelling results that VILI decreased Sox11 and FAK expression, and increasing Sox11 expression activated FAK in alveolar epithelial cells, and then alleviated VILI. First, we showed that HMV induced significant VILI. It is well known that the ratio of lung wet/dry weight reflects the degree of pulmonary edema. Protein levels and cell counts in BALF indicate the changes in permeability of pulmonary capillaries and alveolar epithelial cells. In the present study, the lung wet/dry ratio, the protein concentration and cell number in BALF increased significantly after HMV. These findings indicate the increase in the permeability of pulmonary capillaries and alveolar epithelial cells and appearance of pulmonary edema and exudation, which is the important indicator of acute lung injury. RAGE is a new pattern recognition receptor, widely involved in the pathological process of many diseases. The level of RAGE in BALF was positive correlated with the severity of lung injury [10]. The obvious increase of RAGE level in BALF after HMV indicated severity of lung injury in the present study. Histopathological evaluation found thickened alveolar wall, neutrophil infiltration, haemorrhage, hyline membrane formation and the increased lung injury score. These findings clearly indicated the appearance of VILI after HMV. TUNEL staining showed the involvement of apoptotic alveolar epithelial and interstitial cells in the occurrence and development of VILI after HMV [11]. These findings in the present study are similar with previous reports, in which HMV induced abnormality in wet/dry ratio [12], protein concentration, cell number and RAGE levels in BALF [13], histopathology [14], and apoptosis [15], and further confirmed that HMV can induce VILI. Particularly, we found that HMV significantly down-regulated the expression of Sox11 and FAK either in gene and protein levels companied with the VILI. As a member of the group C of Sox factors, Sox11 can regulate process of tissue development and remodeling, including lung development [16]. Knockout Sox11 in mice induced defects of neurogenesis and lung [2,17]. Furthermore, LPS-induced acute lung injury companied with down-regulation of proteins of Sox family [18,19]. FAK is a non-receptor tyrosine kinase and its activation facilitates cell survival and attachment in culture, while degradation of FAK promotes cell detachment and mobility [20]. The dysfunction of FAK also plays an important role in pathogenesis of lung injury induced by bleomycin [7]. Therefore, the present finding that the expression of Sox11 and FAK significantly down-regulated after HMV companied with VILI showed a clear possibility that the down-regulation of Sox11 and FAK after HMV might be responsible for the pathogenesis of VILI.