A study on the mechanism of airway pressure release ventilation in reducing ARDS pulmonary inflammation by regulating ITGB4-related pathways

MA Aijia; WEI Canzheng; DONG Meiling; CHENG Jiangli; Haiyier Buick Adali; QIN Yiwei; XUE Yang; GAO Hui; ZHAO Lican; LI Jianbo; ZHOU Yongfang; WANG Bo; YANG Jing; KANG Yan

doi:10.3969/j.issn.1674-3806.2024.02.02

Abstract：Objective To analyze the effects of airway pressure release ventilation(APRV)and low tidal volume ventilation(LTV)on inflammation in acute respiratory distress syndrome(ARDS),and to explore the effects and mech-anisms of different mechanical ventilation modes on the related mechanical stress in ARDS.Methods An adult Bama miniature pig model of severe ARDS was constructed,and LTV and APRV ventilation modes were applied for mechani-cal ventilation treatment for 48 hours.The model pigs were divided into blank control group(control group,n=3),dis-ease control group(ARDS group,n=3),LTV mechanical ventilation group(LTV group,n=4)and APRV mechanical ventilation group(APRV group,n=4).The effects of the two ventilation modes on oxygenation index and inflammatory factors were observed.High-throughput sequencing was performed on lung tissues,and the effects of the differential gene integrin beta 4(ITGB4)on inflammation after mechanical ventilation for ARDS were verified at the protein level.The APRV-like stretching model and the LTV-like stretching model were constructed by using the A549 cell line,and 4-hour stretch test was performed in vitro.The effects of the two stretching modes on the secretion of inflammatory cyto-kines were explored by ITGB4.Small interfering ribonucleic acid(RNA)(siRNA)was used for silencing the expression of ITGB4,and the differences in the expression of the ITGB4-focal adhesion kinase(FAK)-p38-mitogen-activated pro-tein kinase(MAPK)-interleukin-8(IL-8)(ITGB4-FAK-p38-MAPK-IL-8)pathway was compared between the LTV+siRNA group and the APRV+siRNA group.The p38 inhibitor of SB203580 was used to intervene the cells,and the difference in the level of IL-8 expression was compared between the LTV+SB203580 group and the APRV+SB203580 group.Results After successful modeling of severe ARDS and 48-hour ventilation,the levels of IL-6 and IL-8 in the alveolar lavage fluid and lung tissues in the APRV group were significantly lower than those in the LTV group(P＜0.05).How-ever,there were no statistically significant differences in IL-1 and tumor necrosis factor-α(TNF-α)between the two groups(P＞0.05).The results of high-throughput sequencing in transcriptome showed the significant enrichment of extracellular matrix(ECM)-receptor interaction pathway and focal adhesion signaling pathway after mechanical venti-lation.In the lung tissues,the levels of ITGB4,p-FAK,p-p38 protein expressions in the APRV group were significantly lower than those in the LTV group(P＜0.05).In the cell stretching model,LTV and APRV-like stretches were repeated in vitro cells,and cyclic stretching for 4 hours resulted in a significant increase in cellular IL-8 levels(P＜0.05),but did not significantly change the level of IL-6(P＞0.05).The levels of IL-8,ITGB4,p-FAK and p-p38 expressions in the APRV group were significantly lower than those in the LTV group(P＜0.05).Silencing ITGB4 could significantly down-regulate the levels of p-FAK and p-p38 expressions in the APRV group and the LTV group after mechanical stretc-hing,and the down-regulation trend was obvious in the APRV+siRNA group,but there were no statistically significant differences in the down-regulations between the APRV+siRNA group and the LTV+siRNA group(P＞0.05).After the use of p38 inhibitor,the level of p-p38 phosphorylation in the APRV+SB203580 group was significantly down-regulated compared with that in the LTV+SB203580 group(P=0.032).Conclusion APRV mechanical ventilation mode sig-nificantly improves the secretion of inflammatory factor IL-8 after severe ARDS through the ITGB4-p38-MAPK pathway,which may provide a potential intervention target for the treatment of ARDS.