Background: Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI. Methods: Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model. Results: Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β3 or β5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown β3 integrin significantly decreased survival in ALI mice. Notably, knockdown of β5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice. Conclusion: These findings support the β3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.

Background Postoperative delirium (POD) is considered as a relatively common and serious problem after major abdominal surgery procedures. It is presumed to be preventable in most of cases. The purpose of this study was to develop and evaluate a POD prediction model for patients undergoing abdominal surgery. Methods From July 2019 to December 2019, patients underwent elective abdominal surgery in our hospital were retrospectively analyzed, and their demographics, pre-operative evaluation, intra-operative and anesthesiologic factors were recorded. Based on the results of the multivariate regression analyzes using P < 0.05 and P < 0.001 as two significance level, we obtained 2 different prediction models comprising of 10 and 4 factors respectively. After factorizing the risk of overfitting and cross-validation, we proposed a final POD prediction model consisting of 4 predictors. From January 2021 to December 2021, 346 more qualifying patients were enrolled for the external validation of the 4-factor model. The study was retrospectively registered on the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) with ID ChiCTR2100047405. Results After screening, 838 patients were included as the training cohort and 10.9% (91/838) of the patients manifested POD. Those patients who developed POD were more likely to be aged more than 60 years (OR = 1.345, P =0.005), with history of diazepam usage (OR = 3.622, P =0.003), history of cerebrovascular disease (OR = 2.150, P = 0.012) and intraoperative positive fluid balance (OR = 1.41, P <0 .001). The optimum cut-off point of the predicted probability that maximized the sum of sensitivity and specificity was 0.12. The fitting set AUC was 0.703 (95%CI: 0.637–0.753). The cross validation set AUC was 0.684 (SD = 0.068) and the external validation AUC of the model was 0.63 (95%CI: 0.511–0.758), quite closed to that of the fitting set, which indicated that the selected model was robust. Conclusions The 4-factor POD prediction model shows good prediction efficiency and can prompt for prophylactic intervention in patients at risk for POD. Trial registration : A retrospective registration of the study has been submitted to the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) with Registration ID ChiCTR2100047405 (18/06/2021).

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