Chuan Xiao

Alveolar hypercoagulation and fibrinolytic inhibition are critical mechanisms contributing to refractory hypoxemia in acute respiratory distress syndrome (ARDS). The nuclear factor kappa‐B (NF‐κB) pathway is known to play a role in these processes. Lysophosphatidic acid receptor 1 (LPAR1) has been identified as being associated with the NF‐κB pathway. We hypothesize that LPAR1 may regulate alveolar hypercoagulation and fibrinolytic inhibition in ARDS, potentially through modulation of the NF‐κB pathway. The rat model of acute respiratory distress syndrome (ARDS) was induced via inhalation of lipopolysaccharide (LPS). In some rats, pulmonary tissue was subjected to either overexpression or knockdown of the LPAR1 gene using lentiviral‐mediated transfection prior to LPS exposure. The impact of LPAR1 modulation on alveolar hypercoagulation, fibrinolytic inhibition, acute lung injury, and the NF‐κB signaling pathway in the ARDS rat model was investigated. In vitro, the expression level of LPAR1 in LPS‐stimulated type II alveolar epithelial cells (AECII) was monitored over time. Additionally, we assessed the influence of LPAR1 on the expression of tissue factor (TF) and plasminogen activator inhibitor‐1 (PAI‐1), as well as its role in the NF‐κB signaling pathway within these cells. The potential influence of LPAR1 on the hypercoagulation and fibrinolytic inhibition in LPS‐induced ARDS via the NF‐κB signaling pathway was also examined. An increase in LPAR1 expression was observed in the lung tissue of rats with ARDS. Our findings indicated that overexpression of LPAR1 significantly intensified lung injury and the wet‐to‐dry (W/D) ratio, both of which are induced by LPS, while the knockdown of LPAR1 substantially reduced these effects. Inhalation of LPS resulted in elevated expression levels of TF, plasminogen activator inhibitor‐1 (PAI‐1), as well as increased activity of TF, PAI‐1, and thrombin in bronchoalveolar lavage fluid (BALF). These effects were exacerbated by LPAR1 overexpression but were notably diminished by LPAR1 knockdown. Overexpression of LPAR1 further activated the LPS‐induced NF‐κB signaling pathway, whereas reduced LPAR1 expression significantly dampened NF‐κB activation. In cellular studies, LPAR1 levels began to rise 6 h post‐LPS stimulation, peaked at 24 h, and subsequently declined. LPS stimulation also increased TF and PAI‐1 expression and activated the NF‐κB signaling pathway. The enhancements of TF and PAI‐1 expressions observed in LPAR1‐overexpressing conditions were markedly counteracted by LPAR1 knockdown. Rescue experiments validated that the inhibition of the NF‐κB signaling pathway significantly reversed the upregulation of TF and PAI‐1 caused by LPAR1 overexpression in LPS‐stimulated RLE‐6TN cells. The findings of our study provide evidence that LPAR1 exacerbates LPS‐induced alveolar hypercoagulation and the inhibition of fibrinolysis in LPS‐induced ARDS through the NF‐κB signaling pathway. The LPAR1/NF‐κB signaling axis may represent a promising target for further investigation into the molecular mechanisms underlying ARDS.

Background: Sepsis is a globally recognized health issue that continues to contribute significantly to mortality and morbidity in intensive care units (ICUs). The association between mean arterial pressure (MAP) and prognosis among patients with patients is yet to be demonstrated. Objective: The aim of this study was to explore the association between MAP and 28-day mortality in ICU patients with sepsis using data from a large, multicenter database. Methods: This is a retrospective cohort study. We extracted data of 35,010 patients with sepsis from the MIMIC-IV (Medical Information Mart for Intensive Care) database between 2008 and 2019, according to the Sepsis 3.0 diagnostic criteria. The MAP was calculated as the average of the highest and lowest readings within the first 24 hours of ICU admission, and patients were divided into 4 groups based on the mean MAP, using the quadruple classification approach. Other worst-case indications from the first 24 hours of ICU admission, such as vital signs, severity of illness scores, laboratory indicators, and therapies, were also gathered as baseline data. The independent effects of MAP on 28-day mortality were explored using binary logistic regression and a two-piecewise linear model, with MAP as the exposure and 28-day mortality as the outcome variables, respectively. To address the nonlinearity relationship, curve fitting and a threshold effect analysis were performed. Results: A total of 34,981 patients with sepsis were included in the final analysis, the mean age was 66.67 (SD 16.01) years, and the 28-day mortality rate was 16.27% (5691/34,981). The generalized additive model and smoothed curve fitting found a U-shaped relationship between MAP and 28-day mortality in these patients. The recursive algorithm determined the low and high inflection points as 70 mm and 82 mm Hg, respectively. Our data demonstrated that MAP was negatively associated with 28-day mortality in the range of 34.05 mm Hg-69.34 mm Hg (odds ratio [OR] 0.93, 95% CI 0.92-0.94; P<.001); however, once the MAP exceeded 82 mm Hg, a positive association existed between MAP and 28-day mortality of patients with sepsis (OR 1.01; 95% CI 1.01-1.02, P=.002). Conclusions: There is a U-shaped association between MAP and the probability of 28-day mortality in patients with sepsis. Both the lower and higher MAP were related with a higher risk of mortality in patients with sepsis. These patients have a decreased risk of mortality when their MAP remains between 70 and 82 mm Hg.

Background: Andrographolide (Andro) has been confirmed to ameliorate alveolar hypercoagulation and fibrinolysis inhibition via NF-κB pathway in acute respiratory distress syndrome (ARDS), but the specific target of Andro is unknown.Purpose: Our aim is to explore the specific target of Andro through which the drug exerted its effects on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS.Methods: AECII was treated with different doses of Andro for 1 h, and then stimulated with LPS for 24 h. Expressions of tissue factor (TF), plasminogen activator inhibitor (PAI)-1 and tissue factor pathway inhibitor (TFPI) were detected. Concentrations of thrombin-antithrombin complex (TAT), pro-collagen type III peptide (PIIIP), antithrombin III (ATIII) and activated protein C (APC) in cell supernatant were measured by enzyme linked immunosorbent assay (ELISA). NF-κB signaling pathways activation was simultaneously determined. AECII with p65 down-/over-expression were used as control.Results: Andro effectively inhibited TF and PAI-1 and promoted TFPI expressions on AECII induced by LPS stimulation. Andro also significantly suppressed the productions of TAT and PIIIP but promoted ATIII and APC secretions from the LPS-treated cell. Furthermore, Andro application obviously inhibited NF-κB signaling pathway activation provoked by LPS, as shown by decreased level of phosphorylation (p‑)-IKKβ/IKKβ, p-p65/p65 and p65 DNA binding activity. The effects of Andro on those factors were obviously strengthened by down- but were weakened by up-regulation of p65 gene in AECII cell.Conclusions: Our data demonstrates that targeting AECII is the mechanism by which Andro ameliorates alveolar hypercoagulaiton and fibrinolytic inhibition via NF-κB pathway in ARDS. Andro is worth to be clinically further studied in ARDS treatment.