Xuebijing alleviates LPS-induced acute lung injury by downregulating pro-inflammatory cytokine production and inhibiting gasdermin-E-mediated pyroptosis of alveolar epithelial cells.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response. Regrettably, the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition. Xuebijing (XBJ), a traditional Chinese medicine recognized for its potent anti-inflammatory properties, exhibits promise as a potential therapeutic agent for ALI/ARDS. This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism. To this end, we established an LPS-induced ALI model and treated ALI mice with XBJ. Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%. Moreover, XBJ substantially suppressed the production of TNF-α, IL-6, and IL-1ß in the lung tissue. Subsequently, we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses. Furthermore, we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-α production. Therefore, this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-α release.

α7nAChR activation in AT2 cells promotes alveolar regeneration through WNT7B signaling in acute lung injury.

Reducing inflammatory damage and improving alveolar epithelium regeneration are two key approaches to promoting lung repair in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Stimulation of cholinergic α7 nicotinic acetylcholine receptor (α7nAChR, coded by Chrna7) signaling could dampen lung inflammatory injury. However, whether activation of α7nAChR in alveolar type II (AT2) cells promotes alveolar epithelial injury repair and underlying mechanisms is elusive. Here, we found that α7nAChR was expressed on AT2 cells and was upregulated in response to LPS-induced ALI. Meanwhile, deletion of Chrna7 in AT2 cells impeded lung repair process and worsened lung inflammation in ALI. Using in vivo AT2 lineage-labeled mice and ex vivo AT2 cell-derived alveolar organoids, we demonstrated that activation of α7nAChR expressed on AT2 cells improved alveolar regeneration by promoting AT2 cells to proliferate and subsequently differentiate toward alveolar type I cells. Then, we screened out the WNT7B signaling pathway by the RNA-Seq analysis of in vivo AT2 lineage-labeled cells and further confirmed its indispensability for α7nAChR activation-mediated alveolar epithelial proliferation and differentiation. Thus, we have identified a potentially unrecognized pathway in which cholinergic α7nAChR signaling determines alveolar regeneration and repair, which might provide us a novel therapeutic target for combating ALI.

The prediction of lymphocyte count and neutrophil count on the efficacy of Xuebijing adjuvant treatment for severe community-acquired pneumonia: A post hoc analysis of a randomized controlled trial.

BACKGROUND: Adjuvant Xuebijing therapy exhibited a protective effect on severe community-acquired pneumonia (SCAP) in previous studies. Blood inflammatory biomarkers related to the disease subtype and severity of SCAP might be associated with the effects of Xuebijing on clinical outcomes of SCAP. PURPOSE: To investigate whether neutrophils or lymphocytes are a useful biomarker of the therapeutic effect of Xuebijing on mortality and inflammation damage index. STUDY DESIGN: A post hoc analysis of a randomized, placebo-controlled and double-blinded clinical trial of Xuebijing in patients with SCAP (Clinical Trial Registration: ChiCTR-TRC-13003534). METHODS: We compared 28-day mortality (primary outcome) and four clinical scores (secondary outcome), including pneumonia severity index (PSI) score, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score, and systemic inflammatory response syndrome (SIRS) score, according to the baseline strata of neutrophil count and lymphocyte count. RESULTS: A total of 675 patients were included in the analyses, of which 334 received Xuebijing and 341 received the placebo. Xuebijing was more effective in SCAP patients with higher lymphocyte counts and lower neutrophil counts. In the lymphocyte-dominated inflammation (LDI) subgroup, defined as neutrophil count <13 × 109 cells/l and lymphocyte count ≥0.65 × 109 cells/l, Xuebijing reduced 28-day mortality by 15% while mortality of the neutrophil-dominated inflammation (NDI) subgroup decreased by 4.7% (p = 0.050). There was also greater improvement in the PSI, SOFA, APACHE II, and SIRS scores following Xuebijing treatment in the LDI subgroup compared with the NDI subgroup. CONCLUSIONS: Xuebijing treatment shows stronger protective effects in SCAP patients with higher lymphocyte and lower neutrophil counts. Our findings may facilitate the selection of the most appropriate treatments for individual patients with SCAP, including who will receive Xuebijing injections.

Molecular mechanisms and roles of pyroptosis in acute lung injury.

ABSTRACT: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which are characterized by excessive inflammation and accompanied by diffuse injury of alveoli, can result in severe respiratory failures. The morbidity and mortality of patients remain high because the major treatments for ALI/ARDS are mainly supportive due to the lack of effective therapies. Numerous studies have demonstrated that the aggravation of coronavirus disease 2019 (COVID-19) leads to severe pneumonia and even ARDS. Pyroptosis, a biological process identified as a type of programed cell death, is mainly triggered by inflammatory caspase activation and is directly meditated by the gasdermin protein family, as well as being associated with the secretion and release of pro-inflammatory cytokines. Clinical and experimental evidence corroborates that pyroptosis of various cells in the lung, such as immune cells and structural cells, may play an important role in the pathogenesis of "cytokine storms" in ALI/ARDS, including those induced by COVID-19. Here, with a focus on ALI/ARDS and COVID-19, we summarized the recent advances in this field and proposed the theory of an inflammatory cascade in pyroptosis to identify new targets and pave the way for new approaches to treat these diseases.

Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer.

Background: Immune checkpoint inhibitors (ICIs) have led to dramatic improvements in survival a subset of patients with non-small cell lung cancer (NSCLC); however, they have been shown to cause life-threatening toxicity such as immune checkpoint inhibitor-related pneumonitis (CIP). Our previous studies have shown that chronic obstructive pulmonary disease (COPD) and circulating cytokines are associated with clinical outcomes in NSCLC patients receiving ICIs. However, the relationship between these factors and the development of CIP is unclear. In this study, we retrospectively assessed NSCLC patients receiving ICIs to identify CIP risk factors. Methods: This retrospective cohort study reviewed medical records of NSCLC patients receiving ICIs targeting programmed cell death 1 (PD-1) or its ligand PD-L1 between March 2017 and December 2020 at Zhongshan Hospital Fudan University. CIP was diagnosed by the treating investigator. Clinical characteristics and baseline plasma cytokines were collected. Logistic regression was used to compare clinical characteristics and circulating cytokine levels between patients with and without CIP to identify CIP risk factors. Results: Of 164 NSCLC patients who received ICIs, CIP developed in 20 cases (12.2%). The presence of COPD [odds ratio (OR), 7.194; 95% confidence interval (CI): 1.130 to 45.798; P=0.037] and PD-L1 expression of ≥50% (OR, 7.184; 95% CI: 1.154 to 44.721; P=0.035) were independently associated with a higher incidence of CIP, whereas a higher baseline level of interleukin-8 (IL-8) was associated with a lower incidence of CIP (OR, 0.758; 95% CI: 0.587 to 0.978; P=0.033). The independent risk factors from final multivariate analysis were incorporated into a nomogram to predict the incidence of CIP. The nomogram model receiver operating characteristic (ROC) curve had a good predictive accuracy of 0.883 (95% CI: 0.806 to 0.959). Conclusions: Increased risk of CIP independently associated with history of COPD, tumor PD-L1 expression ≥50%, and low baseline IL-8 level. The nomogram may hold promise for CIP risk assessment in the administration of ICIs.