Zhang D, et al. Allergy Asthma Immunol Res. 2024 Jul;16(4):399-421. https://doi.org/10.4168/aair.2024.16.4.399

The inflammatory storm is a hallmark of acute respiratory distress syndrome (ARDS), yet effective therapies remain unavailable. FK506‐binding protein 51 (FKBP5) has emerged as a regulator of inflammatory responses. In this study, FKBP5 expression was markedly increased in patients with sepsis and correlated with both cytokine levels and disease severity. Using sepsis‐induced ARDS models in Fkbp5 ^−/− and bone marrow chimeric mice, this study demonstrated that non‐haematopoietic FKBP5 mitigates inflammatory injury. Single‐cell transcriptomic analysis identified fibroblasts and epithelial cells as the primary sources of non‐haematopoietic FKBP5 in the lung injury. Conditional deletion of FKBP5 in fibroblasts ( Col1a2 ‐iCre Fkbp5 ^flox/flox ) confirmed the essential role of fibroblast FKBP5 in the inflammatory response during ARDS. Mechanistically, FKBP5‐mediated necroptosis of alveolar fibroblasts triggered NF‐κB activation, proinflammatory cytokine release, neutrophil recruitment, and the establishment of an inflammatory microenvironment in alveolar epithelial tissue. These findings suggest a potential therapeutic strategy targeting fibroblast FKBP5 and provide a foundation for future clinical investigation in ARDS management.

Purpose: To assess the metabolites associated with Pseudomonas aeruginosa infection by analyzing the microbial diversity and metabolomics in lower respiratory tract of bronchiectasis patients and to explore the therapeutic approaches for Pseudomonas aeruginosa infection. Methods: Bronchoalveolar lavage fluid samples from bronchiectasis patients and controls were analyzed by 16S rRNA and ITS sequencing, and metabolomic analysis was performed by liquid chromatography/mass spectrometry. A co-culture model of air-liquid interface cultured human bronchial epithelial cell with Pseudomonas aeruginosa was constructed to verify the correlation between sphingosine metabolism, acid ceramidase expression, and Pseudomonas aeruginosa infection. Results: After screening, 54 bronchiectasis patients and 12 healthy controls were included. Sphingosine levels in bronchoalveolar lavage fluid were positively correlated with lower respiratory tract microbial diversity and negatively correlated with the abundance of Pseudomonas spp. Moreover, sphingosine levels in bronchoalveolar lavage fluid and acid ceramidase expression levels in lung tissue specimens were significantly lower in bronchiectasis patients than in healthy controls. Sphingosine levels and acid ceramidase expression levels were also significantly lower in bronchiectasis patients with positive Pseudomonas aeruginosa cultures than in bronchiectasis patients without Pseudomonas aeruginosa infection. Acid ceramidase expression in air-liquid interface cultured human bronchial epithelial cell had significantly increased after 6 h of Pseudomonas aeruginosa infection, while it had decreased significantly after 24 h of infection. In vitro experiments showed that sphingosine had a bactericidal effect on Pseudomonas aeruginosa by directly disrupting its cell wall and cell membrane. Furthermore, adherence of Pseudomonas aeruginosa on bronchial epithelial cells was significantly reduced after sphingosine supplementation. Conclusion: Down-regulation of acid ceramidase expression in airway epithelial cells of bronchiectasis patients leads to insufficient metabolism of sphingosine, which has a bactericidal effect, and consequently weakens the clearance of Pseudomonas aeruginosa; thus, a vicious circle is formed. Exogenous supplementation with sphingosine aids bronchial epithelial cells in resisting Pseudomonas aeruginosa infection.

Background The aim of the study was to assess the efficacy and side-effects of intrapleural treatment in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). Methods The medical records of NSCLC patients with MPEs diagnosed in four Chinese hospitals from October 2014 to December 2019 were searched. The Kaplan–Meier method is used to calculate median overall survival (MOS) and subgroup analyses are done. Results A total of 285 patients were evaluated; 81.1% of patients received intrapleural treatment, and no patients received talc pleurodesis. MOS of the whole cohort was 21 months. Patients were divided into three groups: erythromycin group (EG; intrapleural treatment with drugs and erythromycin); intrathoracic treatment group (ITG; intrapleural treatment with drugs); control group (CG; no drug treatment in the pleural cavity). The MOS of patients in the EG, ITG and CG was 20, 22, and 19 months, respectively. Among patients who received only chemotherapy as systemic therapy, the MOS of intrathoracic administration group (IAG; i.e., EG and ITG) was longer than that of CG (12 vs. 6 months; p = 0.034), and the MOS of patients with a ratio of carcinoembryonic antigen in pleural effusion (PE-CEA): CEA in blood (B-CEA) ≤1 is worse than that of patients with a ratio >1 (4 vs. 12 months, p = 0.021) and that of CG (4 vs. 6 months, p = 0.442). Conclusions Intrapleural treatment can prolong the survival of NSCLC patients with MPE who do not receive targeted treatment or who only receive chemotherapy. The PE-CEA: B-CEA ratio can be used to predict the efficacy if intrapleural treatment is indicated.

Pulmonary fibroblasts coordinate the progression of airway inflammation through multiple pathways. However, the role and underlying mechanisms of its subtype, bronchial fibroblasts, under TNF‐α induction remain unclear. This study found that TNF‐α was highly expressed in the airway with asthma patients. Gene sequencing found that a large number of inflammatory cytokines were expressed in TNF‐α‐induced human bronchial fibroblasts, such as IL‐6 , IL‐1β , IL‐15 , TNF , CX3CL1 , DAPK2 , TSLP , CCL2 , CCL5 , CCL7 , CXCL1 , CXCL2 , CXCL3 , CXCL5 , and CXCL6 , which are closely related to eosinophil or neutrophil inflammation. GO enrichment pathways based on the background of the upregulated DEGs showed that TNF‐α‐induced bronchial fibroblasts are closely associated with the programmed cell necrosis signaling, Th2 cytokines production, eosinophils, neutrophils, and so on. Then, western blot showed that the expression levels of IL‐1β and TNF‐α in TNF‐α‐induced bronchial fibroblasts considerably increased, and the expression levels of fibronectin, COL1A1, and TGFβ1 were substantially decreased. ELISA results showed that CCL2, CCL5, CCL7, TSLP, CXCL1, CXCL2, IL‐6, and IL‐1β levels were considerably increased under TNF‐α‐induced bronchial fibroblasts supernatant. In conclusion, our study results indicate that TNF‐α‐induced bronchial fibroblasts play an important role in airway inflammation.