ABSTRACT
Neutrophil extracellular traps (NETs) and pyroptosis are critical events in lung injury. This study investigated whether ficolin-A influenced NET formation through pyroptosis to exacerbate lipopolysaccharide (LPS)-induced lung injury. The expression of ficolin-A/2, NETs, and pyroptosis-related molecules was investigated in animal and cell models. Knockout and knockdown (recombinant protein) methods were used to elucidate regulatory mechanisms. The Pearson correlation coefficient was used to analyze the correlation between ficolins and pyroptosis- and NET-related markers in clinical samples. In this study, ficolin-2 (similar to ficolin-A) showed significant overexpression in patients with acute respiratory distress syndrome. In vivo, knockout of Fcna, but not Fcnb, attenuated lung inflammation and inhibited NET formation in the LPS-induced mouse model. DNase I further alleviated lung inflammation and NET formation in Fcna knockout mice. In vitro, neutrophils derived from Fcna-/- mice showed less pyroptosis and necroptosis than those from the control group after LPS stimulation. Additionally, GSDMD knockdown or Nod-like receptor protein 3 inhibitor reduced NET formation. Addition of recombinant ficolin-2 protein to human peripheral blood neutrophils promoted NET formation and pyroptosis after LPS stimulation, whereas Fcn2 knockdown had the opposite effect. Acute respiratory distress syndrome patients showed increased levels of pyroptosis- and NET-related markers, which were correlated positively with ficolin-2 levels. In conclusion, these results suggested that ficolin-A/2 exacerbated NET formation and LPS-induced lung injury via gasdermin D-mediated pyroptosis.
Subject(s)
Extracellular Traps , Mice, Knockout , Neutrophils , Phosphate-Binding Proteins , Pyroptosis , Extracellular Traps/metabolism , Animals , Mice , Phosphate-Binding Proteins/metabolism , Humans , Neutrophils/metabolism , Neutrophils/pathology , Ficolins , Lectins/metabolism , Lipopolysaccharides , Mice, Inbred C57BL , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Male , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/geneticsABSTRACT
BACKGROUND: Nearly half of bronchiectasis patients receiving bronchial artery embolization (BAE) still have recurrent hemoptysis, which may be life-threatening. Worse still, the underlying risk factors of recurrence remain unknown. METHODS: A retrospective cohort was conducted of patients with idiopathic bronchiectasis who received BAE from 2015 to 2019 at eight centers. Patients were followed up for at least 24 months post BAE. Based on the outcomes of recurrent hemoptysis and recurrent severe hemoptysis, a Cox regression model was used to identify risk factors for recurrence. RESULTS: A total of 588 individuals were included. The median follow-up period was 34.0 months (interquartile range: 24.3-53.3 months). The 1-month, 1-year, 2-year, and 5-year cumulative recurrent hemoptysis-free rates were 87.2%, 67.5%, 57.6%, and 49.4%, respectively. The following factors were relative to recurrent hemoptysis: 24-h sputum volume (hazard ratio [HR] = 1.99 [95% confidence interval [95% CI]: 1.25-3.15, p = 0.015]), isolation of Pseudomonas aeruginosa (HR = 1.50 [95% CI: 1.13-2.00, p = 0.003]), extensive bronchiectasis (HR = 2.00 [95% CI: 1.29-3.09, p = 0.002]), and aberrant bronchial arteries (AbBAs) (HR = 1.45 [95% CI: 1.09-1.93, p = 0.014]). The area under the receiver operating characteristic curve of the nomogram was 0.728 [95% CI: 0.688-0.769]. CONCLUSIONS: Isolation of Pseudomonas aeruginosa is an important independent predictor of recurrent hemoptysis. The clearance of Pseudomonas aeruginosa might effectively reduce the hemoptysis recurrence rate.
Subject(s)
Bronchiectasis , Embolization, Therapeutic , Humans , Bronchial Arteries , Pseudomonas aeruginosa , Retrospective Studies , Recurrence , Hemoptysis/diagnosis , Hemoptysis/therapy , Embolization, Therapeutic/adverse effects , Bronchiectasis/diagnosis , Bronchiectasis/therapy , Treatment OutcomeABSTRACT
In general, non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitors (TKIs). However, most patients experience resistance within 1-2 years after treatment. The histological explanation for the acquired resistance is that malignant transformation occurs during cancer treatment. To date, the transformation from adenocarcinoma to squamous cell carcinoma associated with EGFR-TKI use remains poorly reported. We report a case of stage IV lung adenocarcinoma with EGFR mutations that converted to squamous cell carcinoma due to long-term administration of EGFR-TKIs. This report strengthens histological evolution as a source of acquired drug resistance.