Exosomal Tenascin-C primes macrophage pyroptosis amplifying aberrant inflammation during sepsis-induced acute lung injury.

Sepsis-induced acute lung injury (ALI) is a serious complication of sepsis and the predominant cause of death. Exosomes released by lung tissue cells critically influence the progression of ALI during sepsis by modulating the inflammatory microenvironment. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbates ALI in septic infection remain undefined. Our study found increased levels of exosomal Tenascin-C (TNC) in the plasma of both patients and mice with ALI, showing a strong association with disease progression. By integrating exosomal proteomics with transcriptome sequencing and experimental validation, we elucidated that LPS induce unresolved endoplasmic reticulum stress (ERs) in alveolar epithelial cells (AECs), ultimately leading to the release of exosomal TNC through the activation of PERK-eIF2α and the transcription factor CHOP. In the sepsis mouse model with TNC knockout, we noted a marked reduction in macrophage pyroptosis. Our detailed investigations found that exosomal TNC binds to TLR4 on macrophages, resulting in an augmented production of ROS, subsequent mitochondrial damage, activation of the NF-κB signaling pathway, and induction of DNA damage response. These interconnected events culminate in macrophage pyroptosis, thereby amplifying the release of inflammatory cytokines. Our findings demonstrate that exosomal Tenascin-C, released from AECs under unresolved ER stress, exacerbates acute lung injury by intensifying sepsis-associated inflammatory responses. This research provides new insights into the complex cellular interactions underlying sepsis-induced ALI.

Establishment and visualization of a model based on high-resolution CT qualitative and quantitative features for prediction of micropapillary or solid components in invasive lung adenocarcinoma.

OBJECTIVE: To predict the existence of micropapillary or solid components in invasive adenocarcinoma, a model was constructed using qualitative and quantitative features in high-resolution computed tomography (HRCT). METHODS: Through pathological examinations, 176 lesions were divided into two groups depending on the presence or absence of micropapillary and/or solid components (MP/S): MP/S- group (n = 128) and MP/S + group (n = 48). Multivariate logistic regression analyses were used to identify independent predictors of the MP/S. Artificial intelligence (AI)-assisted diagnostic software was used to automatically identify the lesions and extract corresponding quantitative parameters on CT images. The qualitative, quantitative, and combined models were constructed according to the results of multivariate logistic regression analysis. The receiver operating characteristic (ROC) analysis was conducted to evaluate the discrimination capacity of the models with the area under the curve (AUC), sensitivity, and specificity calculated. The calibration and clinical utility of the three models were determined using the calibration curve and decision curve analysis (DCA), respectively. The combined model was visualized in a nomogram. RESULTS: The multivariate logistic regression analysis using both qualitative and quantitative features indicated that tumor shape (P = 0.029 OR = 4.89; 95% CI 1.175-20.379), pleural indentation (P = 0.039 OR = 1.91; 95% CI 0.791-4.631), and consolidation tumor ratios (CTR) (P < 0.001; OR = 1.05; 95% CI 1.036-1.070) were independent predictors for MP/S + . The areas under the curve (AUC) of the qualitative, quantitative, and combined models in predicting MP/S + were 0.844 (95% CI 0.778-0.909), 0.863 (95% CI 0.803-0.923), and 0.880 (95% CI 0.824-0.937). The combined model of AUC was the most superior and statistically better than qualitative model. CONCLUSION: The combined model could assist doctors to evaluate patient's prognoses and devise personalized diagnostic and treatment protocols for patients.

Macrophage-derived exosomal aminopeptidase N aggravates sepsis-induced acute lung injury by regulating necroptosis of lung epithelial cell.

Sepsis-induced acute lung injury (ALI) is a serious sepsis complication and the prevailing cause of death. Circulating plasma exosomes might exert a key role in regulating intercellular communication between immunological and structural cells, as well as contributing to sepsis-related organ damage. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbate ALI in septic infection remains undefined. Therefore, we investigated the effect of macrophage-derived exosomal APN/CD13 on the induction of epithelial cell necrosis. Exosomal APN/CD13 levels in the plasma of septic mice and patients with septic ALI were found to be higher. Furthermore, increased plasma exosomal APN/CD13 levels were associated with the severity of ALI and fatality in sepsis patients. We found remarkably high expression of APN/CD13 in exosomes secreted by LPS-stimulated macrophages. Moreover, c-Myc directly induced APN/CD13 expression and was packed into exosomes. Finally, exosomal APN/CD13 from macrophages regulated necroptosis of lung epithelial cells by binding to the cell surface receptor TLR4 to induce ROS generation, mitochondrial dysfunction and NF-κB activation. These results demonstrate that macrophage-secreted exosomal APN/CD13 can trigger epithelial cell necroptosis in an APN/CD13-dependent manner, which provides insight into the mechanism of epithelial cell functional disorder in sepsis-induced ALI.