The loss of normal alveolar capillary and deregulated angiogenesis occurs simultaneously in idiopathic pulmonary fibrosis (IPF); however the contributions of specific endothelial subpopulations in the development of pulmonary fibrosis are poorly understood. Herein, we perform single-cell RNA sequencing to characterize the heterogeneity of endothelial cells (ECs) in bleomycin (BLM)-induced lung fibrosis in rats. One subpopulation, characterized by the expression of Nos3 and Cav1, is mostly distributed in non-fibrotic lungs and also highly expresses genes related to the “response to mechanical stimulus” and “lung/heart morphogenesis” processes. Another subpopulation of ECs expanded in BLM-treated lungs, characterized by Cxcl12, is observed to be closely related to the pro-fibrotic process in the transcriptome data, such as “regulation of angiogenesis,” “collagen binding,” and “chemokine activity,” and spatially localized to BLM-induced neovascularization. Using CellPhoneDB software, we generated a complex cell–cell interaction network, which predicts the potential roles of EC subpopulations in recruiting monocytes, inducing the proliferation of fibroblasts and promoting the production and remolding of the extracellular matrix (ECM). Taken together, our data demonstrate the high degree of heterogeneity of ECs in fibrotic lung and it is proposed that the interaction between ECs, macrophages, and stromal cells contributes to pathologic IPF.

The occurrence and development of acute lung injury (ALI) involve a variety of pathological factors and complex mechanisms. How pulmonary cells communicate with each other and subsequently trigger an inflammatory cascade remains elusive. Extracellular vesicles (EVs) are a critical class of membrane-bound structures that have been widely investigated for their roles in pathophysiological processes, especially in immune responses and tumor progression. Most of the current knowledge of the functions of EVs is related to functions derived from viable cells (e.g., microvesicles and exosomes) or apoptotic cells (e.g., apoptotic bodies); however, there is limited understanding of the rapidly progressing inflammatory response in ALI. Herein, a comprehensive analysis of micron-sized EVs revealed a mass production of 1-5 μm pyroptotic bodies (PyrBDs) release in the early phase of ALI induced by lipopolysaccharide (LPS). Alveolar macrophages were the main source of PyrBDs in the early phase of ALI, and the formation and release of PyrBDs were dependent on caspase-1. Furthermore, PyrBDs promoted the activation of epithelial cells, induced vascular leakage and recruited neutrophils through delivery of damage-associated molecular patterns (DAMPs). Collectively, these findings suggest that PyrBDs are mainly released by macrophages in a caspase-1-dependent manner and serve as mediators of LPS-induced ALI.

The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluatedin vitroandin vivo. Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day⁻¹) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.

AMP‐activated protein kinase (AMPK) serves as a “supermetabolic regulator” that helps maintain cellular energy homeostasis. However, the role of AMPK in glucose metabolism reprogramming in lung cancer remains unclear. Here, our study shows that low AMPK expression correlates with metastasis and clinicopathologic parameters of non–small‐cell lung cancer. Low AMPK significantly enhances the Warburg effect in HBE and A549 cells, which in turn induces the expression of mesenchymal markers and enhances their invasion and migration. At the mechanistic level, low AMPK up‐regulates HK2 expression and glycolysis levels through HDAC4 and HDAC5. Collectively, our findings demonstrate that low AMPK‐induced metabolism can promote epithelial‐mesenchymal transition progression in normal bronchial epithelial cells and lung cancer cells, and increase the risk for tumour metastasis.

In patients with non-small-cell lung cancer (NSCLC) treated with neoadjuvant chemoimmunotherapy, lymph node (LN) status is classified as ypN0 and ypN+. However, ypN0 includes patients who either had LN metastasis before neoadjuvant therapy (cN+/ypN0) or those who never developed LN metastasis (cN0/ypN0). The prognostic implications of these different LN statuses are not well understood. A retrospective analysis was conducted on patients with NSCLC who underwent surgery after neoadjuvant chemoimmunotherapy at 4 centers in China from 2019 to 2022. Patients were grouped by their LN status into ``natural'' N0 (cN0/ypN0), ``downstaged'' N0 (cN+/ypN0), and ypN+ (cN+/ypN+). Out of 527 initially enrolled patients, 186 met the inclusion criteria: 34 (18.3%) had ``natural'' N0, 95 (51.1%) had ``downstaged'' N0, and 57 (30.6%) had ypN+. The median follow-up was 24 months (11-64 months). Disease-free survival (DFS) and overall survival (OS) were significantly lower in ypN+ compared to ``natural'' N0 and ``downstaged'' N0 (DFS: P < .001; OS: P < .001). However, no significant difference in either DFS (P = .695) or OS (P = .814) were observed between ``natural'' N0 and ``downstaged'' N0. Subgroup analysis showed that the MPR/ypN0 group had significantly better DFS compared to the non-MPR/ypN0 (P = .008), MPR/ypN+ (P = .028), and non-MPR/ypN+ groups (P < .001). For OS, MPR/ypN0 group was significantly superior to non-MPR/ypN+ (P < .001) and showed a trend toward better OS than non-MPR/ypN0 (P = .067) and MPR/ypN+ (P = .067). Notably, no significant differences were observed in either DFS (P = .908) or OS (P = .943) between non-MPR/ypN0 and MPR/ypN+ groups. The non-MPR/ypN+ group had the poorest survival outcomes in both DFS and OS. Achieving ypN0 status after neoadjuvant chemoimmunotherapy strongly predicts favorable outcomes in patients with NSCLC, regardless of pretreatment cN status. Combining MPR with LN status effectively differentiates patient prognoses.

Background: There are many studies on neoadjuvant immunotherapy for locally advanced non‐small cell lung cancer (NSCLC) patients. Expert consensus recommends neoadjuvant immunotherapy for patients with resectable stage IB–IIIA NSCLC. However, there are few clinical studies or cases to verify this.Methods: Data were collected from all NSCLC patients who underwent surgical resection after neoadjuvant chemoimmunotherapy admitted to the Affiliated Hospital of Xuzhou Medical University and Xuzhou Central Hospital between September 2020 and April 2021. Data collected included patient information, relevant examination results, intraoperative parameters, postoperative complications, pathological changes, and 90‐day mortality.Results: In total, 25 patients achieved R0 resection. Eleven (44%) patients completed surgery by thoracotomy, and three (12%) procedures were changed from minimally invasive procedures due to dense adhesions of hilar lymph nodes, which rendered it difficult to dissect the blood vessels. Thirteen (52%) patients achieved a major pathological response (MPR) with eight (32%) of these patients having a pathological complete response (pCR). Twenty‐two (88%) patients showed radiological regression, and three (12%) patients had stable disease. The median drainage time was 8.50 (3–27) days. Thirteen (52%) postoperative complications were observed, but none were above grade 3.Conclusions: In this study, neoadjuvant chemoimmunotherapy was found to reduce tumor volume, cause pathological downstaging, and raise the surgical resection rate of patients with locally advanced NSCLC, and achieve a 100% R0 resection rate. There was an acceptable rate of postoperative complications. Thus, neoadjuvant chemoimmunotherapy is safe and practical.