上皮细胞和成纤维细胞均通过TGF-β1和GSK-3β途径被激活，在肺纤维化合并肺腺癌的合并症中存在差异

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-05-09 DOI:10.1016/j.lfs.2025.123696

Chenguang Yang , Zijian Qin , Hu Ma , Huanqin Liu , Mengdan Hou , Jing Wei , Hongyan Guo , Xiang An , Feng Yang , Aijun Yang , Yamei Dang , Fangfang Zhang

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引用次数: 0

摘要

目的肺腺癌（LUAD）的合并常加重肺纤维化（PF），而肺腺癌（LUAD）的合并常导致患者死亡，而非肺癌。尽管许多研究揭示了肺癌切除和放疗导致PF加重的机制，但肺癌本身对PF的影响仍然是一个谜。材料与方法共培养小鼠肺细胞与小鼠LUAD细胞，探讨LUAD对PF发病和进展的影响，并通过气管内注射博来霉素（BLM）和LUAD细胞原位移植建立PF与LUAD合并症模型。此外，免疫荧光、免疫组织化学和分子分析被用于阐明LUAD合并症加剧PF的机制。我们发现LUAD显著加重了PF。在LUAD微环境下，肺上皮细胞上皮-间充质转化（epithelial-mesenchymal transition， EMT）主要被激活，肺成纤维细胞向肌成纤维细胞的转化被显著诱导。TGF-β和GSK-3β通路在肺上皮细胞和成纤维细胞中被不同程度激活。此外，临床样本证实了这些途径参与了LUAD合并LUAD的PF患者肺部病变中LUAD诱导的PF加重过程。本研究初步揭示了LUAD通过TGF-β和GSK-3β通路不同程度地调节上皮细胞和成纤维细胞，从而加重PF。实际上，靶向TGF-β和GSK-3β通路可能是预防LUAD患者PF加重的潜在策略。

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Epithelial cells and fibroblasts are both activated via TGF-β1 and GSK-3β pathways differentially in the comorbidity of pulmonary fibrosis with lung adenocarcinoma

Aims

Pulmonary fibrosis (PF) is always exacerbated by the comorbidity of lung adenocarcinoma (LUAD), and patients frequently died from the complications of PF instead of lung cancer. Although many studies have unveiled the mechanisms underlying PF exacerbation due to lung cancer resection and radiotherapy, the influence of lung cancer itself on PF remains enigmatic.

Materials and methods

We cocultivated mouse pulmonary cells with mouse LUAD cells to explore the influence of LUAD on the pathogenesis and progression of PF. Additionally, a comorbidity model of PF with LUAD was established in mice via intratracheal injection of bleomycin (BLM) followed by in situ transplantation of LUAD cells. Furthermore, immunofluorescence, immunohistochemistry, and molecular analyses were employed to elucidate the mechanisms underlying the exacerbation of PF by the comorbidity of LUAD.

Key findings

We found that PF was significantly exacerbated by LUAD. In the microenvironment of LUAD, the epithelial-mesenchymal transition (EMT) was predominantly activated in lung epithelial cells, while the transformation of lung fibroblasts into myofibroblasts was markedly induced. The TGF-β and GSK-3β pathways were differentially activated in lung epithelial cells and fibroblasts. Furthermore, clinical samples confirmed the involvement of these pathways in the process of PF exacerbation induced by LUAD in patients' lung lesions of PF with LUAD.

Significance

This study initially reveals that LUAD exacerbates PF by modulating epithelial cells and fibroblasts through TGF-β and GSK-3β pathways differentially. Practically, targeting the pathways of TGF-β and GSK-3β may promise a potential strategy for the prophylaxis of PF exacerbation in patients with LUAD.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.