Boo Hye-Jin, Min Hye-Young, Lim Heung-Bin, Lee Euni, Lee Ho-Young
Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Histology, College of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
Inflamm Regen. 2024 Jun 21;44(1):31. doi: 10.1186/s41232-024-00344-3.
Tobacco smoking causes pulmonary inflammation, resulting in emphysema, an independent risk factor for lung cancer. Induction of insulin-like growth factor 2 (IGF2) in response to lung injury by tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and polycyclic aromatic hydrocarbon benzo[a]pyrene in combination (NB), is critical for the proliferation of alveolar type 2 cells (AT2s) for lung repair. However, persistent IGF2 overexpression during NB-induced severe injury results in hyperproliferation of AT2s without coordinated AT2-to-AT1 differentiation, disrupting alveolar repair, which leads to the concurrent development of emphysema and lung cancer. The current study aims to verify the role of IGF2 signaling in the associated development of emphysema and cancer and develop effective pharmaceuticals for the diseases using animal models that recapitulate the characteristics of these chronic diseases.
The pathogenesis of pulmonary emphysema and cancer was analyzed by lung function testing, histological evaluation, in situ zymography, dihydroethidium staining, and immunofluorescence and immunohistochemistry analyses utilizing mouse models of emphysema and cancer established by moderate exposure to NB for up to seven months.
Moderate NB exposure induced IGF2 expression in AT2s during the development of pulmonary emphysema and lung cancer in mice. Using AT2-specific insulin receptor knockout mice, we verified the causative role of sustained IGF2 signaling activation in AT2s in emphysema development. IGF2-targeting strategies, including voltage-dependent calcium channel blocker (CCB) and a neutralizing antibody, significantly suppressed the NB-induced development of emphysema and lung cancer. A publicly available database revealed an inverse correlation between the use of calcium channel blockers and a COPD diagnosis.
Our work confirms sustained IGF2 signaling activation in AT2s couples impaired lung repair to the concurrent development of emphysema and cancer in mice. Additionally, CCB and IGF2-specific neutralizing antibodies are effective pharmaceuticals for the two diseases.
吸烟会导致肺部炎症，进而引发肺气肿，而肺气肿是肺癌的一个独立危险因素。烟草致癌物4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁醇和多环芳烃苯并[a]芘联合作用（NB）引起肺损伤时，胰岛素样生长因子2（IGF2）的诱导对于肺泡Ⅱ型细胞（AT2s）增殖以进行肺修复至关重要。然而，在NB诱导的严重损伤过程中，IGF2持续过表达会导致AT2s过度增殖，而没有协调的AT2向AT1分化，从而破坏肺泡修复，进而导致肺气肿和肺癌同时发生。本研究旨在验证IGF2信号在肺气肿和癌症相关发展中的作用，并利用重现这些慢性疾病特征的动物模型开发针对这些疾病的有效药物。
通过肺功能测试、组织学评估、原位酶谱分析、二氢乙锭染色以及免疫荧光和免疫组织化学分析，利用中度暴露于NB长达七个月建立的肺气肿和癌症小鼠模型，分析肺气肿和癌症的发病机制。
在小鼠肺气肿和肺癌发展过程中，中度NB暴露诱导AT2s中IGF2表达。使用AT2特异性胰岛素受体敲除小鼠，我们验证了AT2s中持续的IGF2信号激活在肺气肿发展中的因果作用。针对IGF2的策略，包括电压依赖性钙通道阻滞剂（CCB）和中和抗体，显著抑制了NB诱导的肺气肿和肺癌发展。一个公开可用的数据库显示钙通道阻滞剂的使用与慢性阻塞性肺疾病（COPD）诊断之间呈负相关。
我们的工作证实了AT2s中持续的IGF2信号激活将受损的肺修复与小鼠肺气肿和癌症的同时发生联系起来。此外，CCB和IGF2特异性中和抗体是治疗这两种疾病的有效药物。
