Leukocyte Signalling Laboratory, Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
School of Health and Biomedical Science, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, Victoria, Australia; and.
Am J Respir Cell Mol Biol. 2023 Jul;69(1):99-112. doi: 10.1165/rcmb.2022-0463OC.
The epidemiological patterns of incident chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma are changing, with an increasing fraction of disease occurring in patients who are never-smokers or were not exposed to traditional risk factors. However, causative mechanism(s) are obscure. Overactivity of Src family kinases (SFKs) and myeloid cell-dependent inflammatory lung epithelial and endothelial damage are independent candidate mechanisms, but their pathogenic convergence has not been demonstrated. Here we present a novel preclinical model in which an activating mutation in Lyn, a nonreceptor SFK that is expressed in immune cells, epithelium, and endothelium-all strongly implicated in the pathogenesis of COPD-causes spontaneous inflammation, early-onset progressive emphysema, and lung adenocarcinoma. Surprisingly, even though activated macrophages, elastolytic enzymes, and proinflammatory cytokines were prominent, bone marrow chimeras formally demonstrated that myeloid cells were not disease initiators. Rather, lung disease arose from aberrant epithelial cell proliferation and differentiation, microvascular lesions within an activated endothelial microcirculation, and amplified EGFR (epidermal growth factor receptor) expression. In human bioinformatics analyses, expression was increased in patients with COPD and was correlated with increased expression, a known lung oncogenic pathway, and was linked to COPD. Our study shows that a singular molecular defect causes a spontaneous COPD-like immunopathology and lung adenocarcinoma. Furthermore, we identify Lyn and, by implication, its associated signaling pathways as new therapeutic targets for COPD and cancer. Moreover, our work may inform the development of molecular risk screening and intervention methods for disease susceptibility, progression, and prevention of these increasingly prevalent conditions.
慢性阻塞性肺疾病（COPD）和肺腺癌的发病模式正在发生变化，越来越多的患者从不吸烟或没有接触过传统的危险因素。然而，其致病机制尚不清楚。Src 家族激酶（SFKs）的过度活跃和髓样细胞依赖性炎症性肺上皮和内皮损伤是独立的候选机制，但它们的致病机制尚不清楚。在这里，我们提出了一个新的临床前模型，在该模型中，表达于免疫细胞、上皮细胞和内皮细胞中的非受体 SFK Lyn 的激活突变导致自发性炎症、早发性进行性肺气肿和肺腺癌。令人惊讶的是，尽管激活的巨噬细胞、弹性酶和促炎细胞因子很明显，但骨髓嵌合体正式证明髓样细胞不是疾病的启动者。相反，肺部疾病是由异常的上皮细胞增殖和分化、激活的内皮微循环中的微血管损伤以及表皮生长因子受体（EGFR）表达的放大引起的。在人类生物信息学分析中，在 COPD 患者中表达增加，并且与增加的表达相关，这是已知的肺致癌途径，与 COPD 相关。我们的研究表明，单一的分子缺陷导致自发性 COPD 样免疫病理学和肺腺癌。此外，我们确定 Lyn 及其相关信号通路是 COPD 和癌症的新治疗靶点。此外，我们的工作可能为这些日益流行疾病的易感性、进展和预防提供分子风险筛查和干预方法的发展提供信息。
