发生慢性阻塞性肺疾病（COPD）和肺腺癌的流行病学类型正在改变，而且越来越多的疾病发生在从未吸烟或未暴露于传统风险因素的患者中。然而，其致病机制仍然不明确。Src家族激酶（SFK）的过度活化和依赖于髓系细胞的炎症性肺上皮和内皮损伤是独立的候选机制，但其致病聚合尚未得到证明。在这里，我们提出了一种新的临床前模型，其中Lyn，一种表达在免疫细胞、上皮和内皮中的非受体SFK，在COPD发病机制中都有强烈的影响，发生激活突变，引起自发性炎症、早期进行性气肿和肺腺癌。令人惊讶的是，尽管活化巨噬细胞、弹性酶酶和促炎细胞因子显著，但骨髓嵌合体严格证明髓系细胞不是疾病的启动因素。相反，肺部疾病源于异常的上皮细胞增殖和分化、活化内皮微循环内的微血管损伤以及放大的表皮生长因子受体（EGFR）表达。在人类生物信息学分析中，LYN表达在COPD患者中增加，并与已知的肺癌通路EGFR表达增加相关，LYN与COPD有关。我们的研究表明，一个独特的分子缺陷会导致自发性COPD样免疫病理学和肺腺癌。此外，我们确定了Lyn及其相关信号通路是COPD和癌症的新治疗靶点。此外，我们的研究可能为这些日益普遍的疾病易感性、进展和预防的分子风险筛选和干预方法的发展提供了参考。

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 not exposed to traditional risk factors. However, causative mechanism(s) are obscure. Over-activity of Src family kinases (SFK) 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, pre-clinical model where an activating mutation in Lyn, a non-receptor 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, although activated macrophages, elastolytic enzymes and pro-inflammatory 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 epidermal growth factor receptor (EGFR) expression. In human bioinformatics analyses, LYN expression was increased in patients with COPD, and correlated with increased EGFR expression, a known lung oncogenic pathway, and LYN 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 development of molecular risk screening and intervention methods for disease susceptibility, progression and prevention of these increasingly prevalent conditions.