Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRas^LA2, and cRaf-BxB). In contrast, NOD.Cg-Prkdc^scid Il2rgtm1Wjl/SzJ immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing human lung cancer cells with macrophages and lymphocytes strongly up-regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)–mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1 model. We conclude that lung cancer–associated PH represents a distinct PH category; targeting inflammation in the microenvironment and PDE5 offers a potential therapeutic option.

呼吸困难是晚期肺癌的常见，毁灭性且知之甚少的症状。在我们的队列中，在进行计算机断层扫描以诊断肺癌的519例患者中，有250例的平均肺动脉直径> 28 mm，表明存在肺动脉高压（PH）。在人类肺癌组织中，我们始终观察到血管重塑和血管周围炎性细胞积累（巨噬细胞/淋巴细胞）增加。在三种肺癌小鼠模型（LLC1，KRas ^LA2和cRaf-BxB）中模拟了血管重塑，PH和血管周炎性细胞蓄积。与此相反，NOD.Cg-PRKDC ^SCID Il2rgtm1Wjl / SZJ免疫缺陷异种移植物和显性负突变体IKK2三重转基因（Sftpc-rtTA / Tet-O-Ikk2DN）小鼠未出现PH。将人类肺癌细胞与巨噬细胞和淋巴细胞共培养会强烈上调细胞因子的释放，引起迁移，凋亡抗性和磷酸二酯酶5（PDE5）介导的人类肺血管细胞上调，这是PH的典型特征。PDE5抑制剂西地那非在LLC1模型中大大抑制了PH。我们得出的结论是，肺癌相关的PH代表不同的PH类别。靶向微环境中的炎症，PDE5提供了潜在的治疗选择。