期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 9, 期 416, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aai9048
关键词
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资金
- Max Planck Society
- Excellence Cluster Cardio-Pulmonary System
- Verein zur Forderung der Krebsforschung in Giessen e.V.
- Von-Behring-Rontgen-Stiftung grant
- Rhon Klinikum AG grant
- LOEWE UGMLC grant
- German Center for Lung Research (DZL)
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 micro-environment and PDE5 offers a potential therapeutic option.
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