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Sci Transl Med ; 9(416)2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29141888

RESUMO

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, KRasLA2 , and cRaf-BxB). In contrast, NOD.Cg-PrkdcscidIl2rgtm1Wjl/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.


Assuntos
Dispneia/fisiopatologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/fisiopatologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Células Dendríticas , Dispneia/imunologia , Ecocardiografia , Humanos , Hipertensão Pulmonar/etiologia , Imuno-Histoquímica , Técnicas In Vitro , Inflamação/imunologia , Inflamação/fisiopatologia , Neoplasias Pulmonares/complicações , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Linfócitos T/metabolismo
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