Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk

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.

• Pullamsetti, S. S.
• Kojonazarov, B.
• Storn, S.
• Gall, H.
• Salazar, Y.
• Wolf, J.
• Weigert, A.
• El-Nikhely, N.
• Ghofrani, H. A.
• Krombach, G. A.
• Fink, L.
• Gattenlohner, S.
• Rapp, U. R.
• Schermuly, R. T.
• Grimminger, F.
• Seeger, W.
• Savai, R.