Prostacyclin analogs stimulate VEGF production from human lung fibroblasts in culture

• Published in: American journal of physiology. Lung cellular and molecular physiology 2008-06, Vol.294 (6), p.L1226-L1232
• Main Authors: Kamio, Koichiro, Sato, Tadashi, Liu, Xiangde, Sugiura, Hisatoshi, Togo, Shinsaku, Kobayashi, Tetsu, Kawasaki, Shin, Wang, Xingqi, Mao, Lijun, Ahn, Youngsoo, Holz, Olaf, Magnussen, Helgo, Rennard, Stephen I
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases - physiology; Adult; Carbazoles - pharmacology; Cell Culture Techniques; Cells; Cells, Cultured; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacology; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Iloprost - pharmacology; Kinases; Lung - cytology; Lungs; Prostaglandins I - pharmacology; Pyrroles - pharmacology; RNA, Messenger - metabolism; Signal transduction; Stimulation, Chemical; Studies; Vascular Endothelial Growth Factor A - biosynthesis
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00129.2007

1 Division of Pulmonary Medicine, Nippon Medical School, Tokyo, Japan; 2 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska; 3 The Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan; 4 Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan; 5 The Third Department of Internal Medicine, Mie University Graduate School of Medicine, Mie, Japan; 6 Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan; 7 Department of Rheumatology, Peking University Third Hospital, Beijing, China; and 8 Center for Pneumology and Thoracic Surgery, Hospital Grosshansdorf, Grosshansdorf, Germany Submitted 2 April 2007 ; accepted in final form 9 April 2008 Prostacyclin is a short-lived metabolite of arachidonic acid that is produced by several cells in the lung and prominently by endothelial cells. It increases intracellular cAMP levels activating downstream signaling thus regulating vascular mesenchymal cell functions. The alveolar wall contains a rich capillary network as well as a population of mesenchymal cells, i.e., fibroblasts. The current study evaluated the hypothesis that prostacyclin may mediate signaling between endothelial and mesenchymal cells in the alveolar wall by assessing the ability of prostacyclin analogs to modulate fibroblast release of VEGF. To accomplish this study, human lung fibroblasts were cultured in routine culture on plastic support and in three-dimensional collagen gels with or without three prostacyclin analogs, carbaprostacyclin, iloprost, and beraprost, and the production of VEGF was evaluated by ELISA and quantitative real-time PCR. Iloprost and beraprost significantly stimulated VEGF mRNA levels and protein release in a concentration-dependent manner. These effects were blocked by the adenylate cyclase inhibitor SQ-22536 and by the protein kinase A (PKA) inhibitor KT-5720 and were reproduced by a direct PKA activator but not by an activator of exchange protein directly activated by cAMP (Epac), indicating that cAMP-activated PKA signaling mediated the effect. Since VEGF serves to maintain the pulmonary microvasculature, the current study suggests that prostacyclin is part of a bidirectional signaling network between the mesenchymal and vascular cells of the alveolar wall. Prostacyclin analogs, therefore, have the potential to modulate the maintenance of the pulmonary microcirculation by driving the production o