Transforming growth factor beta induces vascular endothelial growth factor elaboration from pleural mesothelial cells in vivo and in vitro.
Vascular endothelial growth factor (VEGF) increases vascular permeability and is important in pleural effusion formation. In studies using transforming growth factor beta (TGF-beta) to produce pleurodesis, we observed that although TGF-beta was more effective than talc or doxycycline, it induced transient production of large pleural effusions. We hypothesized that TGF-beta stimulates VEGF production in pleural tissues in vivo, and by mesothelial cells in vitro. New Zealand White rabbits (n = 33) were given TGF-beta(2) (1.7 or 5.0 microg), talc (400 mg/kg), doxycycline (10 mg/kg), or buffer intrapleurally. Pleural fluid was collected at 24 h. Intrapleural injection of TGF-beta(2) induced a dose-dependent increase in VEGF production. The pleural fluid VEGF level was 2-fold higher in rabbits given 5.0 microg of TGF-beta(2) than in those given 1.7 microg of TGF-beta(2) and 3-fold higher than in those given buffer. VEGF levels were higher after the injection of TGF-beta(2) than after administration of talc or doxycycline. The pleural fluid VEGF correlated significantly with the volume of pleural effusions (r = 0.79, p < 0.00001). In vitro, TGF-beta(2) stimulated a dose-dependent increase in VEGF production from murine pleural mesothelial cells. At 4 and 24 h, TGF-beta(2), but not talc or doxycycline, induced a significant increase in VEGF, when compared with controls. The mesothelial cell VEGF production was significantly reduced by anti-TGF-beta antibody in the TGF-beta(2), talc, and control (buffer and medium) groups. In conclusion, mesothelial cells are an important source of VEGF. TGF-beta increases the VEGF production by mesothelial cells in vivo and in vitro.
Gary Lee
Y C
YC
Department of Pulmonary Medicine, St. Thomas Hospital and Vanderbilt University, Nashville, Tennessee 37202, USA. ycgarylee@hotmail.com
Melkerneker
Dee
D
Thompson
Philip J
PJ
Light
Richard W
RW
Lane
Kirk B
KB
D000704:Analysis of Variance; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D016228:Endothelial Growth Factors / Q000502:physiology*; D004848:Epithelium / Q000187:drug effects* / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007958:Leukocyte Count; D016014:Linear Models; D008222:Lymphokines / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010994:Pleura / Q000166:cytology*; D010996:Pleural Effusion / Q000737:chemistry / Q000166:cytology / Q000188:drug therapy* / Q000209:etiology*; D018700:Pleurodesis / Q000009:adverse effects* / Q000379:methods*; D011506:Proteins / Q000032:analysis; D011817:Rabbits; D013627:Talc / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011506:Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013627:Talc; D007770:L-Lactate Dehydrogenase; D004318:Doxycycline