Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.
Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH(2)-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.
Kasahara
Y
Y
Division of Pulmonary Sciences and Critical Care Medicine, Pulmonary Hypertension Center, Department of Medicine, University of Colorado Health Sciences Center, Denver, USA.
Tuder
R M
RM
Taraseviciene-Stewart
L
L
Le Cras
T D
TD
Abman
S
S
Hirth
P K
PK
Waltenberger
J
J
Voelkel
N F
NF
D000792:Angiography; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology*; D007797:Laminin; D008168:Lung / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011509:Proteoglycans; D011656:Pulmonary Emphysema / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor
D061945:Caspase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007211:Indoles; D007797:Laminin; D018809:Proliferating Cell Nuclear Antigen; D011480:Protease Inhibitors; D011509:Proteoglycans; D011758:Pyrroles; D017978:Receptors, Growth Factor; C093260:benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene; C059485:matrigel; D001224:Aspartic Acid; C116890:Semaxinib; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases