Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury.
BACKGROUND
The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.


METHODS
VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.


RESULTS
VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF121, VEGF165 and VEGF189 isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF165 and VEGF121 protein which was increased by LPS (p < 0.05). VEGF165 upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (sflt) (p < 0.05).


CONCLUSIONS
These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.
Department of Clinical Science at North Bristol, University of Bristol Paul O'Gorman Lifeline Centre, Southmead Hospital, Westbury-on-Trym, Bristol, UK. andrewmedford@hotmail.com
Andrew R L
AR
Medford
Samantha K
SK
Douglas
Sofia I H
SI
Godinho
Kay M
KM
Uppington
Lynne
L
Armstrong
Kathleen M
KM
Gillespie
Berendine
B
van Zyl
Terry D
TD
Tetley
Nassif B N
NB
Ibrahim
Ann B
AB
Millar
D000368:Aged; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism*; D055370:Lung Injury / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism*
D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse