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Title: Pretreatment with recombinant human vascular endothelial growth factor virus replication and inflammation in a perinatal lamb model of RSV infection

Author
item MEYERHOLZ, DAVID - IOWA STATE UNIVERSITY
item GALLUP, JACK - IOWA STATE UNIVERSITY
item TATJANA, LAZIC - IOWA STATE UNIVERSITY
item DE MACEDO, MARCIA - IOWA STATE UNIVERSITY
item Lehmkuhl, Howard
item ACKERMANN, MARK - IOWA STATE UNIVERSITY

Submitted to: Viral Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/26/2006
Publication Date: 10/31/2006
Citation: Meyerholz, D.K., Gallup, J.M., Tatjana, L., De Macedo, M.M., Lehmkuhl, H.D., Ackermann, M.R. 2006. Pretreatment with Recombinant Human Vascular Endothelial Growth Factor Virus Replication and Inflammation in a Perinatal Lamb Model of RSV Infection. Viral Immunology. 20(1):188-196.

Interpretive Summary: Preterm and young infants are at increased risk for pulmonary immaturity characterized by insufficient surfactant production as well as increased risk for severe manifestations of RSV infection. In sheep, RSV disease severity has similar age-dependent characteristics and sheep are born with several related immune processes similar to humans making them a valuable model to study lung infection by this important respiratory virus. Vascular endothelial growth factor (VEGF) is increasingly recognized as a perinatal regulator of lung maturation and surfactant protein expression. Innate immune components have antimicrobial activity against pulmonary pathogens including respiratory syncytial virus (RSV). Our hypothesis is that VEGF pretreatment therapy would increase innate immune gene expression and decrease RSV disease in the perinatal lamb RSV model. Newborn lambs were pretreated with VEGF, betamethasone or saline, and then inoculated with RSV or sterile media. In RSV-infected lambs, VEGF therapy increased the mean daily body temperature, decreased airway neutrophil exudate and reduced RSV replication compared to betamethasone or saline pretreatment. This novel study demonstrates VEGF pretreatment decreases RSV disease. These results provide information on pathogenesis of RSV.

Technical Abstract: Vascular endothelial growth factor (VEGF) is increasingly recognized as a perinatal regulator of lung maturation and surfactant protein expression. Innate immune components including surfactant proteins A and D, and beta defensins have putative antimicrobial activity against pulmonary pathogens including respiratory syncytial virus (RSV). Preterm and young infants are at increased risk for pulmonary immaturity characterized by insufficient surfactant production as well as increased risk for severe manifestations of RSV infection. Our hypothesis is that VEGF pretreatment therapy would increase innate immune gene expression and decrease RSV disease in the perinatal lamb RSV model. Newborn lambs were pretreated with VEGF, betamethasone or saline, and then inoculated with RSV or sterile media. Tissues were collected at five days post inoculation corresponding to the initiation of severe lesions and peak viral replication. In control lambs, pretreatment with VEGF caused an increase in sheep beta defensin 1 (SBD1) mRNA expression, but no alteration in surfactant proteins A and D were detected. In RSV-infected lambs, VEGF therapy increased the mean daily body temperature, decreased airway neutrophil exudate and reduced RSV replication compared to betamethasone or saline pretreatment. Furthermore, VEGF therapy significantly mitigated RSV-induced increase in SP-A mRNA expression and decrease in SP-D mRNA expression. This novel study demonstrates VEGF pretreatment mitigates RSV disease and in addition VEGF regulation of innate immune genes is dependent on RSV infection status.