Pretreatment with recombinant human vascular endothelial growth factor reduces virus replication and inflammation in a perinatal lamb model of respiratory syncytial virus infection.
Vascular endothelial growth factor (VEGF) is increasingly recognized as a perinatal regulator of lung maturation and surfactant protein expression. 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 respiratory syncytial virus (RSV) infection. Innate immune components including surfactant proteins A and D, and beta-defensins have putative antimicrobial activity against pulmonary pathogens including RSV. Our hypothesis was that recombinant human VEGF (rhVEGF) pretreatment therapy would decrease RSV disease in the perinatal lamb RSV model. Newborn lambs were pretreated with rhVEGF, betamethasone, or saline and then inoculated with bovine RSV or sterile medium. Tissues were collected 5 d postinoculation, corresponding to the initiation of severe lesions and peak viral replication. In RSV-infected lambs, rhVEGF therapy increased the mean daily body temperature, decreased airway neutrophil exudate, and reduced RSV replication compared with betamethasone or saline pretreatment. Furthermore, rhVEGF therapy significantly mitigated the RSV-induced increase in surfactant protein A mRNA expression and decrease in surfactant protein D mRNA expression. In control (non-RSV-infected) lambs, pretreatment with rhVEGF increased sheep beta-defensin-1 (SBD1) mRNA expression, but no alteration in surfactant proteins A and D was detected. This novel study demonstrates that rhVEGF pretreatment mitigates RSV disease and, in addition, rhVEGF regulation of innate immune genes is dependent on RSV infection status.
Meyerholz
David K
DK
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011-1250, USA.
Gallup
Jack M
JM
Lazic
Tatjana
T
de Macedo
Marcia M A
MM
Lehmkuhl
Howard D
HD
Ackermann
Mark R
MR
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D007113:Immunity, Innate; D037663:Pulmonary Surfactant-Associated Protein D / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000627:therapeutic use; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D012756:Sheep; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects*; D023083:beta-Defensins / Q000235:genetics
C406407:DEFB1 protein, human; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D023083:beta-Defensins