Recombinant human Clara cell secretory protein treatment increases lung mRNA expression of surfactant proteins and vascular endothelial growth factor in a premature lamb model of respiratory distress syndrome.
Infant respiratory distress syndrome (IRDS) can lead to impaired alveolarization and dysmorphic vascularization of bronchopulmonary dysplasia. Clara cell secretory protein (CC10) has anti-inflammatory properties but is deficient in the premature infant. Because surfactant and vascular endothelial growth factor (VEGF) profiles are impaired by inflammation and CC10 inhibits lung inflammation, we hypothesized that CC10 may up-regulate surfactant protein (SP) and VEGF expression. Preterm lambs ( N = 24; 126 +/- 3 days [standard error] gestation) with IRDS were randomized to receive 100 mg/kg surfactant, 100 mg/kg surfactant followed by intratracheal 0.5, 1.5, or 5 mg/kg rhCC10 and studied for 4 hours. Gas exchange and lung mechanics were monitored; surfactant protein and VEGF mRNA profiles in lung were assessed. There was a significant rhCC10 dose-dependent increase in respiratory compliance and ventilation efficiency index; both parameters were significantly greater in animals treated with 5 mg/kg rhCC10 than those treated with surfactant alone. Similarly, there was a significant rhCC10 dose and protein-dependent increase in surfactant protein (SP-B > SP-C > SP-A) and dose- and isoform-dependent increase in VEGF (VEGF189 > VEGF165 > VEGF121). These data demonstrate that early intervention with rhCC10 up-regulates surfactant protein and VEGF expression, supporting the role of CC10 to protect against hyperoxia and mechanical ventilation in the immature lung.
Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. marla.wolfson@temple.edu
Marla R
MR
Wolfson
Vicky L
VL
Funanage
Susan M
SM
Kirwin
Aprile L
AL
Pilon
Beth N
BN
Shashikant
Thomas L
TL
Miller
Thomas H
TH
Shaffer
D000818:Animals; D000831:Animals, Newborn; D001688:Biological Products / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism* / Q000494:pharmacology; D011663:Pulmonary Surfactants / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology*; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy* / Q000378:metabolism; D012129:Respiratory Function Tests; D012756:Sheep; D015854:Up-Regulation; D014598:Uteroglobin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D001688:Biological Products; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D011994:Recombinant Proteins; C556389:SCGB1A1 protein, human; D042461:Vascular Endothelial Growth Factor A; D014598:Uteroglobin; C072197:beractant