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

ABSTRACT

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.

KEYWORDS

Clara cell secretory protein (CC10) - respiratory distress syndrome - mechanical ventilation - hyperoxia - surfactant protein expression - VEGF isoform expression - lung inflammation

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