title: Dose response to rhCC10-augmented surfactant therapy in a lamb model of infant respiratory distress syndrome: physiological, inflammatory, and kinetic profiles.
abstract: While surfactant (SF) therapy alone improves respiratory distress syndrome (RDS)-associated gas exchange and lung stability, absence of anti-inflammatory proteins limits efficacy with respect to inflammation. Clara cell secretory protein (CC10), deficient in preterm infants, prevents SF degradation and has anti-inflammatory properties. In this study, intratracheal recombinant human (rh) CC10 (Claragen)-augmented SF (Survanta, Ross) therapy was examined in a premature lamb model of RDS with respect to inflammation and kinetic dose-response profiles. Preterm lambs (n = 24; gestational age: 126 +/- 3 days) were delivered via cesarean section, sedated, ventilated, and randomized into groups: 100 mg/kg SF, 100 mg/kg SF followed by 0.5 mg/kg rhCC10, 100 mg/kg SF followed by 1.5 mg/kg rhCC10, and 100 mg/kg SF followed by 5.0 mg/kg rhCC10. Arterial blood chemistry and lung mechanics were monitored; lungs were lavaged and snap-frozen after 4 h. TNF-alpha, IL-8 in plasma; TNF-alpha, IL-6, IL-8, myeloperoxidase in lung; and rhCC10 in plasma, urine, bronchoalveolar lavage, and lung were analyzed. Improvement in compliance, peak inspiratory pressure, and ventilatory efficiency index were greatest (P < 0.05) with SF + 5.0 mg/kg rhCC10. Plasma, urine, bronchoalveolar lavage, and lung [rhCC10] (where brackets denote concentration) increased (P < 0.01) with dose. Plasma [IL-8] was lower (P < 0.05) with rhCC10 than SF alone. Treatment with at least 1.5 mg/kg rhCC10 resulted in lower (P < 0.05) lung [TNF-alpha], [IL-8], and [myeloperoxidase]; SF + 1.5 mg/kg rhCC10 group had lower (P < 0.05) lung [IL-6], compared with all other groups. Compared with SF alone, SF augmented with at least 1.5 mg/kg rhCC10 decreased RDS-induced lung and systemic inflammation. Given that inflammation may lead to functional compromise, these data suggest that early intervention with rhCC10 may enhance SF therapy and warrant longer duration studies to determine its role to decrease long-term complications of ventilator management.
authors.affiliation: Dept. of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Beth N
authors.initials: BN
authors.lastname: Shashikant
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Miller
authors.forename: Richard W
authors.initials: RW
authors.lastname: Welch
authors.forename: Aprile L
authors.initials: AL
authors.lastname: Pilon
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Shaffer
authors.forename: Marla R
authors.initials: MR
authors.lastname: Wolfson
mesh_terms: D000818:Animals; D001688:Biological Products / Q000008:administration & dosage*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology*; D011663:Pulmonary Surfactants / Q000008:administration & dosage; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy* / Q000503:physiopathology*; D012756:Sheep; D016896:Treatment Outcome; D014598:Uteroglobin / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology
chemical_list: D001688:Biological Products; D016207:Cytokines; D011663:Pulmonary Surfactants; D011994:Recombinant Proteins; C556389:SCGB1A1 protein, human; D014598:Uteroglobin; C072197:beractant