Hshi-chi Koo

Safety and Efficacy of Intratracheal Recombinant Human Clara Cell Protein in a Newborn Piglet Model of Acute Lung Injury

Despite the widespread use of exogenous surfactant, acute and chronic lung injury continues to be a major cause of morbidity in preterm infants. CC10 is a protein produced by Clara cells that inhibits phospholipase A2 and has anti-inflammatory and antifibrotic properties. We studied whether intratracheal (IT) recombinant human Clara cell protein (rhCC10) could safely minimize lung injury in a newborn piglet model of acute lung injury. Twenty-nine newborn piglets were given Survanta and then ventilated for 48 h receiving the following: room air (group 1); 100% O2 (group 2); or 100% O2 and 25, 5, or 1 mg/kg (groups 3, 4, and 5, respectively) of IT rhCC10 (diluted to 2 mL/kg with saline) at time 0. Laboratory studies, oxygen ratios, static pressure-volume curves, bronchoalveolar lavage (for inflammatory markers), and histologic analyses were performed over the 48-h study period. Pulmonary compliance and oxygenation were significantly improved in animals receiving 5 mg/kg IT rhCC10 compared with room air and 100% O2 controls (p < 0.004 and p < 0.05, respectively, ANOVA). Reductions in inflammatory markers were seen in animals receiving rhCC10, although changes did not reach statistical significance. No significant toxicity was noted. rhCC10 appeared safe and improved pulmonary function in this newborn piglet model of hyperoxic lung injury. We speculate that rhCC10 may represent a promising therapy for the prevention of lung injury in preterm infants.

Pharmacologic interactions of exogenous lung surfactant and recombinant human Cu/Zn superoxide dismutase

ABSTRACT: The effect of exogenous surfactant on the pharmacokinetics of intratracheally administered recombinant human superoxide dismutase (rhSOD) was studied. Five groups of rats received the following intratracheally: 1 mL/kg of saline; 5 or 25 mg/kg of rhSOD; or 4 mL/kg of exogenous surfactant followed in 30 min by 5 or 25 mg/ kg of rhSOD. Animals were killed at 24,48, and 72 h, and serum, bronchoalveolar lavage, and lung tissue were analyzed for rhSOD. rhSOD was not detected in the lungs of saline-treated animals or in serum from any animal. At 24 h, lung-tissue rhSOD was higher in rats treated with surfactant and rhSOD versus rhSOD alone (5 mg/kg: 6.8 ± 2.5 versus 0 μg/whole lung, p < 0.05; 25 mg/kg: 29.9 ± 9.6 versus 0.1 ± 0.1 μg/whole lung, p < 0.05). Bronchoalveolar lavage fluid levels correlated well with lung tissue concentrations. By 48 h, lung tissue rhSOD concentrations were insignificant in all groups. rhSOD was still present in lavage fluid from rats treated with surfactant and rhSOD. No rhSOD was detected at 72 h. In separate in vitro experiments, physical and biological drug-drug interaction studies were performed. When radiolabeled rhSOD was combined with exogenous surfactant and centrifuged at 10000 × g for 30 min, 81.3 ± 2.5% of rhSOD was found in the supernatant versus 18.7 ± 2.5% in the surfactant pellet. Serial washing of the surfactant pellet removed virtually all remaining rhSOD. This finding suggests that the rhSOD and surfactant were only weakly associated. Combining rhSOD and exogenous surfactant did not alter the activity of either agent. Data suggest that exogenous surfactant prolongs the t½ of rhSOD in the lung. This finding may be important in determining future rhSOD administration strategies in preterm infants with respiratory distress syndrome who receive exogenous surfactant replacement therapy.

Perfluorochemical Liquid-Adenovirus Suspensions Enhance Gene Delivery to the Distal Lung

We compared lung delivery methods of recombinant adenovirus (rAd): (1) rAd suspended in saline, (2) rAd suspended in saline followed by a pulse-chase of a perfluorochemical (PFC) liquid mixture, and (3) a PFC-rAd suspension. Cell uptake, distribution, and temporal expression of rAd were examined using A549 cells, a murine model using luciferase bioluminescence, and histological analyses. Relative to saline, a 4X increase in transduction efficiency was observed in A549 cells exposed to PFC-rAd for 2–4 h. rAd transgene expression was improved in alveolar epithelial cells, and the level and distribution of luciferase expression when delivered in PFC-rAd suspensions consistently peaked at 24 h. These results demonstrate that PFC-rAd suspensions improve distribution and enhance rAd-mediated gene expression which has important implications in improving lung function by gene therapy.

The Effects of Human Recombinant Granulocyte Colony Stimulating Factor (G-CSF) on Long Injury from Hyperoxia and Mechanical Ventilation in the Neonatal Piglet

The Effects of Human Recombinant Granulocyte Colony Stimulating Factor (G-CSF) on Long Injury from Hyperoxia and Mechanical Ventilation in the Neonatal Piglet

Overexpression of F MN Superoxide Dismutase (MnSOD) or MnSOD/Catalase (CAT) Protects Lung Epithelial Cells Against Oxident Injury

Overexpression of F MN Superoxide Dismutase (MnSOD) or MnSOD/Catalase (CAT) Protects Lung Epithelial Cells Against Oxident Injury