Effects of an intratracheally delivered anti-inflammatory protein (rhCC10) on physiological and lung structural indices in a juvenile model of acute lung injury.

Abstract

Background: Mechanical ventilation results in acute lung trauma that can stimulate processes that alter lung development. Activation of matrix metalloproteinases (MMPs) and their tissue-produced inhibitors (TIMPs) is initiated by the inflammatory response to mechanical ventilation and are involved in breakdown of the basement membrane and parenchymal modeling.

Objectives: The aim of this study was to test the hypothesis that rhCC10, a lung anti-inflammatory mediator, would foster improved lung function, structural preservation, and a reduction in net MMP activity in a juvenile model of acute lung injury.

Methods: Twenty-four juvenile rabbits were saline-lavage-injured and treated with 100 or 25 mg/kg surfactant (Survanta, Ross Labs) with or without rhCC10 (Claragen, Inc.; n=6 per group). Animals were ventilated for 4 h, then euthanized for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, MMP-7, and MMP-9 and TIMPs 1 and 2 in the lung.

Results: Apical lung expansion, reduced with the lower dose of surfactant, was partially restored with the addition of rhCC10. Alveolar septal wall thickness was reduced (p<0.05) with low-dose surfactant plus rhCC10 compared to high-dose surfactant alone. Increased within-group variance in MMP-2 and MMP-9 proteolytic activity was found with the low-dose surfactant and was abolished with rhCC10. MMP-7 was reduced (p<0.05) with rhCC10 administration, independent of surfactant dose.

Conclusions: Intratracheal administration of the anti-inflammatory rhCC10 resulted in preserved lung structure and MMP/TIMP profile after 4 h of mechanical ventilation, in a surfactant dose-dependent manner.