Effect of inhaled cationic poly-peptides on respiratory mechanics in the isolated perfused rat lung

Abstract

The inhalation route is increasingly being considered as a viable option to deliver protein drugs into the body, but there has been few studies dealing with the safety of this strategy. The results of in vitro studies have shown that proteins, especially cationic proteins, can interfere with pulmonary surfactant and affect its surface tension lowering activity. If such an interaction also occurs in vivo it may lead to the inactivation of endogenous pulmonary surfactant and have profound adverse effect on the respiratory mechanics of the lung. To investigate this contention a suitable model which allows the inhalation mode of administration of proteins and the continuous monitoring of lung compliance and other parameters is needed. The objectives of this study consequently were to (1) adapt the isolated perfused rat lung (IPL) to allow the administration of exogenous protein via the inhalation route into the alveoli, and (2) to use the adapted model to investigate the effect which inhaled cationic poly-peptides could have on lung function. It was hypothesised that such inhaled cationic peptides would interact with and inactivate the pulmonary surfactant leading to a decrease in lung compliance The lungs from adult Wistar rats were isolated and mounted in the IPL system. Three administration methods viz. aerosol administration, propellent driven administration and intra-tracheal instillation during positive pressure ventilation were considered.