Submitted on July 29, 2003
Accepted on December 22, 2003
Alveolar macrophages are a primary barrier to pulmonary absorption of macromolecules
Catherine Lombry1, David A. Edwards2, Veronique Preat1, and Rita Vanbever1*
1 Department of Pharmaceutical Technology, Universite catholique de Louvain, Brussels, Belgium
2 Division of Engineering and Applied Sciences, Harvard University, Boston, USA
* To whom correspondence should be addressed. E-mail: vanbever{at}farg.ucl.ac.be.
We demonstrate that a primary source of elimination of inhaled macromolecules following delivery to the lungs and prior to absorption into the systemic circulation owes to clearance by alveolar macrophages (AM). Depletion of AM by liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP) is shown to cause several-fold enhancement in systemic absorption of immunoglobulin G and human chorionic gonadotropin (hCG) following intratracheal instillation in rats. Lowering the doses of IgG delivered to the lungs alleviates local degradation and results in dramatic increase in systemic absorption of the protein as well. Chemical and physical means of minimizing uptake of macromolecules by AM are proposed as novel methods for enhancing protein absorption from the lungs. Such strategies may have important ramifications on the
development of inhalation as an attractive mode of administration of therapeutic proteins to the bloodstream.
