Alveolar macrophages are a primary barrier to pulmonary absorption of macromolecules

Abstract

We demonstrate that a primary source of elimination of inhaled macromolecules after delivery to the lungs and before absorption into the systemic circulation owes to clearance by alveolar macrophages (AM). Depletion of AM by liposome-encapsulated dichloromethylene diphosphonate is shown to cause severalfold enhancement in systemic absorption of IgG and human chorionic gonadotropin after intratracheal instillation in rats. Lowering the doses of IgG delivered to the lungs alleviates local degradation and results in a 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.

Targeting Inhaled Therapy beyond the Lungs

“…The benefits that accrue from each of these strategies are important to the action of the drug. Avoiding macrophage uptake is important for drugs which may be subject to degradation by the enzymes in these cells, which are designed to eliminate both endogenous and exogenous substances of biological origin [23]. Conversely, it may be desirable to target macrophages as a target or a depot.…”

In vivo animal models for drug delivery across the lung mucosal barrier☆

“…Insoluble drugs and carriers deposited in the alveolar region will tend to be taken up by the macrophages, which has recently been demonstrated to pose a primary barrier to pulmonary absorption of macromolecules [23]. They can dispose of particles either by transporting them along the alveolar surface to the mucociliary escalator, by translocation to the tracheobronchial lymph or by internal enzymatic degradation [24].…”

Formulations and Technologies in Growth Hormone Delivery

“…As a result, all of these permit rapid absorption [69]. The first concern in this route of administration is the presence of alveolar macrophages which is a natural defence mechanism [70]. Particle distribution is another fundamental factor that affects the pulmonary delivery of the aerosol drug.…”