Mechanisms of macromolecule absorption by the lungs

Although the pulmonary epithelia seem to be naturally permeable to a variety of peptides and proteins, the mechanisms of absorption are poorly understood. Possible mechanisms of absorption include: transcytosis; paracellular absorption between two cells; paracellular absorption at the tricellular junction at the intersection of three cells; and absorption through epithelial defects caused by senescent (apoptopic) cells. Evidence to support the role of any of these mechanisms in the absorption of a specific therapeutic by the healthy lung is weak. An emerging hypothesis is that for small peptides (i.e., [40 kDa) paracellular transport may dominate, while for larger proteins (i.e.,]40 kDa) transcytosis may be more important. There is some evidence for receptor-mediated transcytosis of albumin. Complicating factors include osmolality, lung volume, smoking and disease states, macromolecule properties and regional differences.