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.