Protein transport across the lung epithelial barrier

Abstract

. Because concentrations of plasma proteins in alveolar fluid can increase in injured lungs (such as with permeability edema and inflammation), understanding how alveolar epithelium handles protein transport is needed to develop therapeutic measures to restore alveolar homeostasis. This review provides an update on recent findings on protein transport across the alveolar epithelial barrier. The use of primary cultured rat alveolar epithelial cell monolayers (that exhibit phenotypic and morphological traits of in vivo alveolar epithelial type I cells) has shown that albumin and IgG are absorbed via saturable processes at rates greater than those predicted by passive diffusional mechanisms. In contrast, secretory component, the extracellular portion of the polymeric immunoglobulin receptor, is secreted into alveolar fluid. Transcytosis involving caveolae and clathrincoated pits is likely the main route of alveolar epithelial protein transport, although relative contributions of these internalization steps to overall protein handling of alveolar epithelium remain to be determined. The specific pathways and regulatory mechanisms responsible for translocation of proteins across lung alveolar epithelium and regulation of the cognate receptors (e.g., 60-kDa albumin binding protein and IgG binding FcRn) expressed in alveolar epithelium need to be elucidated. alveolar epithelial cells; albumin; secretory component; immunoglobulin G MACROMOLECULE TRANSPORT ACROSS alveolar epithelium has been investigated over the years, but little is known to date concerning the mechanisms and underlying pathways regulating transalveolar protein clearance. Alveolar protein clearance is fundamental to the resolution of the transudate and exudate after hydrostatic-and especially high permeability-type pulmonary edema. The inability to clear excess proteins from air spaces is associated with poor prognosis in patients with alveolar flooding pulmonary edema. Clearance of edema fluid via active ion transport processes raises the oncotic pressure that, in the absence of efficient clearance mechanisms for proteins, slows alveolar fluid clearance. Patients with acute respiratory distress syndrome (ARDS), for example, have large quantities of precipitated protein in their air spaces (3), and nonsurvivors have three times more protein in their air spaces than survivors (21). In addition, excess serum proteins in alveolar edema fluid may lead to precipitation and modification of proteins (e.g., by reactive oxygen and nitrogen species). Although macrophages may contribute to clearance of the excess proteins, the integrity of the alveolar epithelial barrier may not be readily re-

Mammalian cells preferentially internalize hydrogel nanodiscs over nanorods and use shape-specific uptake mechanisms

“…It has been previously reported that negatively charged particles are internalized by a caveolae-mediated pathway in epithelial cells (27,(38)(39)(40). Additionally, as the caveolae pathway is involved in transcytosis, this has further significant implications in delivering therapeutic and diagnostic agents across epithelial barriers (41).…”

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

“…Studies have also shown that the transport of particles by macrophages to the larynx that is substantial in rodents is rather small in humans [127]. Extensive reviews have been published on mechanisms of drug absorption in the lungs [128,129,6,130,9,10,131,12], thus they will not be included here.…”

Net absorption of IgG via FcRn-mediated transcytosis across rat alveolar epithelial cell monolayers

“…receptor mediated; saturable transcytosis; net IgG absorption; lung defense; pulmonary immune system ALVEOLAR EPITHELIUM LINES the distal air spaces of the lung and provides high resistance to the leak of solutes and fluid from the surrounding interstitial and vascular spaces (18). Various serum proteins (e.g., albumin, transferrin, and IgG) are known to be present in alveolar fluid lining distal air spaces, although the underlying transport mechanisms that account for their presence are not well delineated (10,12,19). Alveolar protein clearance is essential for resolution of both hydrostatic and (especially) high permeability pulmonary edema.…”

“…Alveolar protein clearance is essential for resolution of both hydrostatic and (especially) high permeability pulmonary edema. Understanding the mechanisms of alveolar protein clearance may be useful in the management of patients with alveolar pulmonary edema and in providing new insights into transpulmonary delivery of exogenous protein drugs.Proteins in the alveolar space may be cleared by endocytosis and degradation inside alveolar epithelial cells, by transcytosis across the alveolar epithelium, or by restricted diffusion through the epithelium (10,12,19,20). The relative contributions of each of these three pathways to total clearance of proteins from the air spaces are not known.…”

“…Proteins in the alveolar space may be cleared by endocytosis and degradation inside alveolar epithelial cells, by transcytosis across the alveolar epithelium, or by restricted diffusion through the epithelium (10,12,19,20). The relative contributions of each of these three pathways to total clearance of proteins from the air spaces are not known.…”