Biochemical evidence for transcytotic absorption of polyaspartamide from the rat lung: Effects of temperature and metabolic inhibitors

Sakagami, Masahiro; Byron, Peter R.; Rypáček, František

doi:10.1002/jps.10188

Cited by 20 publications

(6 citation statements)

References 40 publications

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“…4 and ), since the active transport rate of 125 I‐albumin was inhibited by 51.4 ± 1.2% compared with control lungs. Additionally, monensin, another potent inhibitor of transcytosis (Sakagami et al 2002), significantly decreased the rate of active radio‐labelled albumin transit by 34.0 ± 1.2% (Fig. 4 and ).…”

Section: Resultsmentioning

confidence: 88%

Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs

Buchäckert

Rummel

Vohwinkel

et al. 2012

The Journal of Physiology

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Key points• Under physiological conditions the lung alveoli are impermeable to protein.• In patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) protein-rich oedema fluid accumulates in the distal airspaces and leads to a life-threatening impairment of alveolar gas exchange.• Albumin is a ligand of megalin, a member of the low-density lipoprotein (LDL)-receptor family.• We show that clearance of albumin from the distal air spaces is facilitated by active megalin-mediated transport across the alveolar epithelium.• Understanding of protein clearance mechanisms in the lung may ultimately lead to novel therapeutic approaches for the treatment of ALI/ARDS. AbstractThe alveolo-capillary barrier is effectively impermeable to large solutes such as proteins. A hallmark of acute lung injury/acute respiratory distress syndrome is the accumulation of protein-rich oedema fluid in the distal airspaces. Excess protein must be cleared from the alveolar space for recovery; however, the mechanisms of protein clearance remain incompletely understood. In intact rabbit lungs 29.8 ± 2.2% of the radio-labelled alveolar albumin was transported to the vascular compartment at 37• C within 120 min, as assessed by real-time measurement of 125 I-albumin clearance from the alveolar space. At 4 • C or 22• C significantly lower albumin clearance (3.7 ± 0.4 or 16.2 ± 1.1%, respectively) was observed. Deposition of a 1000-fold molar excess of unlabelled albumin into the alveolar space or inhibition of cytoskeletal rearrangement or clathrin-dependent endocytosis largely inhibited the transport of 125 I-albumin to the vasculature, while administration of unlabelled albumin to the vascular space had no effect on albumin clearance. Furthermore, albumin uptake capacity was measured as about 0.37 mg ml −1 in cultured rat lung epithelial monolayers, further highlighting the (patho)physiological relevance of active alveolar epithelial protein transport. Moreover, gene silencing and pharmacological inhibition of the multi-ligand receptor megalin resulted in significantly decreased albumin binding and uptake in monolayers of primary alveolar type II and type I-like and cultured lung epithelial cells. Our data indicate that clearance of albumin from the distal air spaces is facilitated by an active, high-capacity, megalin-mediated transport process across the alveolar epithelium. Further understanding of this mechanism is of clinical importance, since an inability to clear excess protein from the alveolar space is associated with poor outcome in patients with acute lung injury/acute respiratory distress syndrome.Y. Buchäckert and S. Rummel contributed equally to this work.

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Section: Resultsmentioning

confidence: 88%

Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs

Buchäckert

Rummel

Vohwinkel

et al. 2012

The Journal of Physiology

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“…Nevertheless, the low extent of absorption was unexpected, as the lung is recognized as one of the more permeable epithelial barriers to the systemic absorption of macromolecules, including the display of significant pulmonary absorption of polypeptides and proteins (17). We (27) and others (32) have previously reported on the relatively high bioavailability of macromolecules administered via the lung, including for example that of 4-kDa dextran, which displays an extent of pulmonary absorption of approximately 30% over a 90-min IPRL experiment, an observation which is consistent with 4-kDa dextran absorption in vivo (28). The AMPs utilized in this work are highly cationic, with 22% to 43% of their respective peptide chains comprising basic amino acid residues.…”

Section: Discussionmentioning

confidence: 96%

Pegylation of Antimicrobial Peptides Maintains the Active Peptide Conformation, Model Membrane Interactions, and Antimicrobial Activity while Improving Lung Tissue Biocompatibility following Airway Delivery

Morris

Beck

Fox

et al. 2012

Antimicrob Agents Chemother

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“…The use of IPL preparations to study the lung disposition of several inhaled therapeutics was pioneered by Byron et al and Ryrfeldt et al in the mid 1980's (Table 1) [32,33]. The pulmonary absorption and distribution of low molecular and high molecular weight drugs was addressed in several studies [143][144][145][146][147][148][149][150][151][152]. Ryrfeldt et al investigated the pulmonary disposition of the glucocorticoid budesonide in an isolated rat lung after instillation [153].…”

Section: Application Of Drugmentioning

confidence: 99%

Evaluating the Controlled Release Properties of Inhaled Nanoparticles Using Isolated, Perfused, and Ventilated Lung Models

Beck-Broichsitter

Schmehl

Seeger

et al. 2011

Journal of Nanomaterials

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Polymeric nanoparticles meet the increasing interest for inhalation therapy and hold great promise to improve controlled drug delivery to the lung. The synthesis of tailored polymeric materials and the improvement of nanoparticle preparation techniques facilitate new perspectives for the treatment of severe pulmonary diseases. The physicochemical properties of such drug delivery systems can be investigated using conventional analytical procedures. However, the assessment of the controlled drug release properties of polymeric nanoparticles in the lung remains a considerable challenge. In this context, the isolated lung technique is a promising tool to evaluate the drug release characteristics of nanoparticles intended for pulmonary application. It allows measurements of lung-specific effects on the drug-release properties of pulmonary delivery systems.Ex vivomodels are thought to overcome the common obstacles ofin vitrotests and offer more reliable drug release and distribution data that are closer to thein vivosituation.

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Biochemical evidence for transcytotic absorption of polyaspartamide from the rat lung: Effects of temperature and metabolic inhibitors

Cited by 20 publications

References 40 publications

Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs

Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs

Pegylation of Antimicrobial Peptides Maintains the Active Peptide Conformation, Model Membrane Interactions, and Antimicrobial Activity while Improving Lung Tissue Biocompatibility following Airway Delivery

Evaluating the Controlled Release Properties of Inhaled Nanoparticles Using Isolated, Perfused, and Ventilated Lung Models

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