Active trafficking of alpha 1 antitrypsin across the lung endothelium

Angelia Lockett, Mary Beth Brown, Nieves Santos-Falcon, Natalia I. Rush, Houssam Oueini, Amber J. Oberle, Esther Bolanis, Miryam A. Fragoso, Daniela Petrusca, Karina A. Serban, Kelly S. Schweitzer, Robert Presson, Michael Campos, Irina Petrache

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The homeostatic lung protective effects of alpha-1 antitrypsin (A1AT) may require the transport of circulating proteinase inhibitor across an intact lung endothelial barrier. We hypothesized that uninjured pulmonary endothelial cells transport A1AT to lung epithelial cells. Purified human A1AT was rapidly taken up by confluent primary rat pulmonary endothelial cell monolayers, was secreted extracellularly, both apically and basolaterally, and was taken up by adjacent rat lung epithelial cells co-cultured on polarized transwells. Similarly, polarized primary human lung epithelial cells took up basolaterally-, but not apically-supplied A1AT, followed by apical secretion. Evidence of A1AT transcytosis across lung microcirculation was confirmed in vivo by two-photon intravital microscopy in mice. Time-lapse confocal microscopy indicated that A1AT colocalized with Golgi in the endothelium whilst inhibition of the classical secretory pathway with tunicamycin significantly increased intracellular retention of A1AT. However, inhibition of Golgi secretion promoted non-classical A1AT secretion, associated with microparticle release. Polymerized A1AT or A1AT supplied to endothelial cells exposed to soluble cigarette smoke extract had decreased transcytosis. These results suggest previously unappreciated pathways of A1AT bidirectional uptake and secretion from lung endothelial cells towards the alveolar epithelium and airspaces. A1AT trafficking may determine its functional bioavailablity in the lung, which could be impaired in individuals exposed to smoking or in those with A1AT deficiency.

Original languageEnglish
Article numbere93979
JournalPLoS One
Volume9
Issue number4
DOIs
StatePublished - Apr 17 2014

Fingerprint

alpha 1-Antitrypsin
endothelium
Endothelium
lungs
Lung
endothelial cells
Endothelial cells
secretion
physiological transport
Endothelial Cells
epithelial cells
Transcytosis
Epithelial Cells
tunicamycin
Rats
alpha 1-Antitrypsin Deficiency
cigarettes
rats
Tunicamycin
smoke

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lockett, A., Brown, M. B., Santos-Falcon, N., Rush, N. I., Oueini, H., Oberle, A. J., ... Petrache, I. (2014). Active trafficking of alpha 1 antitrypsin across the lung endothelium. PLoS One, 9(4), [e93979]. https://doi.org/10.1371/journal.pone.0093979

Active trafficking of alpha 1 antitrypsin across the lung endothelium. / Lockett, Angelia; Brown, Mary Beth; Santos-Falcon, Nieves; Rush, Natalia I.; Oueini, Houssam; Oberle, Amber J.; Bolanis, Esther; Fragoso, Miryam A.; Petrusca, Daniela; Serban, Karina A.; Schweitzer, Kelly S.; Presson, Robert; Campos, Michael; Petrache, Irina.

In: PLoS One, Vol. 9, No. 4, e93979, 17.04.2014.

Research output: Contribution to journalArticle

Lockett, A, Brown, MB, Santos-Falcon, N, Rush, NI, Oueini, H, Oberle, AJ, Bolanis, E, Fragoso, MA, Petrusca, D, Serban, KA, Schweitzer, KS, Presson, R, Campos, M & Petrache, I 2014, 'Active trafficking of alpha 1 antitrypsin across the lung endothelium', PLoS One, vol. 9, no. 4, e93979. https://doi.org/10.1371/journal.pone.0093979
Lockett A, Brown MB, Santos-Falcon N, Rush NI, Oueini H, Oberle AJ et al. Active trafficking of alpha 1 antitrypsin across the lung endothelium. PLoS One. 2014 Apr 17;9(4). e93979. https://doi.org/10.1371/journal.pone.0093979
Lockett, Angelia ; Brown, Mary Beth ; Santos-Falcon, Nieves ; Rush, Natalia I. ; Oueini, Houssam ; Oberle, Amber J. ; Bolanis, Esther ; Fragoso, Miryam A. ; Petrusca, Daniela ; Serban, Karina A. ; Schweitzer, Kelly S. ; Presson, Robert ; Campos, Michael ; Petrache, Irina. / Active trafficking of alpha 1 antitrypsin across the lung endothelium. In: PLoS One. 2014 ; Vol. 9, No. 4.
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