Mechanism of α-1 antitrypsin endocytosis by lung endothelium

Sadaf Sohrab, Daniela Petrusca, Angelia Lockett, Kelly S. Schweitzer, Natalia I. Rush, Yuan Gu, Krzysztof Kamocki, Jana Garrison, Irina Petrache

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The integrity of lung alveoli is maintained by proper circulating levels of α-1 antitrypsin (A1AT). Next to cigarette smoking, A1AT deficiency is a major risk factor for lung emphysema development. We recently reported that in addition to neutralizing neutrophil elastases in the extracellular compartment, A1AT is internalized by lung endothelial cells and inhibits apoptosis. We hypothesized that the intracellular uptake of A1AT by endothelial cells may be required for its protective function; therefore, we studied the mechanisms of A1AT internalization by primary rat lung microvascular endothelial cells and the effect of cigarette smoke on this process both in vitro and in vivo (in mice). Purified A1AT was taken up intracellularly by endothelial cells in a time-dependent, dose-dependent, and conformer-specific manner and was detected in the cytoplasm of endothelial cells of nondiseased human lung sections. Despite a critical role for caveoli in endothelial cell endocytosis in general, specific inhibition of clathrin-mediated, but not caveoli-mediated, endocytosis profoundly decreased A1AT internalization and reversed the A1AT's antiapoptotic action. Further more, A1AT associated with clathrin heavy chains, but not with caveolin-1 in the plasma membrane fraction of endothelial cells. Interestingly, cigarette smoke exposure significantly inhibited A1AT uptake both in endothelial cells and in the mouse lung and altered the intracellular distribution of clathrin heavy chains. Our results suggest that clathrin-mediated endocytosis regulates A1AT intracellular function in the lung endothelium and may be an important determinant of the serpin's protection against developing cigarette smoke-induced emphysema.

Original languageEnglish
Pages (from-to)3149-3158
Number of pages10
JournalFASEB Journal
Volume23
Issue number9
DOIs
StatePublished - Sep 2009

Fingerprint

Endothelial cells
Endocytosis
Endothelium
Endothelial Cells
Lung
Tobacco Products
Clathrin Heavy Chains
Smoke
Clathrin
Emphysema
Serpins
Caveolin 1
Leukocyte Elastase
Cell membranes
Rats
Cytoplasm
Smoking
Cell Membrane
Apoptosis

Keywords

  • Apoptosis
  • Caveolin
  • Cigarette smoke
  • COPD
  • Serpin
  • Vascular

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Mechanism of α-1 antitrypsin endocytosis by lung endothelium. / Sohrab, Sadaf; Petrusca, Daniela; Lockett, Angelia; Schweitzer, Kelly S.; Rush, Natalia I.; Gu, Yuan; Kamocki, Krzysztof; Garrison, Jana; Petrache, Irina.

In: FASEB Journal, Vol. 23, No. 9, 09.2009, p. 3149-3158.

Research output: Contribution to journalArticle

Sohrab, S, Petrusca, D, Lockett, A, Schweitzer, KS, Rush, NI, Gu, Y, Kamocki, K, Garrison, J & Petrache, I 2009, 'Mechanism of α-1 antitrypsin endocytosis by lung endothelium', FASEB Journal, vol. 23, no. 9, pp. 3149-3158. https://doi.org/10.1096/fj.09-129304
Sohrab, Sadaf ; Petrusca, Daniela ; Lockett, Angelia ; Schweitzer, Kelly S. ; Rush, Natalia I. ; Gu, Yuan ; Kamocki, Krzysztof ; Garrison, Jana ; Petrache, Irina. / Mechanism of α-1 antitrypsin endocytosis by lung endothelium. In: FASEB Journal. 2009 ; Vol. 23, No. 9. pp. 3149-3158.
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