α1-antitrypsin modulates lung endothelial cell inflammatory responses to TNF-α

Angelia D. Lockett, Samuel Kimani, Godfrey Ddungu, Sabine Wrenger, Rubin M. Tuder, Sabina M. Janciauskiene, Irina Petrache

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

α1-Antitrypsin (A1AT) is an acute-phase reactant, but also a major protective factor against the development of chronic obstructive pulmonary disease, a complex disease with sustained chronic inflammation. The lung-protective effects of A1AT have been attributed to the inhibition of proteases involved in lung matrix fragmentation, macrophage activation, and endothelial-cell apoptosis. More recently, A1AT has been shown to directly interact with or modulate the actions of cytokines such as TNF-α or IL-1 in inflammatory cells, but its effect on the lung endothelium, an active participant in the amplification and resolution of inflammation, has received little attention. An important role of A1AT in modulating lung endothelial inflammatory responses is expected, given the high concentrations of circulating A1AT during inflammation and its active uptake by endothelial cells. We investigated the role of A1AT in primary lung microvascular endothelial cell activation by relevant cytokines such as TNF-α or IL-1b. Despite an initial marked augmentation of TNF-α self-induced transcription, A1AT inhibited TNF-α receptor 1 up-regulation and significantly reduced TNF-α secretion, effects that were associated with inhibition of TNF-α-converting enzyme activity. Furthermore, A1AT inhibited calpain activity, whose activationby TNF-αcontributedto decreased intracellularA1ATconcentrations. These data indicate that A1AT initially facilitates acute responses of the endothelium to TNF-α, followed by selective inhibition of TNF-α-induced-self amplification, which may assist the vasculature in the resolution of chronic inflammation.

Original languageEnglish (US)
Pages (from-to)143-150
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number1
DOIs
StatePublished - Jul 1 2013

    Fingerprint

Keywords

  • COPD
  • Inflammation
  • Proteinase inhibitor
  • Serpin
  • Vascular

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this