Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia

Fruzsina Fonai, Janos K. Priber, Peter B. Jakus, Nikoletta Kalman, Csenge Antus, Edit Pollak, Gergely Karsai, Laszlo Tretter, Balazs Sumegi, Balazs Veres

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Sepsis caused by LPS is characterized by an intense systemic inflammatory response affecting the lungs, causing acute lung injury (ALI). Dysfunction of mitochondria and the role of reactive oxygen (ROS) and nitrogen species produced by mitochondria have already been proposed in the pathogenesis of sepsis; however, the exact molecular mechanism is poorly understood. Oxidative stress induces cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT), leading to organ failure in sepsis. In previous studies mPT was inhibited by cyclosporine A which, beside CypD, inhibits cyclophilin A, B, C and calcineurin, regulating cell death and inflammatory pathways. The immunomodulatory side effects of cyclosporine A make it unfavorable in inflammatory model systems. To avoid these uncertainties in the molecular mechanism, we studied endotoxemia-induced ALI in CypD-/- mice providing unambiguous data for the pathological role of CypD-dependent mPT in ALI. Our key finding is that the loss of this essential protein improves survival rate and it can intensely ameliorate endotoxin-induced lung injury through attenuated proinflammatory cytokine release, down-regulation of redox sensitive cellular pathways such as MAPKs, Akt, and NF-κB and reducing the production of ROS. Functional inhibition of NF-κB was confirmed by decreased expression of NF-κB-mediated proinflammatory genes. We demonstrated that impaired mPT due to the lack of CypD reduces the severity of endotoxemia-induced lung injury suggesting that CypD specific inhibitors might have a great therapeutic potential in sepsis-induced organ failure. Our data highlight a previously unknown regulatory function of mitochondria during inflammatory response.

Original languageEnglish
Pages (from-to)2563-2573
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

Keywords

  • Acute lung injury
  • Cyclophilin D
  • Lipopolysaccharide
  • NF-κB
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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