title: Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia.
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.
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary.
authors.forename: Fruzsina
authors.initials: F
authors.lastname: Fonai
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary.
authors.forename: Janos K
authors.initials: JK
authors.lastname: Priber
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jakus
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary.
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Kalman
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary.
authors.forename: Csenge
authors.initials: C
authors.lastname: Antus
authors.affiliation: Department of Comparative Anatomy and Developmental Biology, Faculty of Sciences, University of Pecs, Pecs, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Pollak
authors.affiliation: Department of Comparative Anatomy and Developmental Biology, Faculty of Sciences, University of Pecs, Pecs, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Karsai
authors.affiliation: Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Tretter
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary; Szentagothai Research Center, University of Pecs, Pecs, Hungary; MTA-PTE Nuclear and Mitochondrial Interactions Research Group, Pecs, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical Faculty, University of Pecs, Pecs, Hungary. Electronic address: balazs.veres@aok.pte.hu.
authors.forename: Balazs
authors.initials: B
authors.lastname: Veres
keywords: Acute lung injury; Cyclophilin D; Lipopolysaccharide; NF-κB; Reactive oxygen species