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dc.contributor.author Fónai, Fruzsina
dc.contributor.author Pribér, János Krisztián
dc.contributor.author Jakus, Péter
dc.contributor.author Kálmán, Nikoletta
dc.contributor.author Antus, Csenge Petra
dc.contributor.author Tretter, László
dc.contributor.author Sümegi, Balázs
dc.contributor.author Veres, Balázs
dc.date.accessioned 2016-05-27T09:55:11Z
dc.date.available 2016-05-27T09:55:11Z
dc.date.issued 2015
dc.identifier 84942279807
dc.identifier.citation pagination=2563-2573; journalVolume=1852; journalIssueNumber=12; journalTitle=BIOCHIMICA ET BIOPHYSICA ACTA;
dc.identifier.uri http://repo.lib.semmelweis.hu//handle/123456789/2371
dc.identifier.uri doi:10.1016/j.bbadis.2015.09.004
dc.description.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-kappaB and reducing the production of ROS. Functional inhibition of NF-kappaB was confirmed by decreased expression of NF-kappaB-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.
dc.relation.ispartof urn:issn:0006-3002
dc.title Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia.
dc.type Journal Article
dc.date.updated 2015-11-18T14:43:56Z
dc.language.rfc3066 en
dc.identifier.mtmt 2943971
dc.identifier.pubmed 26385159
dc.contributor.department PTE/KCS/MTA-PTE Nukleáris-Mitokondriális Interakciók Kutatócsoport
dc.contributor.department PTE/Szentágothai János Kutatóközpont
dc.contributor.department SE/AOK/I/Orvosi Biokémiai Intézet
dc.contributor.institution Pécsi Tudományegyetem
dc.contributor.institution Semmelweis Egyetem


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