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  • Halbgebauer, RebeccaUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

  • Artikel/kapitelEngelska2020

Förlag, utgivningsår, omfång ...

  • 2020-08-26
  • Frontiers Media S.A.2020
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:lnu-98357
  • https://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-98357URI
  • https://doi.org/10.3389/fimmu.2020.02081DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-423031URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and apost hocanalysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney.In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550,). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically,in vitrodata suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibitionin vivomay inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Karasu, EbruUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Braun, Christian K.Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.;Univ Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. (författare)
  • Palmer, AnnetteUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Braumueller, SonjaUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Schultze, AnkeUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Schaefer, FabianUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Bueckle, SarahUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Eigner, AlicaUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Wachter, UlrichUniv Ulm, Inst Anesthesiol Pathophysiol & Proc Dev, Ulm, Germany. (författare)
  • Radermacher, PeterUniv Ulm, Inst Anesthesiol Pathophysiol & Proc Dev, Ulm, Germany. (författare)
  • Resuello, Ranillo R. G.Simian Conservat Breeding & Res Ctr, Makati, Philippines. (författare)
  • Tuplano, Joel V.Simian Conservat Breeding & Res Ctr, Makati, Philippines. (författare)
  • Nilsson Ekdahl, KristinaUppsala universitet,Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),Uppsala University, Sweden,Linnaeus Ctr Biomat Chem, BMC,Klinisk immunologi,Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.(Swepub:uu)krisnil (författare)
  • Nilsson, BoUppsala universitet,Klinisk immunologi(Swepub:uu)bonils (författare)
  • Armacki, MilenaUniv Hosp Ulm, Dept Internal Med, Ulm, Germany. (författare)
  • Kleger, AlexanderUniv Hosp Ulm, Dept Internal Med, Ulm, Germany. (författare)
  • Seufferlein, ThomasUniv Hosp Ulm, Dept Internal Med, Ulm, Germany. (författare)
  • Kalbitz, MiriamUniv Hosp Ulm, Ctr Surg, Dept Traumatol Hand Plast & Reconstruct Surg, Ulm, Germany. (författare)
  • Gebhard, FlorianUniv Hosp Ulm, Ctr Surg, Dept Traumatol Hand Plast & Reconstruct Surg, Ulm, Germany. (författare)
  • Lambris, John D.Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. (författare)
  • van Griensven, MartijnMaastricht Univ, Dept Cell Biol Inspired Tissue Engn, MERLN Inst Technol Inspired Regenerat Med, Maastricht, Netherlands. (författare)
  • Huber-Lang, MarkusUniv Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany. (författare)
  • Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.;Univ Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Frontiers in Immunology: Frontiers Media S.A.11, s. 1-121664-3224

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