000101587 001__ 101587
000101587 005__ 20220124163436.0
000101587 0247_ $$2doi$$a10.7150/thno.49288
000101587 0248_ $$2sideral$$a123854
000101587 037__ $$aART-2021-123854
000101587 041__ $$aeng
000101587 100__ $$aGarzon-Tituana, M
000101587 245__ $$aGranzyme A inhibition reduces inflammation and increases survival during abdominal sepsis
000101587 260__ $$c2021
000101587 5060_ $$aAccess copy available to the general public$$fUnrestricted
000101587 5203_ $$aAims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57BI/6 (WT) and GzmA(-/-) mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNF alpha. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.
000101587 536__ $$9info:eu-repo/grantAgreement/ES/DGA-FEDER/B29-17R$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2014-54763-C2-2-R$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2017-83120-C2-1-R
000101587 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000101587 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000101587 700__ $$0(orcid)0000-0002-8796-2717$$aSierra-Monzon, JL
000101587 700__ $$aComas, L$$uUniversidad de Zaragoza
000101587 700__ $$0(orcid)0000-0002-1861-5981$$aSantiago, L$$uUniversidad de Zaragoza
000101587 700__ $$aKhaliulina-Ushakova, T
000101587 700__ $$aUranga-Murillo, I
000101587 700__ $$aRamirez-Labrada, A
000101587 700__ $$aTapia, E
000101587 700__ $$aMorte-Romea, E
000101587 700__ $$aAlgarate, S
000101587 700__ $$aCouty, L
000101587 700__ $$aCamerer, E
000101587 700__ $$aBird, PI
000101587 700__ $$aSeral, C
000101587 700__ $$aLuque, P
000101587 700__ $$aPano-Pardo, JR
000101587 700__ $$aGalvez, EM
000101587 700__ $$aPardo, J
000101587 700__ $$aArias, M
000101587 7102_ $$11006$$2255$$aUniversidad de Zaragoza$$bDpto. Fisiatría y Enfermería$$cÁrea Enfermería
000101587 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología
000101587 773__ $$g11, 8 (2021), 3781-3795$$pTHERANOSTICS$$tTheranostics$$x1838-7640
000101587 8564_ $$s1834118$$uhttps://zaguan.unizar.es/record/101587/files/texto_completo.pdf$$yVersión publicada
000101587 8564_ $$s2399808$$uhttps://zaguan.unizar.es/record/101587/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000101587 909CO $$ooai:zaguan.unizar.es:101587$$particulos$$pdriver
000101587 951__ $$a2022-01-24-16:17:57
000101587 980__ $$aARTICLE