Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

Abstract Singular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Shinjini Chakraborty, Veronika Eva Winkelmann, Sonja Braumüller, Annette Palmer, Anke Schultze, Bettina Klohs, Anita Ignatius, Axel Vater, Michael Fauler, Manfred Frick, Markus Huber-Lang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f879c60c4cec486cafd3a5402fbf3955
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f879c60c4cec486cafd3a5402fbf3955
record_format	dspace
spelling	oai:doaj.org-article:f879c60c4cec486cafd3a5402fbf39552021-12-02T13:57:59ZRole of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock10.1038/s41598-020-79607-12045-2322https://doaj.org/article/f879c60c4cec486cafd3a5402fbf39552021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79607-1https://doaj.org/toc/2045-2322Abstract Singular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.Shinjini ChakrabortyVeronika Eva WinkelmannSonja BraumüllerAnnette PalmerAnke SchultzeBettina KlohsAnita IgnatiusAxel VaterMichael FaulerManfred FrickMarkus Huber-LangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shinjini Chakraborty Veronika Eva Winkelmann Sonja Braumüller Annette Palmer Anke Schultze Bettina Klohs Anita Ignatius Axel Vater Michael Fauler Manfred Frick Markus Huber-Lang Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
description	Abstract Singular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.
format	article
author	Shinjini Chakraborty Veronika Eva Winkelmann Sonja Braumüller Annette Palmer Anke Schultze Bettina Klohs Anita Ignatius Axel Vater Michael Fauler Manfred Frick Markus Huber-Lang
author_facet	Shinjini Chakraborty Veronika Eva Winkelmann Sonja Braumüller Annette Palmer Anke Schultze Bettina Klohs Anita Ignatius Axel Vater Michael Fauler Manfred Frick Markus Huber-Lang
author_sort	Shinjini Chakraborty
title	Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
title_short	Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
title_full	Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
title_fullStr	Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
title_full_unstemmed	Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
title_sort	role of the c5a-c5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f879c60c4cec486cafd3a5402fbf3955
work_keys_str_mv	AT shinjinichakraborty roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT veronikaevawinkelmann roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT sonjabraumuller roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT annettepalmer roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT ankeschultze roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT bettinaklohs roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT anitaignatius roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT axelvater roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT michaelfauler roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT manfredfrick roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock AT markushuberlang roleofthec5ac5areceptoraxisintheinflammatoryresponsesofthelungsafterexperimentalpolytraumaandhemorrhagicshock
_version_	1718392296394719232

Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

Ejemplares similares