RT Journal Article
T1 Role of Toll-like receptor 4 in intravascular hemolysis-mediated injury.
A1 Vazquez-Carballo, Cristina
A1 Herencia, Carmen
A1 Guerrero-Hue, Melania
A1 Garcia-Caballero, Cristina
A1 Rayego-Mateos, Sandra
A1 Morgado-Pascual, Jose Luis
A1 Opazo-Rios, Lucas
A1 Gonzalez-Guerrero, Cristian
A1 Vallejo-Mudarra, Mercedes
A1 Cortegano, Isabel
A1 Gaspar, Maria Luisa
A1 de Andres, Belen
A1 Egido, Jesus
A1 Moreno, Juan Antonio
K1 TLR4
K1 Acute kidney injury
K1 Heme
K1 Hemoglobin
K1 Inflammation
K1 Intravascular hemolysis
K1 Oxidative stress
AB Massive intravascular hemolysis is a common characteristic of several pathologies. It is associated with the release of large quantities of heme into the circulation, promoting injury in vulnerable organs, mainly kidney, liver, and spleen. Heme activates Toll-like receptor 4 (TLR4), a key regulator of the inflammatory response; however, the role of TLR4 in hemolysis and whether inhibition of this receptor may protect from heme-mediated injury are unknown. We induced intravascular hemolysis by injection of phenylhydrazine in wildtype and Tlr4-knockout mice. In this model, we analyzed physiological parameters, histological damage, inflammation and cell death in kidney, liver, and spleen. We also evaluated whether heme-mediated-inflammatory effects were prevented by TLR4 inhibition with the compound TAK-242, both in vivo and in vitro. Induction of massive hemolysis elicited acute kidney injury characterized by loss of renal function, morphological alterations of the tubular epithelium, cell death, and inflammation. These pathological effects were significantly ameliorated in the TLR4-deficient mice and in wildtype mice treated with TAK-242. In vitro studies showed that TAK-242 pretreatment reduced heme-mediated inflammation by inhibiting the TLR4/NF-κB (nuclear factor kappa B) axis. However, analysis in liver and spleen indicated that TLR4 deficiency did not protect against the toxic accumulation of heme in these organs. In conclusion, TLR4 is a key molecule involved in the renal inflammatory response triggered by massive intravascular hemolysis. TLR4 inhibition may be a potential therapeutic approach to prevent renal damage in patients suffering from hemolysis. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PB John Wiley & Sons
YR 2022
FD 2022-07-25
LK http://hdl.handle.net/10668/22428
UL http://hdl.handle.net/10668/22428
LA en
NO Vázquez-Carballo C, Herencia C, Guerrero-Hue M, García-Caballero C, Rayego-Mateos S, Morgado-Pascual JL, et al. Role of Toll-like receptor 4 in intravascular hemolysis-mediated injury. J Pathol. 2022 Nov;258(3):236-249
NO This research was funded by Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI20/00375, PI20/00487; and DTS19/00093) (Co-funded byEuropean Regional Development Fund/European Social Fund ‘A way to make Europe’/‘Investing in your future’), Spanish Biomedical Research Centre in Cardiovascular  Diseases (CIBERCV), Consejería de Salud y Familias FEDER, Junta de Andalucía (PIGE-0052-2020), and Spanish Society of Nephrology (SEN). The ‘PFIS’ and ‘Sara Borrell’ training programs of the ISCIII supportedthe salary of MGH (FI18/00310), CH (CD17/00030) and SR-M (CD19/00021). The Spanish Ministry of Science and Innovation supported the salary of JAM (RYC 2017-22369) and JLM-P (FJC2019-042028-I) (Co-funded by European Regional Development Fund/European Social Fund ‘A way to make Europe’/‘Investing in your future’). Cordoba University supported the salary of CGC. Funding for open access charge: Universidad de Cordoba / CBUA.
DS RISalud
RD Apr 6, 2025