Septic shock is the most severe complication of sepsis, being characterized by a systemic inflammatory response following bacterial infection, leading to multiple organ failure and dra-matically high mortality. Aquaporin‐9 (AQP9), a membrane channel protein mainly expressed in hepatocytes and leukocytes, has been recently associated with inflammatory and infectious re-sponses, thus triggering strong interest as a potential target for reducing septic shock‐dependent mortality. Here, we evaluated whether AQP9 contributes to murine systemic inflammation during endotoxic shock. Wild type (Aqp9+/+; WT) and Aqp9 gene knockout (Aqp9−/−; KO) male mice were submitted to endotoxic shock by i.p. injection of lipopolysaccharide (LPS; 40 mg/kg) and the related survival times were followed during 72 h. The electronic paramagnetic resonance and confocal microscopy were employed to analyze the nitric oxide (NO) and superoxide anion (O2−) produc-tion, and the expression of inducible NO‐synthase (iNOS) and cyclooxigenase‐2 (COX‐2), respec-tively, in the liver, kidney, aorta, heart and lung of the mouse specimens. LPS‐treated KO mice survived significantly longer than corresponding WT mice, and 25% of the KO mice fully recov-ered from the endotoxin treatment. The LPS‐injected KO mice showed lower inflammatory NO and O2− productions and reduced iNOS and COX‐2 levels through impaired NF‐κB p65 activation in the liver, kidney, aorta, and heart as compared to the LPS‐treated WT mice. Consistent with these results, the treatment of FaO cells, a rodent hepatoma cell line, with the AQP9 blocker HTS13268 prevented the LPS‐induced increase of inflammatory NO and O2−. A role for AQP9 is suggested in the early acute phase of LPS‐induced endotoxic shock involving NF‐κB signaling. The modulation of AQP9 expression/function may reveal to be useful in developing novel endotoxemia therapeutics

Ablation of aquaporin‐9 ameliorates the systemic inflammatory response of lps‐induced endotoxic shock in mouse

Tesse Angela;Calamita Giuseppe
2021

Abstract

Septic shock is the most severe complication of sepsis, being characterized by a systemic inflammatory response following bacterial infection, leading to multiple organ failure and dra-matically high mortality. Aquaporin‐9 (AQP9), a membrane channel protein mainly expressed in hepatocytes and leukocytes, has been recently associated with inflammatory and infectious re-sponses, thus triggering strong interest as a potential target for reducing septic shock‐dependent mortality. Here, we evaluated whether AQP9 contributes to murine systemic inflammation during endotoxic shock. Wild type (Aqp9+/+; WT) and Aqp9 gene knockout (Aqp9−/−; KO) male mice were submitted to endotoxic shock by i.p. injection of lipopolysaccharide (LPS; 40 mg/kg) and the related survival times were followed during 72 h. The electronic paramagnetic resonance and confocal microscopy were employed to analyze the nitric oxide (NO) and superoxide anion (O2−) produc-tion, and the expression of inducible NO‐synthase (iNOS) and cyclooxigenase‐2 (COX‐2), respec-tively, in the liver, kidney, aorta, heart and lung of the mouse specimens. LPS‐treated KO mice survived significantly longer than corresponding WT mice, and 25% of the KO mice fully recov-ered from the endotoxin treatment. The LPS‐injected KO mice showed lower inflammatory NO and O2− productions and reduced iNOS and COX‐2 levels through impaired NF‐κB p65 activation in the liver, kidney, aorta, and heart as compared to the LPS‐treated WT mice. Consistent with these results, the treatment of FaO cells, a rodent hepatoma cell line, with the AQP9 blocker HTS13268 prevented the LPS‐induced increase of inflammatory NO and O2−. A role for AQP9 is suggested in the early acute phase of LPS‐induced endotoxic shock involving NF‐κB signaling. The modulation of AQP9 expression/function may reveal to be useful in developing novel endotoxemia therapeutics
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/381583
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 9
  • ???jsp.display-item.citation.isi??? ND
social impact