Deficiency of long‐chain acyl‐CoA synthetase 4 leads to lipopolysaccharide‐induced mortality in a mouse model of septic shock

Abstract

Long‐chain acyl‐CoA synthetase 4 (ACSL4) converts free highly unsaturated fatty acids (HUFAs) into their acyl‐CoA esters and is important for HUFA utilization. HUFA‐containing phospholipids produced via ACSL4‐dependent reactions are involved in pathophysiological events such as inflammatory responses and ferroptosis as a source for lipid mediators and/or a target of oxidative stress, respectively. However, the in vivo role of ACSL4 in inflammatory responses is not fully understood. This study sought to define the effects of ACSL4 deficiency on lipopolysaccharide (LPS)‐induced systemic inflammatory responses using global Acsl4 knockout (Acsl4 KO) mice. Intraperitoneal injection of LPS‐induced more severe symptoms, including diarrhea, hypothermia, and higher mortality, in Acsl4 KO mice within 24 h compared with symptoms in wild‐type (WT) mice. Intestinal permeability induced 3 h after LPS challenge was also enhanced in Acsl4 KO mice compared with that in WT mice. In addition, plasma levels of some eicosanoids in Acsl4 KO mice 6 h post‐LPS injection were 2‐ to 9‐fold higher than those in WT mice. The increased mortality observed in LPS‐treated Acsl4 KO mice was significantly improved by treatment with the general cyclooxygenase inhibitor indomethacin with a partial reduction in the severity of illness index for hypothermia, diarrhea score, and intestinal permeability. These results suggest that ACSL4 deficiency enhances susceptibility to endotoxin at least partly through the overproduction of cyclooxygenase‐derived eicosanoids.

Prostacyclin synthase deficiency exacerbates inflammatory reactions in lipopolysaccharide-induced sepsis in vivo

“…Sepsis was induced by a single intraperitoneal (i.p.) injection of LPS (5 mg/kg, Sigma Aldrich (St. Louis, MO, USA); lipopolysaccharides from Escherichia coli 0111: B4) dissolved in saline [7,14]. The control group received the same volume of saline.…”