Alox12/15 Deficiency Exacerbates, While Lipoxin A 4 Ameliorates Hepatic Inflammation in Murine Alcoholic Hepatitis.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A ₄ (LXA ₄ ), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA ₄ on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15 ^+/+ and Alox12/15 ^-/- mice, with or without supplementation of LXA ₄ . Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA ₄ significantly lowered transaminase levels only in Alox12/15 ^-/- mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA ₄ injection attenuated selected parameters of disease progression in Alox12/15 ^-/- mice, its beneficial impact on immunity was also apparent in Alox12/15 ^+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.
(Copyright © 2020 Queck, Fink, Sirait-Fischer, Rüschenbaum, Thomas, Snodgrass, Geisslinger, Baba, Trebicka, Zeuzem, Weigert, Lange and Brüne.)