5-lipoxygenase (5-LOX) inhibition by zileuton reduces the amount of neutrophils that reaches the liver during liver regeneration after partial hepatectomy (PH)

LORENZETTI, FLORENCIA; VERA MARINA C.; LUCCI, ALVARO; COMANZO, CARLA G.; FERRETTI, ANABELA C.; CARRILLO, MARÍA C.; CEBALLOS, MARÍA P.; QUIROGA, ARIEL D.; ALVAREZ, MARÍA DE L.

Rosario

Congreso; Reunión anual SAFIS 2019 ROSARIO; 2019

5-LOX is the first and main enzyme that participates in thesynthesis of leukotrienes. LTB4 is a leukotriene involved ininflammation and also is a potent chemoattractant ofneutrophils. Previous studies from our lab showed thattreatment with a 5-LOX inhibitor produces a decrease inhepatic LTB4 content and a reduction in liver proliferationafter 70% PH in rats, indicating that LTB4 is necessary forliver regeneration. Additionally, it was reported that liverregeneration was impaired after neutrophils depletion.Objective: To study if the reduction in hepatic LTB4reduces the levels of polymorphonuclear leukocytes(PMNs) post-PH which could be necessary to trigger liverregeneration at early times after PH. Methods and results:Adult male Wistar rats were subjected to sham surgery orPH (70 % liver removal). Two hours before surgery,animals received a specific inhibitor of 5-LOX, zileuton (Zi)40 mg/kg BW or the drug vehicle. Liver samples wereobtained at 3 and 5h post-PH. We studied byimmunohistochemistry and qRT-PCR the myeloperoxidase(MPO) levels (marker of neutrophils) and we found asignificant increment in the levels of MPO-positive cells inthe hepatectomized animals treated with vehicle (controlPH) respect to the sham (+300%*). On the other hand, theanimals that received the 5-LOX inhibitor showed adecrease in MPO-positive cells (-62,5%# 5h post-PH) andMPO mRNA levels (-38,48%# 3h post-PH) respect tocontrol PH rats. Also, by immunofluorescence andconfocal microscopy we analyzed a specific marker of ratneutrophil leukocytes (using anti-neutrophil antibody LSC348005, LSBio) and we observed a significant reductionin the number of positive cells in PH rats treated with Zicompared with control PH rats at 3h post-PH (-36,6%#)(*p