Altered biosynthesis of leukotrienes and lipoxins and host defense disorders in patients with cirrhosis and ascites.
OBJECTIVE
Advanced cirrhosis is associated with impaired leukocyte function, but the mechanism underlying this host defense alteration is unknown. The aim of this study was to investigate the lipoxygenase pathway of arachidonic acid metabolism and its influence in leukocyte trafficking in patients with cirrhosis and ascites.


METHODS
Neutrophils (polymorphonuclear leukocytes [PMN]) were isolated from patients with cirrhosis and ascites and healthy subjects, and 5-lipoxygenase (5-LO) messenger RNA levels and 5-LO-derived products were measured. The effect of leukotrienes (LT) and lipoxins (LX) on PMN adhesion and migration was also assessed.


RESULTS
PMN from patients with cirrhosis showed increased 5-LO messenger RNA expression. However, in vitro generation of LTB4, cysteinyl-containing LT and LX was significantly decreased in cirrhotic patients. Interestingly, a close relationship between the activity of the renin-angiotensin system and LXA4 biosynthesis was observed both in vitro and in vivo. PMN isolated from cirrhotic patients with ascites showed significantly decreased adhesion and migration in response to LTB4. LXA4 did not provoke PMN adhesion and migration, but rather abrogated the differences between control and cirrhotic PMN. Cirrhotic monocytes showed marked impairment in adherence to laminin when stimulated with either LTB4 or LXA4.


CONCLUSIONS
These results show the existence of altered biosynthesis of LT and LX and defective response to these lipoxygenase products in leukocytes from patients with cirrhosis and ascites. This abnormality may be relevant to the pathogenesis of host defense disorders in chronic liver disease.
Clària
J
J
DNA Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain. claria@medicina.ub.es
Titos
E
E
Jiménez
W
W
Ros
J
J
Ginès
P
P
Arroyo
V
V
Rivera
F
F
Rodés
J
J
D000804:Angiotensin II / Q000097:blood; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D001201:Ascites / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D007975:Leukotriene B4 / Q000096:biosynthesis*; D044045:Lipoxins; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis
D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D012333:RNA, Messenger; C040527:lipoxin A4; D000804:Angiotensin II; D007975:Leukotriene B4; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase