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Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct–ligated mice
Author(s) -
Gujral Jaspreet S.,
Farhood Anwar,
Bajt Mary Lynn,
Jaeschke Hartmut
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50341
Subject(s) - liver injury , pathology , cholestasis , medicine , extravasation , bile duct , pathophysiology , inflammation , necrosis , alanine transaminase , aspartate transaminase , cd18 , integrin alpha m , biology , alkaline phosphatase , receptor , biochemistry , enzyme
Obstruction of the common bile duct in a variety of clinical settings leads to cholestatic liver injury. An important aspect of this injury is hepatic inflammation, with neutrophils as the prominent cell type involved. However, the pathophysiologic role of the infiltrating neutrophils during cholestatic liver injury remains unclear. Therefore, we tested the hypothesis that neutrophils contribute to the overall pathophysiology by using bile duct‐ligated (BDL) wild‐type animals and mice deficient in the β 2 integrin CD18. In wild‐type animals, neutrophils were activated systemically as indicated by the increased expression of Mac‐1 (CD11b/CD18) and L‐selectin shedding 3 days after BDL. Histologic evaluation (48 ± 10% necrosis) and plasma transaminase levels showed severe liver injury. Compared with sham‐operated controls (< 10 neutrophils per 20 high‐power fields), large numbers of neutrophils were present in livers of BDL mice (425 ± 64). About 60% of these neutrophils had extravasated into the parenchyma. In addition, a substantial number of extravasated neutrophils were found in the portal tract. In contrast, Mac‐1 was not up‐regulated and plasma transaminase activities and the area of necrosis (21 ± 9%) were significantly reduced in CD18‐deficient animals. These mice had overall 62% less neutrophils in the liver. In particular, extravasation from sinusoids and portal venules (PV) was reduced by 91% and 47%, respectively. Immunohistochemical staining for chlorotyrosine, a marker of neutrophil‐derived oxidant stress, was observed in the parenchyma of BDL wild‐type but not CD18‐deficient mice. In conclusion, neutrophils aggravated acute cholestatic liver injury after BDL. This inflammatory injury involves CD18‐dependent extravasation of neutrophils from sinusoids and reactive oxygen formation.