Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice

Abstract

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 ␤ 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 shamoperated 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 neutrophilderived 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. (HEPATOLOGY 2003;38:355-363.)

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

“…The present observations related to neutrophils are consistent with previous literature on neutrophil biology in a mouse model of cholestatic liver damage (Gujral et al 2003;Sitia et al 2004). These reports indicated that accumulated neutrophils in liver were significantly associated with PBC progression.…”

Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis

“…51 We demonstrated that the inflammatory reaction was reduced in the BDL livers of the MMP-13Ϫ/Ϫ mice. Induction of HO-1, an indicator of oxidative stress, 23 was also reduced in the livers of MMP-13Ϫ/Ϫ mice after BDL. Finally, we demonstrated that expression of mRNA for markers of HSC activation, collagen ␣1(I), ␣-SMA (alpha smooth muscle actin), and TIMP-1, was suppressed in the BDL livers of MMP-13Ϫ/Ϫ mice.…”

“…2B). Because neutrophil infiltration in the liver during BDL is a pathological feature of liver injury 23 and neutrophils are a source of MMP-9, 24 neutrophil accumulation in the sinusoids was evaluated by staining for chloroacetate esterase. Severe neutrophil infiltration in the sinusoids was observed in the BDL livers of MMP-13ϩ/ϩ mice.…”

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

“…22 Also, after sterile cell death, neutrophils emigrate to sites of necrosis where they may participate in the healing and removal of cell debris. 23 However, uncontrolled neutrophil migration and activation is detrimental in several inflammatory diseases, such as endotoxemic shock, 24 alcoholic hepatitis, 25 gout, 10 arthritis, 11 obstructive cholestasis, 26 ischemia-reperfusion (I/R) injury, 12 and several others. 27 In spite of previous reports regarding the detrimental role of neutrophils in liver injury, data from distinct groups are controversial.…”