Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis.
OBJECTIVE
Alcoholic hepatitis (AH) is characterized by hepatocellular damage, inflammation, and fibrosis. We performed a prospective study to associate hepatic expression of the CXC subfamily of chemokines with histology findings and prognosis of patients with AH.


METHODS
Liver biopsy samples from 105 patients with AH and 5 normal liver samples (controls) were evaluated for steatosis, inflammation, fibrosis, and cholestasis. Computer-based morphometric analysis assessed the numbers of infiltrating CD3+ T cells and CD15+ cells (neutrophils); terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining was used to quantify apoptosis. Expression of CXC and CC chemokines and selected signaling components were assessed by quantitative reverse-transcription polymerase chain reaction; protein levels of interleukin (IL)-8 and Gro-alpha also were determined by immunohistochemistry. Serum levels of IL-8 and Gro-alpha were measured by enzyme-linked immunosorbent assay. The Cox regression model identified variables associated with mortality.


RESULTS
Most patients (75%) had severe AH; their 90-day mortality rate was 21.9%. In AH liver samples, expression of the CXC subfamily members IL-8, Gro-alpha, CXCL5, CXCL6, CXCL10, and platelet factor 4 was up-regulated and compared with controls. The CC chemokine CCL2, but not CCL5, also was up-regulated. Higher expression levels of IL-8, CXCL5, Gro-gamma, and CXCL6 were associated with worse prognosis. Expression of CXC components correlated with neutrophil infiltration and the severity of portal hypertension. In the multivariate analysis, IL-8 protein levels were an independent predictor of 90-day mortality. IL-8 and Gro-alpha serum levels did not correlate with prognosis.


CONCLUSIONS
Hepatic expression of CXC components correlates with prognosis of patients with AH. Reagents that target CXC chemokines might be developed as therapeutics.
Dominguez
Marlene
M
Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, CIBER de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain.
Miquel
Rosa
R
Colmenero
Jordi
J
Moreno
Montserrat
M
García-Pagán
Joan-Carles
JC
Bosch
Jaime
J
Arroyo
Vicente
V
Ginès
Pere
P
Caballería
Juan
J
Bataller
Ramón
R
D017209:Apoptosis; D001706:Biopsy; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006519:Hepatitis, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020287:In Situ Nick-End Labeling; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D016209:Interleukin-8