Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity.
BACKGROUND
Although timely surgical treatment of liver disease can interrupt inflammation and reduce fibrosis, the mechanisms of repair are unknown. We questioned whether these mechanisms of repair include changes in the inflammatory infiltrate and associated biological activity of matrix metalloproteinases (MMPs) 8 and 2.


METHODS
Rats (n >or= 3) underwent biliary ductal suspension for 7 days followed by decompression. Livers were collected after 7 days of obstruction (d0) and after 2, 5, and 7 days of repair (d2, d5, d7, respectively), and assessed morphometrically for collagen, polymorphonuclear cells (PMNs), Kupffer cells (KCs), and inflammatory mononuclear phagocytes (MNPs). In situ zymography was performed by using fluorogenic substrates for MMP-8 and MMP-2 to spatially localize enzymatic activity.


RESULTS
Cholestatic injury resulted in significantly elevated (P <or= .001) collagen deposition (3-fold), and elevated numbers of MNPs (10-fold), KCs (5-fold), and PMNs (4-fold), compared with shams. PMNs remained elevated through d7, while collagen deposition, KCs, and MNPs returned to sham levels by d2. In situ zymography showed no significant changes in MMP-2 activity after cholestatic injury and repair. MMP-8 activity was significantly (P <or= .05) elevated only during repair. Activity was localized to fibrotic portal triads containing PMNs.


CONCLUSIONS
Cholestatic injury results in increased fibrosis, MNPs, KCs, and PMNs but no MMP-2 or MMP-8 activity. Biliary decompression results in increased MMP-8 activity co-localized to areas of portal fibrosis and PMN accumulation. We conclude that secretion of MMP-8 by neutrophils may play a critical role in resolving the fibrotic scar generated during cholestasis.
Harty
Mark W
MW
Department of Surgery, Brown Medical School, Rhode Island and Hasbro Children's Hospitals, Providence 02903, USA.
Huddleston
Hannah M
HM
Papa
Elaine F
EF
Puthawala
Tauquir
T
Tracy
Aaron P
AP
Ramm
Grant A
GA
Gehring
Stephan
S
Gregory
Stephen H
SH
Tracy
Thomas F
TF
D000818:Animals; D001663:Bilirubin / Q000097:blood; D002779:Cholestasis / Q000276:immunology* / Q000378:metabolism* / Q000601:surgery; D003094:Collagen / Q000378:metabolism; D019299:Decompression, Surgical; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains
D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D001663:Bilirubin