Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver.
Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically involved in degradation of extracellular matrix, and their inhibition is discussed as a promising strategy against hepatic ischemia-reperfusion (I/R) injury. Here, we analyzed the role of MMP-2 and -9 for leukocyte migration and tissue injury in sham-operated mice and in mice after I/R, treated with a MMP-2/9 inhibitor or vehicle. Using zymography, we show that the MMP-2/9 inhibitor abolished I/R-induced MMP-9 activation, whereas MMP-2 activity was not detectable in all groups. As demonstrated by intravital microscopy, MMP-9 inhibition attenuated postischemic rolling and adherence of total leukocytes in hepatic postsinusoidal venules, CD4+ T cell accumulation in sinusoids, and neutrophil transmigration. These effects were associated with reduction of plasma tumor necrosis factor alpha (TNF-alpha) levels and endothelial expression of CD62P. Motility of interstitially migrating leukocytes was assessed by near-infrared reflected light oblique transillumination microscopy in the postischemic cremaster muscle. Upon MMP-9 blockade, leukocyte migration velocity and curve-line and straight-line migration distances were reduced significantly as compared with the vehicle-treated I/R group. Postischemic sinusoidal perfusion failure, hepatocellular apoptosis, and alanine aminotransferase activity were only slightly reduced after MMP-9 inhibition, whereas aspartate aminotransferase activity and mortality were significantly lower. In conclusion, MMP-9 is involved in the early recruitment cascades of neutrophils and CD4+ T cells, promotes neutrophil and T cell transmigration during hepatic I/R, and is required for motility of interstitially migrating leukocytes. MMP-9 blockade is associated with an attenuation of TNF-alpha release and endothelial CD62P expression, weakly protects from early microvascular/hepatocellular I/R damage, but improves postischemic survival.
Institute for Surgical Research, University of Munich, Marchioninistr. 27, D-81377 Munich, Germany. andrej.khandoga@med.uni-muenchen.de
Andrej
A
Khandoga
Julia S
JS
Kessler
Marc
M
Hanschen
Alexander G
AG
Khandoga
Dorothe
D
Burggraf
Christoph
C
Reichel
Gerhard F
GF
Hamann
Georg
G
Enders
Fritz
F
Krombach
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics; D007511:Ischemia / Q000503:physiopathology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014699:Venules
D000950:Antigens, Ly; C415426:CTTHWGFTLC peptide; D004151:Dipeptides; C480309:Ly6G antigen, mouse; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D019007:P-Selectin; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017493:Leukocyte Common Antigens; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9