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Treatment of male C3Heb\/FeJ mice with Gal\/ET or Gal\/TNF caused the formation of numerous gaps in SECs at 4 h when no neutrophil extravasation occurred. Six hours after Gal\/ET or Gal\/TNF treatment, blood elements started to penetrate to the extrasinusoidal space through large gaps. Treatment with ET alone caused sinusoidal neutrophil accumulation but no gap formation, neutrophil extravasation, or hemorrhage. Gal\/ET treatment increased hepatic MMP-2 and MMP-9 mRNA expression (6.7- and 11-fold, respectively). Pretreatment with 2-[(4-biphenylsulfonyl) amino]-3-phenyl-propionic acid, an MMP-2\/MMP-9 inhibitor (5 mg\/kg), minimized gap formation after Gal\/ET and Gal\/TNF treatment. The MMP inhibitor reduced injury only in the Gal\/ET model mainly due to reduced TNF formation. The MMP inhibitor attenuated sinusoidal neutrophil accumulation at 6 h but failed to attenuate Gal\/TNF-induced liver injury at 7 h due to excessive apoptosis. These results suggest that Gal\/ET or Gal\/TNF activates MMPs, which are responsible for SEC gap formation. Although the initial appearance of gap formation is independent of neutrophils, the gaps allow initial contact of neutrophils with damaged hepatocytes. 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