Alterations in liver parenchyma after sialoadenectomy in mice: contribution of neutrophils and macrophages to the removal of damaged hepatocytes.

Surgical excision of submandibular salivary glands (sialoadenectomy) alters cell turnover in mice liver. Here we show that the liver of adult mice contained scattered leukocyte infiltration foci whose size was in the range of the diameter of hepatocytes. The number of infiltration foci in the liver increased soon after sialoadenectomy and remained high for several weeks. Neutrophils were recruited on dying hepatocytes soon after the initiation of the apoptotic process. Kupffer cells appeared later in the process. Just 2 days after sialoadenectomy, the number of type I infiltration foci (corresponding to the first stage) had increased 5-fold. Since these alterations in liver structure are coincident with a transient decrease in plasma EGF concentration, we studied whether inhibition of EGF receptor by means of genistein injection produced a similar effect. After three days of genistein administration, the number of type I infiltration foci increased 3.5-fold. Sialoadenectomized mice were more susceptible than controls to endotoxin shock. While 90% of sham-operated mice survived a burst of 100 microg lipopolysaccharide/Kg (combined with D-galactosamine 750 mg/Kg), only 50% of sialoadenectomized mice survived. The surviving sialoadenectomized mice recovered more slowly than the controls, as indicated by the high plasma alanine transaminase activity a week after the burst. We conclude that (i) neutrophils and macrophages participate in the process of apoptotic hepatocyte removal in a sequential manner; (ii) although the alteration of liver structure induced by sialoadenectomy is mild, it has delayed consequences on the ability of the liver to deal with aggressive insults.