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Lipocalin‐2 (LCN2) was originally isolated from human neutrophils and termed neutrophil gelatinase‐associated lipocalin (NGAL). However, the functions of LCN2 and the cell types that are primarily responsible for LCN2 production remain unclear. To address these issues, hepatocyte‐specific Lcn2 knockout (Lcn2^Hep–/–) mice were generated and subjected to bacterial infection (with Klesbsiella pneumoniae or Escherichia coli) or partial hepatectomy (PHx). Studies of Lcn2^Hep–/– mice revealed that hepatocytes contributed to 25% of the low basal serum level of LCN2 protein (∼62 ng/mL) but were responsible for more than 90% of the highly elevated serum LCN2 protein level (∼6,000 ng/mL) postinfection and more than 60% post‐PHx (∼700 ng/mL). Interestingly, both Lcn2^Hep–/– and global Lcn2 knockout (Lcn2^–/–) mice demonstrated comparable increases in susceptibility to infection with K. pneumoniae or …