Heme oxygenase-1 inhibitor tin-protoporphyrin improves liver regeneration after partial hepatectomy

Aims: This study investigates the effects of the heme oxygenase-1 (HO-1) inhibitor tin protoporphyrin IX (SnPP), on rat liver regeneration following 2/3 partial hepatectomy (PH) in order to clarify the controversial role of HO-1 in the regulation of cellular growth. Main methods: Male Wistar rats received a subcutaneous injection of either SnPP (10 mu moles/kg body weight) or saline 12 h before PH and 0, 12 and 24 h after surgery. Rats were killed from 0.5 to 36 h after PH. Bromodeoxyuridine (BrdU) incorporation was used to analyze cell proliferation. Immunohistochemistry, Western blot analysis and quantitative Real Time-PCR were used to assess molecular and cellular changes after PH. Key findings: Data obtained have shown that administration of SnPP caused an increased entry of hepatocytes into S phase after PH, as demonstrated by labeling (L.I.) and mitotic (M.I.) indexes. Furthermore, enhanced cell cycle entry in PH-animals pre-treated with SnPP was associated with an earlier activation of IL-6 and transcription factors involved in liver regeneration, such as phospho-JNK and phospho-STAT3. Significance: Summarizing, data here reported demonstrate that inhibition of HO-1 enhances rat liver regeneration after PH which is associated to a very rapid increase in the levels of inflammatory mediators such as IL-6, phopsho-JNK and phospho-STAT3, suggesting that HO-1 could act as a negative modulator of liver regeneration. Knowledge about the mechanisms of liver regeneration can be applied to clinical problems caused by delayed liver growth, and HO-1 repression may be a mechanism by which cells can faster proliferate in response to tissue damage.