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

• Published in: Life sciences (1973) Vol. 204; pp. 9 - 14
• Main Authors: Pibiri, Monica, Leoni, Vera Piera, Atzori, Luigi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2018; Elsevier BV
• Subjects: Animals; Body weight; Bromodeoxyuridine; Cell cycle; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cytokines; Enzyme Inhibitors - pharmacology; Heme; Heme oxygenase; Heme oxygenase (decyclizing); Heme Oxygenase-1 - antagonists & inhibitors; Hepatectomy; Hepatocytes; Hepatocytes - drug effects; Immunohistochemistry; Inflammation; Inhibitors; Interleukin 6; Interleukin-6 - metabolism; Laboratory animals; Liver; Liver diseases; Liver regeneration; Liver Regeneration - drug effects; Male; Metalloporphyrins - pharmacology; Oxygenase; Polymerase chain reaction; Protoporphyrin; Protoporphyrin IX; Protoporphyrins - pharmacology; Rats; Rats, Wistar; Regeneration; S phase; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Surgery; Tin; Tin protoporphyrin; Tin protoporphyrin IX; Transcription activation; Transcription factors; Tin protoporphyrin IX; Liver regeneration; Heme oxygenase
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2018.05.011

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. Male Wistar rats received a subcutaneous injection of either SnPP (10 μmoles/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. 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. 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.