Hepatocyte growth factor prevents multiple organ injuries in endotoxemic mice through a heme oxygenase-1-dependent mechanism

Biochem Biophys Res Commun. 2009 Mar 6;380(2):333-7. doi: 10.1016/j.bbrc.2009.01.080. Epub 2009 Jan 24.

Abstract

Acute renal failure (ARF) and acute respiratory distress syndrome (ARDS) are still lethal diseases during sepsis, whereas heme oxygenase-1 (HO-1) elicits a host defense response to sepsis. Herein, we provide evidence that hepatocyte growth factor (HGF) prevents ARF and ARDS via enhanced induction of HO-1. Lipopolysaccharide (LPS)-treated mice manifested renal and pulmonary injuries similar to those observed in septic patients, while HGF enhanced the HO-1 induction in renal tubular cells and in lung macrophages. As a result, onsets of ARF and ARDS were blocked by HGF in septic mice. Notably, an HO-1 inhibitor (SnPP) diminished the protective effects of HGF on LPS-induced organ injuries. Furthermore, the inhibitory effect of HGF on up-regulation of interleukin-1beta and interleukin-18 was largely restored by SnPP. This is the first report showing that "growth factor therapy" successfully inhibits both ARDS and ARF during endotoxemia, partially via HO-1-dependent suppression of hyper-cytokinemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / immunology*
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control
  • Animals
  • Disease Models, Animal
  • Endotoxemia / complications*
  • Female
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / metabolism*
  • Hepatocyte Growth Factor / pharmacology
  • Hepatocyte Growth Factor / physiology*
  • Hepatocyte Growth Factor / therapeutic use
  • Humans
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Kidney Tubules / drug effects
  • Kidney Tubules / immunology
  • Kidney Tubules / pathology
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Macrophages, Alveolar / immunology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / metabolism*
  • Metalloporphyrins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Multiple Organ Failure / etiology
  • Multiple Organ Failure / immunology*
  • Multiple Organ Failure / pathology
  • Multiple Organ Failure / prevention & control
  • Protoporphyrins / pharmacology
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Respiratory Distress Syndrome / etiology
  • Respiratory Distress Syndrome / immunology*
  • Respiratory Distress Syndrome / pathology
  • Respiratory Distress Syndrome / prevention & control
  • Systemic Inflammatory Response Syndrome / etiology
  • Systemic Inflammatory Response Syndrome / immunology

Substances

  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • Membrane Proteins
  • Metalloporphyrins
  • Protoporphyrins
  • Recombinant Proteins
  • Hepatocyte Growth Factor
  • tin protoporphyrin IX
  • Heme Oxygenase-1
  • Hmox1 protein, mouse