Hepatocyte growth factor prevents multiple organ injuries in endotoxemic mice through a heme oxygenase-1-dependent mechanism.
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.
Kamimoto
Miyuki
M
Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, 2-2-B7 Yamadaoka, Suita, Osaka 565-0871, Japan.
Mizuno
Shinya
S
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
D058186:Acute Kidney Injury / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications*; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D011524:Protoporphyrins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000276:immunology
D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008665:Metalloporphyrins; D011524:Protoporphyrins; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse