Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy

Abstract

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.

Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

“…Gelatin zymography was performed with extracted proteins from the liver (50 g) as previously described. 9 Quantitative Real-Time Reverse-Transcriptase Polymerase Chain Reaction. Extracted RNA from the liver and the isolated cells was reverse-transcribed, and quantitative real-time polymerase chain reaction with probe-primers sets of SphK1, TIMP-1, and 18S ribosomal RNA (Applied Biosystems, Foster City, CA) was performed using Taqman analysis (ABI Prism 7000 Sequence Detection System, Applied Biosystems).…”

“…9 Although pro-and antiapoptotic mechanisms of apoptosis have been demonstrated, mechanisms of liver hemorrhage are not well understood.…”

TIMP3 checks inflammation

“…Consistent with this in vitro activity, TIMP3 blocks the release of TNF from cells in tissue culture 12 . TNF is a key inflammatory mediator that causes severe liver damage by a variety of mechanisms 13 (Fig. 1).…”

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

“…Unfortunately, TNF also possesses strong proinflammatory properties, and its use is often accompanied by unacceptable shock symptoms, such as hypotension and organ failure (2)(3)(4). Initial studies in patients showed that the maximum tolerated dose (MTD) that can be applied systemically in humans is too low for effective tumor therapy (5).…”