A combination of proteasome inhibitors and antibiotics prevents lethality in a septic shock model.
Our recent studies with lactacystin, a prototype proteasome inhibitor, have suggested that the proteasome is a key regulator of LPS-induced signaling pathways contributing to the inflammatory process. Moreover, lactacystin protects animals from LPS-induced shock. Therefore, we sought to identify other less toxic compounds that would block the chymotrypsin-like activity of the proteasome or LPS-induced nitric oxide (NO). After screening over 100 natural compounds (based on chemistry and inhibition of LPS-induced biological activities), we now report for the first time that quercetin, like lactacystin (the prototype proteasome inhibitor), and mevinolin are also inhibitors of the chymotrypsin-like activity of the cellular proteasome within living cells. In addition, this study also suggests that mevinolin and quercetin both have relatively potent anti-inflammatory effects on LPS-treated macrophages in vitro. Interestingly, both of these compounds behave like lactacystin in that they block LPS-induced NO to a greater extent than TNF-alpha. The results of our experiments clearly suggest that mevinolin, in combination with the antibiotic imipenem, can provide protection against polymicrobial septic lethality induced by cecal-ligation and puncture in mice. Collectively, these studies strongly support the conclusion that therapeutic targeting of cellular proteasomes, in conjunction with standard antimicrobial therapy, may be of considerable survival benefit in the treatment of septic shock.
Reis
Julia
J
Departments of Basic Medical Science, Pharmacology/Toxicology, Surgery, and Shock/Trauma Research Center, University of Missouri-Kansas City, Kansas City Missouri, USA.
Tan
Xiaoyu
X
Yang
Rongjie
R
Rockwell
Cheryl E
CE
Papasian
Christopher J
CJ
Vogel
Stefanie N
SN
Morrison
David C
DC
Qureshi
Asaf A
AA
Qureshi
Nilofer
N
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015378:Imipenem / Q000737:chemistry / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000276:immunology; D008148:Lovastatin / Q000737:chemistry / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009569:Nitric Oxide / Q000032:analysis / Q000276:immunology; D061988:Proteasome Inhibitors; D011794:Quercetin / Q000737:chemistry / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015378:Imipenem; D011794:Quercetin; D008148:Lovastatin