Sepsis precipitates a systemic inflammatory stimulus that causes systemic release of
cytokines and sequestration of polymorphonuclear neutrophils, resulting in degranulation of
matrix metalloproteinases (
MMPs), which causes extracellular matrix basement membrane degradation. One of the important anti-inflammatory properties of
tetracyclines is their ability to inhibit
MMPs. In this study, we focused on the regulation of
MMPs in
sepsis and their reduction by treatment with nonantimicrobial chemically modified
tetracyclines (CMTs), which retain their anti-inflammatory activity.
Sepsis was induced by cecal
ligation and
puncture (CLP) method. At 24 h and 1 h before CLP, some rats received
CMT-3 (25 mg/kg), another group of rats received hydroxamate (H; an inhibitor of
MMP; 25 mg/kg), and untreated rats received saline by gavage. At 0 h, 0.5 h, 1.5 h, and 24 h after CLP, blood and liver samples were collected. Plasma and liver MMP-9 by zymography and Western immunoblotting, plasma
nitric oxide by measuring
nitrate level, plasma
glutamic oxaloacetic transaminase (GOT) and
glutamic pyruvic transaminase (GPT) by enzymatic method, and liver
gelatinase by radiolabeled
gelatin lysis assay and 24 h mortality were determined. Plasma MMP-9 (92 kDa),
nitrate, and GOT and GPT levels were elevated compared with the time 0 level and reached peak at 1.5 h CLP and remained high for 24 h. Both
CMT-3 and H treatment reduced GOT,GPT,
92-kDa gelatinase, and
nitrate levels throughout the 24 h.
CMT-3 and H are equally effective in
sepsis treatment. The 24-h mortality for CLP rats was 30%, whereas pretreatment with
CMT-3 and H resulted in 0% mortality. Hepatic MMP-9 and
gelatinase activity increased significantly after CLP, and pretreatment with
CMT-3 and H inhibited these expressions. These results indicate the beneficial effect of
CMT-3 in preventing the increase in GOT, GPT, NO, MMP-9,
gelatinase activity, and the ensuing
septic shock.