Inhibition of matrix metalloproteinases by chemically modified tetracyclines in sepsis.
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.
Maitra
Subir R
SR
Department of Emergency Medicine and Surgery, School of Medicine, State University of New York, Stony Brook, New York 11794-7400, USA. smaitra@notes.mL.sunysb.edu
Bhaduri
Sikha
S
Valane
Patrick D
PD
Tervahartiala
Taina
T
Sorsa
Timo
T
Ramamurthy
Nungavarm
N
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D005109:Extracellular Matrix / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D010949:Plasma / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology*; D012772:Shock, Septic; D012965:Sodium Chloride / Q000494:pharmacology; D013754:Tetracyclines / Q000494:pharmacology*; D013997:Time Factors
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009566:Nitrates; D013754:Tetracyclines; C117155:tetracycline CMT-3; D009569:Nitric Oxide; D012965:Sodium Chloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D018093:Gelatinases; D020782:Matrix Metalloproteinases