Antisense inhibition of secretory and cytosolic phospholipase A2 reduces the mortality in rats with sepsis*
Abstract
Phospholipase A(2) has been implicated to play a pivotal role in the pathogenesis of sepsis syndrome. The two major forms of phospholipase A(2) isoenzymes, secretory phospholipase A(2) and cytosolic phospholipase A(2), are overexpressed during sepsis. The objective of this study was to test the hypothesis that inhibition of the overexpressed secretory phospholipase A(2) and cytosolic phospholipase A(2) during sepsis benefits the disease's eventual outcome. Short-chain antisense oligonucleotide molecules were designed with the aid of computer software programs, and their in vitro efficacies were assessed in cell culture systems based on inhibition of target protein expression. The in vivo efficacies were determined in intact sepsis rats using 35-day survival rate as a primary efficacy end point. Animal research laboratory at a university. Male Sprague-Dawley rats (180-200 g). Sepsis was induced by cecal ligation and puncture. Antibiotics were administered subcutaneously once daily at 12 mg/kg, for 20 days. Oligonucleotides (antisense or mismatch) were administered intravenously once daily at 2 mg/kg to 0.8 mg/kg in a decreasing order, for 20 days. In cell culture systems, 21 of the 105 antisense constructs were found to be effic...Continue Reading
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