shTACE/rPOA를 이용한 LPS로 유도된 급성 호흡기질환의 유전자 치료

Abstract

TNF-α converting enzyme(TACE, also known as ADAM17) is a disintegrin and metalloprotease. TACE is known to be involved in processing of proTNF-α in cell membrane into soluble form TNF α. TNF-α, released by TACE, is related in many kind of pathophysiology. Membrane associated proTNF-αstill can serve as a ligand for TNF receptors and to activate lymphocytes, affect cellular cytotoxicity, enhance prostaglandin release, and up regulate adhesion molecules. Therefore targeting soluble TNF via TACE inhibition instead directly down regulate proTNF has advantages in controlling inflammatory disease. In this report, we examined of gene therapy to determine whether TACE shRNA could efficiently down regulating the LPS induced inflammation in vivo. TACE shRNA was conjugated to reducible poly(oligo-D-arginine)(rPOA). The rPOA facilitates the TACE shRNA delivery both in vitro and in vivo. Especially,treatment of rPOA/shTACE decreasedneutrophils and total cell concentrations in bronchoalveolarlavage(BAL)fluid. Also the treatment reduced activation of TNF-α and number of inflammatory cells in lung tissue. In conclusion, silencing TACE with rPOA effectively down regulated the TACE expression in vitro and in vivo, and it reduced the airway inflammation in inflammatory disease such as acute lung injury.