EFFECT OF TRIFLUOROMETHYL KETONE-BASED ELASTASE INHIBITORS ON NEUTROPHIL FUNCTION IN-VITRO

Neutrophils release elastase, which is known secondarily to cause tiss ue damage. However, it is rapidly inactivated by the endogenous alpha( 1)-proteinase inhibitor (alpha(1)Pi). Nevertheless, under pathological conditions, alpha(1)Pi is inactivated by oxidants released from neutr ophils, resulting in an excess of elastase at the site of inflammation , This elastase/alpha(1)Pi imbalance has been implicated as a pathogen ic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema, Elastase inhibitors, which do not interfere with the micro bicidal activity of neutrophils and are resistant to neutrophil-releas ed oxidants, would undoubtedly represent an important advance in the m anagement of neutrophil-mediated tissue injury. We report that a new f amily of elastase inhibitors ICI200355 and ZD0892 Tvas found to be res istant toward superoxide, hypochlorous acid, hydrogen peroxide, hydrox yl radical, and peroxynitrite mediated degradation as well as having n o effect on the formation of these oxidants by activated neutrophils, More importantly, we found that these inhibitors did not interfere wit h the ability of hunan neutrophils to phagocytose and to kill Staphylo coccus aureus. In conclusion, a new potent class of elastase inhibitor s, while blocking the effects of neutrophil elastase, was found not to impede various physiological functions of human neutrophils, in parti cular the ability of these phagocytic cells to phagocytose and kill ba cteria.