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Effect of trifluoromethyl ketone‐based elastase inhibitors on neutrophil function in vitro
Author(s) -
Huang YuIng,
Surichamorn Wanida,
Cao GuanLiang,
Meng Min,
Pou Sovitj,
Rosen Gerald M.,
Salcedo Theodora W.,
Strimpler Anne,
Veale Chris,
Bernstein Peter R.,
Bonuccelli Catherine M.
Publication year - 1998
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.64.3.322
Subject(s) - elastase , superoxide , myeloperoxidase , phagocytosis , neutrophil elastase , in vitro , pancreatic elastase , microbiology and biotechnology , inflammation , neutrophil extracellular traps , hypochlorous acid , biology , immunology , chemistry , pharmacology , biochemistry , enzyme
Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous α 1 ‐proteinase inhibitor (α 1 Pi). Nevertheless, under pathological conditions, α 1 Pi is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/α 1 Pi imbalance has been implicated as a pathogenic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema. Elastase inhibitors, which do not interfere with the microbicidal activity of neutrophils and are resistant to neutrophil‐released oxidants, would undoubtedly represent an important advance in the management of neutrophil‐mediated tissue injury. We report that a new family of elastase inhibitors ICI200355 and ZD0892 was found to be resistant toward superoxide, hypochlorous acid, hydrogen peroxide, hydroxyl radical, and peroxynitrite mediated degradation as well as having no effect on the formation of these oxidants by activated neutrophils. More importantly, we found that these inhibitors did not interfere with the ability of human neutrophils to phagocytose and to kill Staphylococcus aureus . In conclusion, a new potent class of elastase inhibitors, while blocking the effects of neutrophil elastase, was found not to impede various physiological functions of human neutrophils, in particular the ability of these phagocytic cells to phagocytose and kill bacteria. J. Leukoc. Biol . 64: 322–330; 1998.