In vitro suppression of serum elastase-inhibitory capacity by reactive oxygen species generated by phagocytosing polymorphonuclear leukocytes.

Carp, H.; Janoff, Aaron

doi:10.1172/jci109364

Cited by 271 publications

(100 citation statements)

References 11 publications

(10 reference statements)

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“…The inactivation of ctrproteinase inhibitor might be produced by oxidation of a methionine residue near the proteinase inhibitory site, possibly by oxygen free radicals (23)(24)(25). It is known that oxygen free radicals generated by complement activated neutrophils or other processes are important mediators of tissue injury in a great variety of diseases (26,27).…”

Section: Discussionmentioning

confidence: 99%

Amidolytic and Immuno-Nephelometric Determination of α1-Proteinase Inhibitor and α2-Macroglobulin in Serum with Calculation of Specific Inhibitor Activities in Health and Disease

Gressner¹,

Peltzer²

1984

Clinical Chemistry and Laboratory Medicine

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Summary:In sera of healthy persons (n = 50) and patients with a variety of diseases (n = 197) the two major proteinase inhibitors, αι-proteinase inhibitor (oti-antitrypsin) and ai-macroglobulin, were measured by two methods: a chromogenic (amidolytic) Substrate assay to assess the functional activities, and a laser nephelometric method to determine the immunoreactive concentrations of the respective proteins. The specific proteinase inhibitor activities defined s the number of inhibitor units per g inhibitor protein were calculated.The precision and accuracy of both assays were found to be similar, showing a satisfactory correlation of results for the sera of healthy persons (r ?= 0.916 for cta-macroglobulin and 0.988 for cti-proteinase inhibitor). In diseased individuals the correlation was lower than in normal persons (0.862 for a2-macroglobulin and 0.907 for αϊ-proteinase inhibitor). A poor correlation was obtained in patients with liver diseases (r = 0.586 for αι-proteinase inhibitor and 0.852 for ai-macroglobulin).Reference ranges were established for functional and immunological concentrations and for specific inhibitor activities, respectively. Normal values followed a Gaussian distribution.In patients with various diseases including those with acute phase response, the specific inhibitor activities of ctrproteinase inhibitor re reduced significantly; this is because inhibitor activity shows a smaller relative increase than immunoreactivity. Among the various diseases, no significant differences were noted. The specific inhibitor activity of az-macroglobulin changed significantly only in patients with carcinoma, liver diseases and trauma. Follow up of some patients shows also intraindividual Variation of specific proteinase inhibitor activities. Amidolytische und immun-nephelometrische Bestimmung von a/-Proteinase-Inhibitor und

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Section: Discussionmentioning

confidence: 99%

Amidolytic and Immuno-Nephelometric Determination of α1-Proteinase Inhibitor and α2-Macroglobulin in Serum with Calculation of Specific Inhibitor Activities in Health and Disease

Gressner¹,

Peltzer²

1984

Clinical Chemistry and Laboratory Medicine

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“…The alPI was exposed directly to the gas-phase smoke from one cigarette. The smoke was bubbled through the alPI solutions either immediately after being drawn or after being allowed to age the indicated length of time in the syringe (15 We have shown (9) that NO2 itself does not cause alPI to lose EIC and H202 alone also causes no inactivation (9,65). However, inactivation does occur when NO2 is bubbled into an alPI solution containing 1 mM H202.…”

Section: The Tar Radical(s) In Cigarette Smoke: Esr Studiesmentioning

confidence: 96%

“…(20) could act as a substrate for the myeloperoxidase system of PMN to form, in the presence of chloride anions, hypochlorous acid, a powerful oxidizing agent (63). In vitro studies have shown that methionines in alPI are oxidized and the alPI is inactivated in vitro by all of these oxidants: stimulated PMN preparations (64), a combination of H202 and O2 generated by xanthine oxidase (65), and the myeloperoxidase system (66,67). A second major pathway for cigarette smoke-induced inactivation of alPI is the direct oxidation of alPI by components in the smoke itself.…”

Section: The Tar Radical(s) In Cigarette Smoke: Esr Studiesmentioning

confidence: 99%

Free-Radical Chemistry of Cigarette Smoke and Its Toxicological Implications

Church¹,

Pryor²

1985

Environmental Health Perspectives

330

297

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Cigarette smoke contains two very different populations of free radicals, one in the tar and one in the gas phase. The tar phase contains several relatively stable free radicals; we have identified the principal radical as a quinone/hydroquinone (Q/QH2) complex held in the tarry matrix. We suggest that this Q/QH2 polymer is an active redox system that is capable of reducing molecular oxygen to produce superoxide, eventually leading to hydrogen peroxide and hydroxyl radicals. In addition, we have shown that the principal radical in tar reacts with DNA in vitro, possibly by covalent binding.The gas phase of cigarette smoke contains small oxygen-and carbon-centered radicals that are much more reactive than are the tar-phase radicals. These gas-phase radicals do not arise in the flame, but rather are produced in a steady state by the oxidation of NO to NO2, which then reacts with reactive species in smoke such as isoprene. We suggest that these radicals and the metastable products derived from these radical reactions may be responsible for the inactivation of a,-proteinase inhibitor by fresh smoke.Cigarette smoke oxidizes thiols to disulfides; we suggest the active oxidants are NO and NO2. The effects of smoke on lipid peroxidation are complex, and this is discussed. We also discuss the toxicological implications for the radicals in smoke in terms of a number of radical-mediated disease processes, including emphysema and cancer.

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“…In humans, endogenous antiproteases are known to be inactivated by oxidant generated from stimulated neutrophils [22][23][24][25][26][27]. For instance, ␣ 1 Pi, an endogenous elastase inhibitor that accounts for about 90% of the elastase-inhibitory capacity of human serum [19] and provides most of the protection against neutrophil elastase in the lower respiratory tract [10,20], has been reported to be inactivated by leukocyte-derived oxidants, including superoxide [22], hydrogen peroxide [22], hypochlorous acid [24,26,43], and hydroxyl radical [48].…”

Section: Resultsmentioning

confidence: 99%

“…Given the existence of these powerful antiprotease defenses, it would appear unlikely that elastase could mediate tissue injury. Nevertheless, ␣ 1 Pi is susceptible to oxidant inactivation, resulting in incomplete inhibition of elastase [21][22][23][24][25][26][27]. Therefore, the development of drugs that specifically inhibit elastase and are resistant to oxidant inactivation would unquestionably be valuable therapeutic targets in the management of neutrophilmediated tissue injury at sites of inflammation.…”

Section: Introductionmentioning

confidence: 99%

Effect of trifluoromethyl ketone-based elastase inhibitors on neutrophil function in vitro

Huang

Surichamorn

Cao

et al. 1998

Journal of Leukocyte Biology

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Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous ␣ 1 -proteinase inhibitor (␣ 1 Pi). Nevertheless, under pathological conditions, ␣ 1 Pi is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/␣ 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.

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In vitro suppression of serum elastase-inhibitory capacity by reactive oxygen species generated by phagocytosing polymorphonuclear leukocytes.

Cited by 271 publications

References 11 publications

Amidolytic and Immuno-Nephelometric Determination of α1-Proteinase Inhibitor and α2-Macroglobulin in Serum with Calculation of Specific Inhibitor Activities in Health and Disease

Amidolytic and Immuno-Nephelometric Determination of α1-Proteinase Inhibitor and α2-Macroglobulin in Serum with Calculation of Specific Inhibitor Activities in Health and Disease

Free-Radical Chemistry of Cigarette Smoke and Its Toxicological Implications

Effect of trifluoromethyl ketone-based elastase inhibitors on neutrophil function in vitro

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