Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro.
Oxidants derived from the atmosphere or from activated pulmonary phagocytes mediate functional inactivation of alpha-1-protease inhibitor (alpha-1-PI). Chronic exposure to these oxidants may cause emphysema. In this study we have investigated the effects of the antioxidants ascorbate, cysteine (10(-4) M to 10(-1) M), and dapsone (10(-6) M to 10(-3) M) on the oxidative inactivation of human alpha-1-PI by leukoattractant-activated polymorphonuclear leukocytes (PMNL) in vitro. During exposure of alpha-1-PI to stimulated PMNL in the presence of ascorbate and cysteine at concentrations of greater than 10(-4) M and dapsone at greater than 10(-6) M, the elastase inhibitory activity of alpha-1-PI was preserved. However, exposure of the alpha-1-PI to the antioxidants subsequent to PMNL-mediated oxidative inactivation was not associated with reactivation of elastase inhibitory capacity. Ascorbate, cysteine, and dapsone at concentrations that caused 50% protection of alpha-1-PI did not affect degranulation or the binding of radiolabeled leukoattractant to PMNL. It is suggested that the protective effects of the antioxidants are related to their ability to scavenge superoxide and oxidants generated by the PMNL-myeloperoxidase/H2O2/halide system. Because the effects of ascorbate and especially those of dapsone were observed at concentrations of these agents that are attainable in vivo, our results may have clinical significance.
D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001798:Blood Proteins / Q000037:antagonists & inhibitors*; D003545:Cysteine / Q000494:pharmacology*; D003622:Dapsone / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D010084:Oxidation-Reduction; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000037:antagonists & inhibitors; D010586:Phagocytes / Q000187:drug effects*; D012907:Smoking; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000502:physiology; D000515:alpha 1-Antitrypsin
D000975:Antioxidants; D001798:Blood Proteins; D000515:alpha 1-Antitrypsin; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003622:Dapsone; D009195:Peroxidase; D014969:Xanthine Oxidase; D010196:Pancreatic Elastase; D003545:Cysteine; D001205:Ascorbic Acid