The drug 5-aminosalicylic acid rescues alpha 1-proteinase inhibitor from the neutrophil oxidative inactivation. A possible contribution to its therapeutic action in ulcerative colitis.
The glycoprotein alpha 1-proteinase inhibitor is the specific inhibitor of neutrophil elastase, a major tissue-damaging protease. When incubated with activated neutrophils, alpha 1-proteinase inhibitor lost its pancreatic porcine elastase inhibitory capacity and became incapable of forming a sodium dodecyl sulphate-stable complex with pancreatic porcine elastase. Inhibitors and scavengers of neutrophil-derived reactive oxygen species outlined the crucial role of hypochlorous acid in the alpha 1-proteinase inhibitor inactivation. Moreover, the drug 5-aminosalicylic acid prevented the inactivation of alpha 1-proteinase inhibitor by neutrophils in a dose-dependent manner. Finally, when the capacity of 5-aminosalicylic acid to rescue alpha 1-proteinase inhibitor from the neutrophil-derived attack was plotted as a function of the 5-aminosalicylic acid ability to scavenge neutrophil-derived hypochlorous acid, a positive linear relationship was found. Thus, our results provide a direct evidence that 5-aminosalicylic acid is able to prevent the oxidative inactivation of alpha 1-proteinase inhibitor by neutrophils. Therefore, we suggest that the drug has the potential to limit the elastase-mediated damage of colonic connective tissue by creating a microenvironment of active alpha 1-proteinase inhibitor around the neutrophils.
Ottonello
L
L
Department of Internal Medicine, University of Genova Medical School, Italy.
Dapino
P
P
Pastorino
G
G
Vitale
E
E
Dallegri
F
F
D000636:Aminosalicylic Acids / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000188:drug therapy; D006801:Humans; D008297:Male; D019804:Mesalamine; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D000636:Aminosalicylic Acids; D000515:alpha 1-Antitrypsin; D019804:Mesalamine