A neutrophil-dependent pathway for the generation of a neutral peptide mediator: partial characterization of components and control by alpha-1-antitrypsin.
A biologically active neutral peptide mediator is cleaved from a plasma protein substrate by an alpha-1-antitrypsin-inhibitable serine protease apparently residing on the membrane of the human neutrophil. The peptide mediator has an approximate mol wt of 1,000, and is distinguished from the kinin peptides by a neutral isoelectric point, susceptibility to inactivation by trypsin as well as chymotrypsin and activity on the isolated, atropinized, and antihistamine-treated guinea pig ileum with relatively little action on the estrous rat uterus. The neutrophil protease is fully inhibitable by DFP, trypsin inhibitors from lima or soy bean, and alpha-1-antitrypsin and is associated with the high mol wt fragments of the neutrophil and not the nuclear, lysosomal, or cytoplasmic subcellular fraction. The substrate has an approximate mol wt of 90,000 and is chromatographically separable from kininogen. The exquisite sensitivity of the neutrophil protease to alpha-1-antitrypsin was established both by inhibition with highly purified alpha-1-antitrypsin and by the inability of the protease to generate detectable neutral peptide in a homozygous (ZZ) alpha-1-antitrypsin-deficient patient without heat inactivation of the residual inhibitor. On the other hand, plasma from a (null) alpha-1-antitrypsin-deficient patient supported neutral peptide generation and revealed an additional factor which inactivated neutral peptide.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001920:Bradykinin / Q000037:antagonists & inhibitors; D002850:Chromatography, Gel; D002918:Chymotrypsin / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007525:Isoelectric Focusing; D007704:Kininogens / Q000032:analysis; D007705:Kinins / Q000032:analysis; D009119:Muscle Contraction / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000097:blood* / Q000494:pharmacology; D011480:Protease Inhibitors; D013347:Subcellular Fractions / Q000201:enzymology; D014357:Trypsin / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
D001798:Blood Proteins; D007704:Kininogens; D007705:Kinins; D010455:Peptides; D011480:Protease Inhibitors; D000515:alpha 1-Antitrypsin; D010450:Endopeptidases; D002918:Chymotrypsin; D014357:Trypsin; D001920:Bradykinin