Lysosomal Enzymes in Human Urine: Evidence for Polymorphonuclear Leucocyte Proteinase Involvement in the Pathogenesis of Human Glomerulonephritis

Abstract

Clinical Science and Molecular Medicine (1978), 54,667-672 Summary 1. Lysosomal proteinase activity was assayed in human cadaver kidney, urine, granules from poly morphonuclear leucocytes of normal persons, and urine samples from 154 patients with renal disease.2. Granules from polymorphonuclear leuco cytes showed proteinase activity at acid and neutral pH, whereas cadaver kidney showed proteinase activity at acid pH only.3. The urine from 13 patients with glomerulo nephritis showed proteinase activity at both acid and neutral pH as well as increased amounts of antigenic glomerular basement membrane frag ments. The properties of the urinary proteinases suggested that they had originated in polymorpho nuclear leucocytes.4. Only the urine samples containing these proteinases were capable of degrading isolated human glomerular basement membrane in vitro.5. Clinical recovery, where it occurred, was ac companied by the disappearance of urinary proteinase activity, and reduction in glomerular basement membrane antigen excretion.

Oxidative regulation of neutrophil elastase-alpha-1-proteinase inhibitor interactions.

“…fluids have been shown to contain free neutrophil elastase activity (for recent examples see References [5][6][7][8][9][10][11][12][13][14][15][16]. In association with these findings, analyses of the ac-l-PI status in these pathologic samples revealed the presence of uncomplexed, inactive, and proteolyzed antiproteinase (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…Although other oxidant sources (i.e., hyperoxia, cigarette smoke, or environmental pollutants; e.g., see References 8,73, and 74) and other proteinases (leukocyte or bacterial; references 17-19 and 75) may also contribute to this scheme, it seems clear that triggered neutrophils alone can directly mediate all of these effects. The ability of the neutrophil to release active elastase in the presence of a-1-PI could be useful in physiologic events such as fibrinolysis, wound healing, or host defense, but under pathological conditions, the indiscriminant release of unregulated elastase could exert powerful and longlasting proinflammatory effects (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Finally, these data lend support to our premise that chlorinated oxidants may play a more general role in controlling proteinase activity (76).…”

“…The detection of active neutrophil elastase and modified a-I -PI in tissues and fluids recovered from inflammatory sites is thought to represent a critical component in the pathogenesis of tissue damage (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) (5)(6)(7)(20)(21)(22). Oxidized a-1-PI is completely unable to inhibit PPE, but retains considerable inhibitory activity for neutrophil elastase (3,25).…”

“…In association with these findings, analyses of the ac-l-PI status in these pathologic samples revealed the presence of uncomplexed, inactive, and proteolyzed antiproteinase (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Because the loss of a-l-PI function represents a pivotal step in the pathogenesis ofelastasemediated damage, increasing attention has focused on the identification of those processes capable of inactivating the antiproteinase.…”

Degradation of human glomerular basement membrane by stimulated neutrophils. Activation of a metalloproteinase(s) by reactive oxygen metabolites.

“…It is generally accepted that leukocytes cause proteinuria by damaging the glomerular basement membrane (GBM),I which serves as the major ultrafiltration barrier to restrict the entry of proteins into the urinary space. Indeed, increased excretion of GBM fragments in urine has been observed in a variety of human and experimental glomerular diseases (1,3,5). Apparently even subtle damage to the GBM, composed primarily of type IV collagen, noncollagenous glycoproteins, and glycosaminoglycans, is sufficient to cause marked alteration in its function (3).…”