Comparison of live human neutrophil and alveolar macrophage elastolytic activity in vitro. Relative resistance of macrophage elastolytic activity to serum and alveolar proteinase inhibitors.

Abstract

Again in serum-free media, neutrophils degraded eightfold more elastin than macrophages but only macrophages degraded sepharose-coupled elastin in the presence of 10% serum. Because of these findings, we compared the enzymatic mechanisms of elastin breakdown by macrophages with that of neutrophils. Macrophage elastolytic activity is largely (65-80%) due to a cysteine proteinase(s), at least part of which is Cathepsin B. Approximately half of the cysteine proteinase activity appeared to be expressed at or near the cell surface.

Plasma levels of elastase-specific fibrinopeptides correlate with proteinase inhibitor phenotype. Evidence for increased elastase activity in subjects with homozygous and heterozygous deficiency of alpha 1-proteinase inhibitor.

“…Support for this concept comes from the results of in vitro studies which demonstrate that the inactivation of HNE in the pericellular microenvironment of neutrophils and monocytes requires substantially higher concentrations of aI-proteinase inhibitor than those needed to inactivate free enzyme (7)(8)(9)(10)(11)(12)(13)(14)(15). These findings have led to the suggestion that the proteolytic activity of HNE is confined to the vicinity ofinflammatory cells.…”

“…In the past, it has been difficult to evaluate HNE activity in vivo because the enzyme rapidly binds to its substrates or its inhibitors (3), and because pathogenetically important HNE activity may be confined to localized microenvironments within tissues (7)(8)(9)(10)(11)(12)(13)(14)(15). Recently, we have developed an assay for in vivo HNE activity based on the unique capacity of the enzyme to cleave the Aa2 1 (Val)-Aa22 (Glu) bond on the aminoterminal region of the Aa-chain of fibrinogen (16).…”

“…Hydrolysis of this bond results in release of the fibrinopeptide A-containing fragment Aa 1-21. The original radioimmunoassay for the quantification of Aa 1-21 was indirect (17), and used a specific antiserum against fibrinopeptide A (FPA or Aa [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. This antiserum has its antigenic determinant at the carboxy-terminal region ofthe FPA molecule (17)(18)(19)(20).…”

Cystatin C deficiency in human atherosclerosis and aortic aneurysms

“…Prior studies documenting the capacity of macrophages to use cysteine proteases to degrade elastin found macrophage elastolytic activity to be insensitive to the presence of pericellular serum protease inhibitors (10,28). These findings raise questions as to whether, in spite of the marked reduction of cystatin C in atherosclerotic and aneurysmal lesions and the clinical correlation (Figures 1-3), cystatin C can actually regulate vessel wall matrix remodeling by vascular cells.…”

Emerging Roles for Cysteine Proteases in Human Biology

“…As such, cathepsin K, as well as cathepsins S and L, is also a potent collagenase and gelatinase. Expression of cathepsin K has recently been correlated with a degradative phenotype of macrophages (33,65). Freshly explanted monocytic cells exhibit almost no cathepsin K mRNA.…”