Mediators of Inflammation in Leukocyte Lysosomes

Abstract

Past studies have focused attention on the lysosomal proteinases of polymorphonuclear leukocytes (PMN) as mediators of vascular injury (1-6). A specific association between the hydrolases in these ceils and selected targets in vessel wails was suggested by Cochrane and Aiken, who showed that acid-cathepsins D and E extracted from rabbit PMN granules could digest vascular basement membrane in vitro (5). As pointed out by these same authors, acid-cathepsinmediated vessel damage presupposes significant lowering of local pH. It remains to be determined whether sufficient acidity can be maintained at the tissueblood interface to permit such reactions to occur in vivo.Recently, evidence has appeared of vascular damage by leukocyte proteinases with neutral pH optima. A neutral mucoproteinase has been detected in rabbit PMN granules (7), and neutral proteinases have been purified from Arthus edema fluid in this species (8). Human neutrophiles are also known to contain neutral proteolytic activity or "leukoprotease" (9-12). We recently reported that extracts of human PMN granules could degrade vascular basement membrane at physiological pH in vitro and in vivo (6). Indeed, a neutral collagenase has been found in human PMN granules (13) and may be responsible for the lysis of vascular basement membranes occurring at physiological pH.The present studies were undertaken to examine the neutral proteinases of human neutrophilic leukocytes for possible activity against elastin. This sialoprotein comprises the elastic lamina and supportive fibers present in the walls of arterial and major venous blood vessels. Such activity, if present, would help account for the development of arterial lesions in PMN-mediated arteritis.Our results show that the granules of human PMN contain neutral elastinolyric activity which can be separated from the collagenolytic activity present in these cells. The data also demonstrate that the properties of elastolysis

Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease

“…The expression levels of several serine proteases, such as uPA, human kallikreins 3 and 10 have been reported to be associated with a poor relapse-free and/or overall survival in patients with primary breast cancer. Since the serine protease PMN-E is the only neutral protease that is able to degrade insoluble elastin (Janoff and Schere, 1968;Baugh and Travis, 1976), which is a structural component of breast tissues (Hornebeck et al, 1977), we considered it of interest to study the clinical relevance of PMN-E in breast cancer. Analogous to other serine proteases, the tumour level of PMN-E was also shown to be able to discriminate between primary breast cancer patients with high and low risk of recurrence (Yamashita et al, 1994(Yamashita et al, , 1995b, irrespective of whether adjuvant tamoxifen treatment was given (Yamashita et al, 1995a).…”

“…In contrast to their attributed role in exterminating the tumour, recruited inflammatory cells have been reported to be associated with tumour progression as well (Scholl et al, 1994;Yamashita et al, 1994Yamashita et al, , 1996Shamamian et al, 2000Shamamian et al, , 2001. The responsible protease is thought to be PMN-elastase (PMN-E), a serine protease that can degrade various components of the extracellular matrix directly (Janoff and Schere, 1968;Mainardi et al, 1980;McDonald and Kelley, 1980;Barrett, 1981), or indirectly through either the activation of other proteases (Machovich and Owen, 1990;Shamamian et al, 2001) or the inactivation of their inhibitors (Levin and Santell, 1987;Gramse et al, 1984;Wu et al, 1995). Furthermore, it has been shown that PMN-E is not only produced by neutrophils but by human breast cancer cells as well (Kao and Stern, 1986;Yamashita et al, 1994), and moreover can promote the adhesion of tumour cells to vascular endothelial cells facilitating its role in tumour metastasis (Nozawa et al, 2000).…”

Degradation of cartilage proteoglycan by human leukocyte granule neutral proteases--a model of joint injury. II. Degradation of isolated bovine nasal cartilage proteoglycan.

“…PGS was dissolved in 0.4 M NaOH and kept at room temperature for 24 h. After neutralization with dilute HCl and dialysis against distilled water, the free chondroitin sulfate chains were isolated by DEAE-cellulose chromatography, as described previously (13 PMN granule enzymes and inhibitors. The preparation of G and the isolation of E and CT and their properties have been described in detail previously (15)(16)(17). The activity of the preparation of E used in these studies on tertiary-butyloxyl-carbamyl L-alanine paranitrophenyl ester was 6.9 /umol/min/mg protein, and the activity of the CT preparation on benzoyl tyrosine ethyl ester was 11.0 /hmol/ min/mg protein.…”

Targeting neutrophil elastase in cystic fibrosis

“…Work from Campbell's group looked at the function of NE as regards quantum proteolysis The term neutrophil elastase is partly a misnomer as not only does NE degrade elastin but also degrades almost all extracellular matrix and key plasma proteins. NE has broad substrate specificity and is capable of degrading a wide range of extracellular matrix proteins including elastin, collagen (types I-IV), fibronectin, laminin, and proteolglycans [33][34][35][36][37]. Other extracellular matrix proteins degraded include platelet IIb/IIIa receptor, complement receptor, thrombomodulin, lung surfactant, and cadherins [38][39][40][41][42].…”