Stimulation of human leukocyte elastase by platelet factor 4. Physiologic, morphologic, and biochemical effects on hamster lungs in vitro.

Abstract

A B S T R A C T The purpose of this study was to determine if human platelet factor 4 (PF4) stimulates human leukocyte elastase (HLE) against lung elastin. Lung elastin was purified from hamster lungs and tritiated by reduction with NaB3H4. We found that HLE activity against this substrate is increased by concentrations of PF4 as low as 1.6 ,ugml, and that this stimulation increased linearly with additional PF4. Lungs removed from hamnsters and inflated with solutions containing buffer alone, low dose HLE, HLE plus PF4, or PF4 alone were incubated for 2 h at 370C. Whereas low-dose HLE failed to lower lung elastin when compared to control animals, HLE stimulated by PF4 lowered lung elastin by 20%. PF4 alone had no effect. Furthermore, low-dose HLE failed to alter the mechanical properties ofhamster lungs as measured by pressure-volume curves in saline, although there was a significant loss of lung elasticity in the mid-and highlung volume ranges in lungs treated with HLE and PF4. Morphologic studies revealed that low dose HLE resulted in a minimal emphysemalike lesion whereas HLE plus PF4 caused a significantly more severe lesion. PF4 is capable of stimulating HLE against lung elastin, and this effect may have a role in the pathogenesis of emphysema.

Enhancement of granulocyte-endothelial cell adherence and granulocyte-induced cytotoxicity by platelet release products.

“…That other platelet constituents also may interact with granulocytes and render them more cytotoxic has not been excluded and may be important. For instance, platelets amplify granulocyte adherence to nylon fibers (23), and others have shown platelet Factor IV can increase the activity of granulocyte proteases such as elastase (24). Moreover, evidence has been provided that thrombin-stimulated but not resting platelets (in the presence of endotoxin) enhance granulocyte adherence to nylon fibers (25), further implicating constituents ofthe platelet-release reaction in granulocyte function.…”

Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters.

“…The cationic agents, which include platelet factor 4 (PF4) and histones, probably act by occupying anionic, nonproductive sites and thus directing HLE activity to productive binding sites such as alanine or valine residues (34). Indeed, studies have shown that PF4 can potentiate HLE-induced emphysema (35). While additional studies are needed, it is unlikely that PF4 would have a similar influence on PR-3 because of its substantially lower pl.…”

Stimulation of histamine release from human basophils by human platelet factor 4.

“…Some previously defined functions of PF4, including modulation of the activity of collagenase and elastase (13,14) and stimulation of PMN leukocyte and monocyte chemotaxis (15), appear to result from one or more complex molecular and cellular events. Other functions of PF4, such as the binding and neutralization of heparin (16), are determined largely by charge interactions.…”