Mediators of Inflammation in Leukocyte Lysosomes

Abstract

The vascular permeability-increasing action of rabbit PMNL lysosomes has been studied in skin and cremaster muscle of the rat. Both an extract of frozen-thawed granules and a cathepsin-free cationic protein fraction of the granules (which had previously been demonstrated to cause leukocyte adhesion and emigration in vivo) induce increased vascular permeability in skin and muscle which resembles that produced by histamine or histamine-liberators with respect to the timing of the response and the predominant type of microvessel affected. Extracts of frozen-thawed lysosomes and the inflammatory lysosomal cationic protein both cause disruption of rat mesenteric mast cells in vitro, whereas a granule-free cytoplasmic fraction of PMN leukocytes and a non-inflammatory cationic protein fraction of the granules do not do so under identical test conditions. The mastocytolytic action of lysosomal materials in vitro is not inhibited in the presence of 10 kallikrein-inhibiting units of trasylol per ml. The mast cell rupturing fraction of PMNL granules (cationic protein) possesses no detectable peroxidase activity or acid-mucopolysaccharase activity. When compared with compound 48/80 on the basis of estimated molecular weight, the lysosomal cationic protein appears to be at least as active as the latter compound with respect to in vitro mastocytolytic potency. Chronic pretreatment of rats with an agent known to reduce tissue mast cell numbers causes marked suppression of the vascular permeability change normally induced in skin and muscle by lysosomal extracts and cationic protein. Similar results are obtained if lysosomal materials are tested in rats pretreated with an antihistaminic. These observations are discussed with respect to the mode of action of PMNL lysosomes in the early and late phases of local tissue-injury reactions.

The neutrophilic leukocyte in wound repair

“…It is also possible that a decreased fluid exudate in the neutropenic wounds may have accounted for part of the decrease in space that was observed. Factors that might result in a diminished exudate in neutropenic wounds could include the absence of vascular permeability-enhancing substances derived from neutrophils (28,29) or a nonspecific anti-inflammatory effect resulting from transient depletion of complement levels subsequent to ANS, as suggested by previous investigators (30,31).…”

“…These include a collagenase (32), an elastase (33), and a protease (34) all active at neutral pH. In addition, a basic protein fraction derived from rabbit neutrophils has been shown to increase vascular permeability by two different mechanisms, one of which may be related to the release of histamine (28,29).…”

Do Polymorphonuclear Leukocytes Play a Role in Passive Cutaneous Anaphylaxis of the Guinea Pig?

“…The mechanism by which leukocytes, and in particular neutrophils, contribute to the genesis of this type of PCA may be visualized as follows : The union of heterologous y2 antibody with its antigen results in the formation of microprccipitates of immune complexes. Since y2 antibody is complement fixing (O v Bean, 1965). These vasoactive compounds could mediate increases in vascular permeability.…”

Synthesis and Effects on Biological Membranes of Some Oligomere Basic Peptides and Cations (Interactions with Vascular Permeability, Oxidative Phosphorylation and Histamine Liberation)

“…Similar peptides could be isolated from nuclei of bovine granulocytes [Frimmer et al, 1968], Granules of polymorphonuclear exudate leucocytes con tained basic arginine-rich polypeptides which increased vascular permeability, stimulated leucocyte emigration and exhibited anti bacterial activity [Zeya and Spitznagel, 1963;Spitznagel and Zeya. 1964;Janoff and Zweifach, 1964;Janoff et al, 1965;Seegers and Janoff, 1966;Spitznagel, 1966 andScherer and Janoff, 1968;Keller et al, 1968]. Such basic peptides were also found in lysosomes of normal bovine polymorphonuclear leuco cytes of peripheral circulating blood.…”