The Role of Lysosomes in Hypersensitivity Reactions: Tissue Damage by Polymorphonuclear Neutrophil Lysosomes

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Abstract
Summary: Injection of isolated polymorphonuclear neutrophil (PMN) granules into the skin of normal rabbits causes a local leukocytosis and increase in vascular permeability. The permeability increase is dose dependent and maximal at 2 hr. Activity is not affected by dialysis but is almost completely lost after heating at 85°C for 30 min. The granule preparations do not cause contraction of an isolated segment of smooth muscle nor are they affected by doses of cyproheptidine which inhibit the action of histamine and serotonin. Pretreatment of normal recipient rabbits with 5 mg/kg body weight of cortisone-acetate abolishes the vascular response to intact granules, but not lysed granules. It is concluded that cortisone prevents in vivo lysis of the granule by membrane stabilization. All of the permeability increasing properties were located in the 20% ethanol precipitable fraction of PMN granules. This fraction was shown to contain little cathepsin-like protease activity. The majority of the cathepsins were located in the 45 and 80% ethanol precipitable fractions. The active fraction was found by electrophoresis to be the most cationic. The vascular permeability increasing activity of intact or lysed granule preparations was not reduced by the general protease inhibitors phenylmethylsulphonyl fluoride or soybean trypsin inhibitor. It was concluded that the vascular permeability altering properties of PMN granules might not be due to the presence of the cathepsins. The possibility that activity is due to electrostatic charge is presented. The histology of the granule-induced lesions is similar to the histology of the Arthus reaction. There is edema, an accumulation of PMN and vasculitis in both cases, but the granule induced histologic alterations appear at an earlier time after injection than do comparable changes in the Arthus reaction. A possible mechanism for the Arthus reaction is presented.