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January 1994

Enhanced Release of Elastase Is Not Concomitant With Increased Secretion of Granulocyte-Activating Cytokines in Whole Blood From Patients With Sepsis

Author Affiliations

From the Department of Surgery, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany (Messrs Jarrar and Thiele, and Drs Faist and Schildberg); the Department of Clinical Biochemistry, Department of Surgery, Munich City (Dr Jochum); and the Institute of Biological Sciences, Syntex Research, Palo Alto, Calif (Mr Kenney). Dr Ertel is now with the Klinik für Unfallchirurgie, Departement Chirurgie, Universitaetsspital Zuerich (Switzerland).

Arch Surg. 1994;129(1):90-98. doi:10.1001/archsurg.1994.01420250102013

Background:  The proteolytic enzyme elastase released by granulocytes (polymorphonuclear leukocytes [PMN]) in high concentrations during sepsis causes degradation of essential plasma proteins, endothelial damage, and tissue edema. This may result in organ dysfunction and organ failure during sepsis, since increased elastase plasma levels correlate with the mortality rate of patients with sepsis. In vitro studies demonstrated a regulatory role of inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin 1β [IL-1β], IL-8]) upregulatingprotease release by PMN. In this light, the interactions between cytokine release by macrophages and altered elastase secretion during sepsis remain to be determined.

Methods:  An ex vivo model consisting of lipopolysaccharide stimulation of human whole blood as a relevant physiological milieu was used. Heparinized blood was obtained from 20 patients with sepsis syndrome (APACHE II [Acute Physiology and Chronic Health Evaluation II] score 28.5±1.2 points [mean±SD]) on days 0 through 3, 5, 7, and 10 after sepsis diagnosis and from 20 control patients without infection. Blood was incubated with lipopolysaccharide (1 mg/L) for 8 hours. Plasma levels of elastase, TNF-α, IL-1β, and IL-8 were determined using enzyme-linked immunosorbent assay or bioassay (TNF-α), respectively.

Results:  Elastase plasma levels in whole blood from patients with sepsis were increased up to 188% (P<.01) above normal, while the release of TNF-α (-87%), IL-1 β (-91%), and IL-8 (-51%) was markedly (P<.01) decreased compared with control patients. Neutralization of TNF-α or IL-1β did not attenuate the increased release of elastase.

Conclusions:  These data indicate an increased release of elastase by PMN despite a reduced secretion of PMNactivating cytokines. Although priming effects of TNF-α, IL-1β, and IL-8 on protease secretion in vivo cannot be excluded completely, other mediators or mechanisms may be involved in the upregulation of detrimental protease release during sepsis.(Arch Surg. 1994;129:90-98)