Complement Activation and Polymorphonuclear Neutrophil Leukocyte Elastase in Sepsis

Abstract

Complement activation is necessary for an adequate immune and inflammatory response to infections. Activation releases anaphylatoxins that cause vasodilation, increase vascular permeability, and trigger release of polymorphonuclear neutrophil leukocyte (PMN) lysosomal enzyme and oxygen radicals. Under normal circumstances, an orderly progression of such events has a beneficial antimicrobial effect. The same mechanism, however, when uncontrolled, may damage host tissues. To provide information about the clinical importance of such events in sepsis, different complement parameters (C3, C4, and the desarginated forms of C3a [C3a(des)-Arg] and C5a [C5a(des)-Arg]), PMN elastase, and malondialdehyde (a by-product of membrane peroxidation by oxygen radicals) were measured daily in 26 septic patients and correlated with two objectively assessed and previously validated severity scores (acute physiology and chronic health evaluation [APACHE II] and Sepsis Severity Score [SSS]). Nonsurvivors (n = 12) had significantly greater and longer lasting complement activation than that in survivors, as reflected by higher levels of catabolic peptides (C3a(des)-Arg) and lower levels of native proteins (C3 and C4). C3a(des)-Arg, C3, C4, and the C3a(des)-Arg-C3 ratio were correlated with Sepsis Severity Scores. Polymorphonuclear neutrophil leukocyte elastase levels were higher in nonsurvivors and were correlated with C3a(des)-Arg and the C3a(des)-Arg-C3 ratio. Malondialdehyde levels were significantly higher in all patients than in controls, without, however, any relationship to severity of disease or clinical outcome. Since the higher and more persistent the complement activation and polymorphonuclear neutrophil leukocyte stimulation, the worse the patient's prognosis, we conclude that these mechanisms may be important in the clinical development of sepsis.

Administration of C1 Inhibitor Reduces Neutrophil Activation in Patients with Sepsis

“…We found EA and LF levels to increase with disease severity and to correlate with outcome; however, such a relationship was much weaker for LF, as was reported in other studies as well (30). On admission, patients with elevated EA levels showed significantly higher LOD and SOFA scores and had significantly worse renal function than those with normal EA levels, in accordance to published observations reporting EA levels to increase with disease severity and to predict mortality (6,18,30). In contrast, patients with normal EA levels had only mild organ dysfunction.…”

“…Patients suffering from sepsis showed elevated EA levels (13,14,30), which predict clinical outcome (6,30) and correlate with organ dysfunction scores (18,26,35). In this study we confirmed that neutrophils are activated in sepsis; this activation is associated with advanced organ dysfunction.…”

“…Elevated EA levels have been demonstrated in human volunteers upon endotoxin administration and in patients with sepsis (13,14,42,45). In the latter, EA levels correlate well with organ dysfunction scores, disease severity, and outcome, supporting a role for PMN in the pathogenesis of severe sepsis (18,26,30,35). It is unknown, however, which agonists mediate the activation of PMN in sepsis.…”

“…Release of interleukin-8 (IL-8), which is strongly chemotactic for PMN and induces the expression of adhesion molecules on endothelial cells, may encourage activated PMN to adhere to endothelial cells, thereby inducing endothelial damage (1,10,21,33,51). However, other agonists, such as C5a, activated factor XII (FXIIa), or kallikrein, may be involved as well (15,18,38,41,48,49).…”

Alkali treatment of microrough titanium surfaces affects macrophage/monocyte adhesion, platelet activation and architecture of blood clot formation

“…The activation of the coagulation cascade, the complement system and platelet activation in partially heparinized (3 IU/mL) whole human blood was assessed by determining the concentration of specifi c marker proteins after contact with alkali-treated and untreated SBA Ti implant surfaces. The activation of the complement system was assessed by the increase in anaphylatoxin C5a (Gardinali et al, 1992); blood coagulation was determined by an increase in kallikreinlike activity (Griffi n and Cochrane, 1976) and the increase in thrombin-antithrombin complexes (TAT) (Diquélou et al, 1994). Activation of platelets was demonstrated by the release of P-selectin and immunohistological staining against CD62p (Matowicka-Karna et al, 2006).…”