Background We have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents -streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA) -on activation of the complement and kinin systems in plasma of patients with AMI.Methods and Results Forty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twentythree patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with
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.
Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the
vascular and tissue damage of several chronic diseases, including systemic
sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I
and T280M genetic polymorphisms influence CX3CR1 expression and function. We
investigated whether these polymorphisms are associated with PAH secondary to
SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with
limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography.
Homozygosity for 249II as well as the combined presence of 249II and 280MM were
significantly more frequent in patients with SSc compared to controls (17 vs 6%,
p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were
associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75,
p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion,
the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of
patients with SSc-associated PAH suggest a role for the fractalkine system in
the pathogenesis of this
condition. Further, the 249I allele might be associated with susceptibility to SSc.
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