RESUMO
In humans with sepsis, the onset of multiorgan failure (MOF), especially involving liver, lungs, and kidneys, is a well known complication that is associated with a high mortality rate. Our previous studies with the cecal ligation/puncture (CLP) model of sepsis in rats have revealed a C5a-induced defect in the respiratory burst of neutrophils. In the current CLP studies, MOF occurred during the first 48 h with development of liver dysfunction and pulmonary dysfunction (falling arterial partial pressure of O(2), rising partial pressure of CO(2)). In this model an early respiratory alkalosis developed, followed by a metabolic acidosis with increased levels of blood lactate. During these events, blood neutrophils lost their chemotactic responsiveness both to C5a and to the bacterial chemotaxin, fMLP. Neutrophil dysfunction was associated with virtually complete loss in binding of C5a, but binding of fMLP remained normal. If CLP animals were treated with anti-C5a, indicators of MOF and lactate acidosis were greatly attenuated. Under the same conditions, C5a binding to blood neutrophils remained intact; in tandem, in vitro chemotactic responses to C5a and fMLP were retained. These data suggest that, in the CLP model of sepsis, treatment with anti-C5a prevents development of MOF and the accompanying onset of blood neutrophil dysfunction. This may explain the protective effects of anti-C5a in the CLP model of sepsis.
Assuntos
Complemento C5a/fisiologia , Insuficiência de Múltiplos Órgãos/imunologia , Sepse/imunologia , Acidose/imunologia , Acidose/metabolismo , Acidose/prevenção & controle , Alcalose Respiratória/imunologia , Alcalose Respiratória/prevenção & controle , Sequência de Aminoácidos , Animais , Ceco , Quimiotaxia de Leucócito , Complemento C5a/genética , Complemento C5a/imunologia , Complemento C5a/metabolismo , Eletroforese em Gel de Poliacrilamida , Soros Imunes/farmacologia , Radioisótopos do Iodo/metabolismo , Rim/patologia , Rim/ultraestrutura , Ligadura , Masculino , Dados de Sequência Molecular , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/patologia , N-Formilmetionina Leucil-Fenilalanina/sangue , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Ligação Proteica/genética , Ligação Proteica/imunologia , Ratos , Ratos Long-Evans , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Sepse/sangue , Sepse/patologia , TrítioRESUMO
We investigated the in vitro effect of different forms of acidosis (pH 7.0) on the formation of anaphylatoxins C3a and C5a. Metabolic acidosis due to addition of hydrochloric acid (10 micromol/ml blood) or lactic acid (5.5 micromol/ml) to heparin blood (N=12) caused significant activation of C3a and C5a compared to control (both p=0.002). Respiratory acidosis activated C3a (p=0.007) and C5a (p=0.003) compared to normocapnic controls. Making blood samples with lactic acidosis hypocapnic resulted in a median pH of 7.37. In this respiratory compensated metabolic acidosis, C3a and C5a were not increased. These experiments show that acidosis itself and not lactate trigger for activation of complement components C3 and C5.
