RESUMO
Intestinal ischemia-reperfusion injury is dependent on complement. This study examines the role of the alternative and classic pathways of complement and IgM in a murine model of intestinal ischemia-reperfusion. Wild-type animals, mice deficient in complement factor 4 (C4), C3, or Ig, or wild-type mice treated with soluble complement receptor 1 were subjected to 40 min of jejunal ischemia and 3 h of reperfusion. Compared with wild types, knockout and treated mice had significantly reduced intestinal injury, indicated by lowered permeability to radiolabeled albumin. When animals deficient in Ig were reconstituted with IgM, the degree of injury was restored to wild-type levels. Immunohistological staining of intestine for C3 and IgM showed colocalization in the mucosa of wild-type controls and minimal staining for both in the intestine of Ig-deficient and C4-deficient mice. We conclude that intestinal ischemia-reperfusion injury is dependent on the classic complement pathway and IgM.
Assuntos
Proteínas do Sistema Complemento/fisiologia , Imunoglobulina M/fisiologia , Enteropatias/imunologia , Traumatismo por Reperfusão/imunologia , Animais , Complemento C3/deficiência , Complemento C3/genética , Complemento C3/fisiologia , Complemento C4/deficiência , Complemento C4/genética , Complemento C4/fisiologia , Proteínas do Sistema Complemento/deficiência , Proteínas do Sistema Complemento/genética , Edema/patologia , Genes RAG-1/genética , Técnicas Imunoenzimáticas , Enteropatias/patologia , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão/patologiaRESUMO
The aim of this study was to look at the role of alpha 1-acid glycoprotein as a natural anti-inflammatory agent with particular respect to its antineutrophil and anticomplement activity. A recombinantly engineered form of sialyl Lewisx (sLe(x))-bearing alpha 1-acid glycoprotein (sAGP) was administered intravenously to pentobarbital-anesthetized rats after 50 min of intestinal ischemia just before 4 h of reperfusion. A non-sLe(x)-bearing form of AGP (nsAGP) was used as control. sAGP-treated animals had a 62% reduction (P < 0.05) in remote lung injury, assessed by 125I-albumin permeability, compared with those treated with nsAGP (permeability index of 3.61 +/- 0.15 x 10(-3) and 5.18 +/- 0.67 x 10(-3), respectively). There was a reduction in pulmonary myeloperoxidase levels in sAGP-treated rats compared with nsAGP-treated rats. Complement-dependent intestinal injury, assessed by 125I-albumin permeability was reduced by 28% (P < 0.05) in animals treated with sAGP (7.58 +/- 0.63) compared with those treated with nsAGP (10.4 +/- 0.54). We conclude that sAGP ameliorates both complement- and neutrophil-mediated injuries.
Assuntos
Intestinos/irrigação sanguínea , Isquemia/fisiopatologia , Pulmão/patologia , Orosomucoide/farmacologia , Animais , Permeabilidade da Membrana Celular , Via Alternativa do Complemento/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Intestinos/patologia , Radioisótopos do Iodo , Isquemia/prevenção & controle , Pulmão/efeitos dos fármacos , Masculino , Oclusão Vascular Mesentérica , Oligossacarídeos , Peroxidase/análise , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Reperfusão , Antígeno Sialil Lewis XRESUMO
Acid aspiration may result in the development of the acute respiratory distress syndrome, an event associated with significant morbidity and mortality. Although once attributed to direct distal airway injury, the pulmonary failure after acid aspiration is more complex and involves an inflammatory injury mediated by complement (C) and polymorphonuclear leukocytes. This study examines the injurious inflammatory cascades that are activated after acid aspiration. The role of neutrophils was defined by immunodepletion before aspiration, which reduced injury by 59%. The injury was not modified in either P- or E-selectin-knockout mice, indicating that these adhesion molecules were not operative. C activation after aspiration was documented with immunochemistry by C3 deposition on injured alveolar pneumocytes. Animals in which C activation was inhibited with soluble C receptor type 1 (sCR1) had a 54% reduction in injury, similar to the level of protection seen in C3-knockout mice (58%). However C4-knockout mice were not protected from injury, indicating that C activation is mediated by the alternative pathway. Finally, an additive effect of neutrophils and C was demonstrated whereby neutropenic animals that were treated with sCR1 showed an 85% reduction in injury. Thus acid aspiration injury is mediated by neutrophils and the alternative C pathway.