allopurinol and Acute-Phase-Reaction

Considerable research effort has been directed at elucidating the mechanisms underlying the pathophysiologic alterations associated with reperfusion (reoxygenation) of ischemic (hypoxic) tissues. As a consequence of this intensive effort, a large body of evidence has accumulated, implicating a role for reactive oxygen metabolites and activated granulocytes in the genesis of postischemic cellular dysfunction. Figure 1 summarizes a hypothesis that has been proposed to explain the interaction of xanthine oxidase-derived oxidants, granulocyte infiltration, and the microvascular and parenchymal cell dysfunction that occurs in postischemic tissues. According to this scheme, xanthine oxidase-derived oxidants, produced at reperfusion, initiate the formation and release of proinflammatory agents, which subsequently attract and activate granulocytes. The activated neutrophils adhere to the microvascular endothelium, extravasate, and release cytotoxic oxidants and proteases, which contribute to tissue dysfunction. The aim of this review is to summarize the evidence that we and others have accumulated in support of this hypothesis.

Topics: Acute-Phase Reaction; Animals; Granulocytes; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; NADH, NADPH Oxidoreductases; NADPH Oxidases; Neutrophils; Reactive Oxygen Species; Xanthine Oxidase

Tissue injury induces the acute phase response, aimed at minimizing damage and starting the healing process. Polymorphonuclear leukocytes (PMNs) respond to the presence of specific chemoattractants and begin to appear in large numbers. The aim of this study was to investigate the influence of reactive oxygen species (ROS) produced by PMNs on the interaction between colon carcinoma cells and mesothelial cells. An experimental human in vitro model was designed using Caco-2 colon carcinoma cells and primary cultures of mesothelial cells. Tumor cell adhesion to a mesothelial monolayer was assessed after preincubation of the mesothelium with stimulated PMNs and unstimulated PMNs. Mesothelial cells were also incubated with xanthine/xanthine oxidase (X/XO) complex producing ROS after which adhesion of Caco-2 cells was investigated and the expression of adhesion molecules (ICAM-1, VCAM-1, and CD44) by means of enzyme immunoassay. In the control situation the average adhesion of Caco-2 cells to the mesothelial monolayers was 23%. Mesothelial monolayers incubated with unstimulated PMNs showed a 25% increase of tumor cell adhesion (P < 0.05). The adhesion of tumor to the monolayers incubated with the N-formyl-methionyl-leucyl-phenylalanine-stimulated PMNs increased with 40% (P < 0.01). Incubation of the mesothelium with X/XO resulted in an enhancement of adhesion of Caco-2 cells of 70% and an up-regulation of expression of ICAM-1, VCAM-1, and CD44. This study reveals an increase of tumor cell adhesion to the mesothelium induced by incubating the mesothelial monolayers with PMNs. PMNs are producing a number of products, like proteolytic enzymes, cytokines, and ROS. These factors up-regulate the expression of adhesion molecules and in that way stimulate the adhesion of tumor to the mesothelium.

Topics: Acute-Phase Reaction; Caco-2 Cells; Cell Adhesion; Colonic Neoplasms; Cytochromes c; Epithelium; Humans; Immunoenzyme Techniques; In Vitro Techniques; Neoplasm Recurrence, Local; Neutrophils; Reactive Oxygen Species; Reproducibility of Results; Xanthine; Xanthine Oxidase