The generation of oxygen free radicals is known to be involved in the development of the systemic inflammatory response syndrome. In addition to their actions as noxious mediators generated by inflammatory cells, these molecules play also a crucial role contributing to the onset and progression of inflammation in distant organs. In the early stages of the process, free radicals exert their actions via activation of nuclear factors, as NFκB or AP‐1, that induce the synthesis of cytokines. In later stages, endothelial cells are activated due to the synergy between free radicals and cytokines, promoting the synthesis of inflammatory mediators and adhesion molecules. Finally, free radicals exert their toxic effects at the site of inflammation by reacting with different cell components, inducing loss of function and cell death. This review focuses on progress in the understanding the different actions of free radicals at the sequential stages of the development of the systemic inflammatory response. IUBMB Life, 56: 185‐191, 2004

This study aims to determine if the protective role of adenosine in liver ischemic preconditioning is mediated by the activation of adenosine receptors and to ascertain which of these receptors is implicated in the process. Administration of adenosine A₁ and A₂ receptor antagonists to preconditioned animals indicates that hepatic preconditioning is mediated by the activation of adenosine A₂ receptors. Propentofylline (an inhibitor of adenosine transport into cells) in the preconditioned group, subjected to previous administration of an adenosine A₂ receptor antagonist, prevented the negative effect of the latter on the protection offered by preconditioning. An increase of NO production was detected just immediately after hepatic preconditioning, and the administration of an adenosine A₂ receptor antagonist to the preconditioning group prevented this increase, thus abolishing the protective effect of preconditioning. However, the administration of a NO donor to the preconditioned group subjected to previous administration of the adenosine A₂ receptor antagonist was able to maintain the preconditioning effects. In conclusion, these results indicate that, in preconditioning, the protective effect of adenosine could be a result of an increase in extracellular adenosine. This in turn would induce the activation of adenosine A₂ receptors, which, by eliciting an increase in NO generation, would protect against the injury associated with hepatic ischemia–reperfusion.

Rationale: Transplantation of stem cells has been proposed as a strategy for repair of lung fibrosis. Nevertheless, many studies have yielded controversial results that currently limit the potential use of these cells as an efficient treatment. Alveolar type II cells are the progenitor cells of the pulmonary epithelium and usually proliferate after epithelial cell injury. During lung fibrosis, however, the altered regeneration process leads to uncontrolled fibroblast proliferation. Objectives: To investigate whether intratracheal transplantation of isolated alveolar type II cells can halt and reverse the fibrotic process in an experimental model of bleomycin-induced lung fibrosis in rats. Methods: Lung fibrosis was induced in syngeneic female Lewis rats by a single intratracheal instillation of bleomycin (2.5 U/kg). Animals were transplanted with alveolar type II cells from male animals at a dose of 2.5 × 106 cells per animal 3, 7, and 15 days after endotracheal bleomycin instillation. Animals were killed 21 days after the induction of lung fibrosis. Measurements and Main Results: Lung fibrosis was assessed by histologic study and determination of hydroxyproline content. Engraftment of transplanted cells was measured by real-time polymerase chain reaction for the Y chromosome and by fluorescence in situ hybridization for the Y chromosome. Transplantation of alveolar type II cells into damaged lung 3, 7, or 15 days after bleomycin instillation led to reduced collagen deposition, and reduction in the severity of pulmonary fibrosis. Conclusions: This study demonstrates the potential role of alveolar type II cell transplantation in designing future therapies for lung fibrosis.

To evaluate the effect of low molecular weight heparin on plasma xanthine oxidase concentrations and lung inflammatory response during acute pancreatitis. Randomized, controlled trial. Experimental laboratory. Male Wistar rats. Acute pancreatitis was induced by intraductal administration of 5% sodium taurocholate. Low molecular weight heparin (0, 30, 90, or 300 units/kg) was administered immediately after induction of pancreatitis. Lipase and xanthine oxidase plasma concentrations were measured 3 hrs after pancreatitis induction. Expression of P-selectin messenger RNA and myeloperoxidase activity as a marker of neutrophil infiltration were determined in the lung. An increase in xanthine oxidase plasma concentrations was observed during pancreatitis. Administration of heparin also increased plasma xanthine oxidase activity in both control and pancreatitis animals. Measures of xanthine oxidase present in the endothelial surface indicate that during pancreatitis, the enzyme is released from the gastrointestinal endothelium. By contrast, heparin mobilizes xanthine oxidase from almost all organs evaluated. Neutrophil infiltration was increased in the lung during pancreatitis. Heparin administration further increased, in a dose-dependent manner, myeloperoxidase activity and P-selectin expression in the lung in animals with pancreatitis. By contrast, in control animals, heparin had no effect on myeloperoxidase activity and did not induce P-selectin up-regulation. During acute pancreatitis, heparin administration might mobilize xanthine oxidase attached to endothelial cells, originating a free radical-generating system in the circulation that would trigger an inflammatory response in the lung.

Little is known regarding the optimal type of fluid resuscitation in acute pancreatitis (AP). The objective of this article was to compare the effect of lactated Ringer’s solution (LR) vs normal saline (NS) in the inflammatory response in AP. We conducted a triple-blind, randomized, controlled trial. Patients ≥ 18 admitted with AP were eligible. Patients were randomized to receive LR or NS. Primary outcome variables were number of systemic inflammatory response syndrome (SIRS) criteria at 24 hours, 48 hours and 72 hours and blood C-reactive protein (CRP) levels at 48 hours and 72 hours. In vitro complementary experiments were performed to further explore the interaction between pH, lactate and inflammation. Nineteen patients receiving LR and 21 receiving NS were analyzed. The median (p25–p75) number of SIRS criteria at 48 hours were 1 (1–2) for NS vs 1 (0–1) for LR, p = 0.060. CRP levels (mg/l) were as follows: at 48 hours NS 166 (78–281) vs LR 28 (3–124), p = 0.037; at 72 hours NS 217 (59–323) vs LR 25 (3–169), p = 0.043. In vitro, LR inhibited the induction of inflammatory phenotype of macrophages and NF-κB activation. This effect was not observed when using Ringer’s solution without lactate, suggesting a direct anti-inflammatory effect of lactate. Lactated Ringer’s is associated with an anti-inflammatory effect in patients with acute pancreatitis.