IUBMB
Life, 56(4): 185–191, April 2004
Critical Review Oxygen Free Radicals and the Systemic Inflammatory Response Daniel Closa and Emma Folch-Puy Department of Experimental Pathology, IIBB-CSIC-IDIBAPS, Barcelona, Spain
Summary 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 NFkB or AP1, 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 Keywords SIRS;
nuclear factors; inflammation; NADPH-oxidase; xanthine oxidase; sepsis.
neutrophil;
INTRODUCTION Systemic inflammatory response syndrome (SIRS) is a clinical situation caused by a variety of events including sepsis, trauma, burns, pancreatitis and surgery (1). This term was introduced in 1992 by the consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine (2) to recognize the role that endogenous inflammatory mediators play in sepsis. Until this conference, the term ‘sepsis’ was a source of confusion due to the similar use for the terms ‘bacteremia’, ‘severe sepsis’ and ‘septic shock’. Now, SIRS is considered the expression of common inflammatory pathways resulting from the generaReceived 8 March 2004; accepted 28 March 2004 Address correspondence to: Dr. Emma Folch-Puy, Dept. Experimental Pathology, IIBB-CSIC, c/ Rossello´ 161, 78, 08036 Barcelona, Spain. Tel: 34/93/363 83 57; Fax: 34/93/363 83 01. E-mail:
[email protected] ISSN 1521-6543 print/ISSN 1521-6551 online # 2004 IUBMB DOI: 10.1080/15216540410001701642
tion and interaction of various humoral and cellular mediators (3). There is a progression in the severity of the disease state from simple SIRS to multiple organ dysfunction syndrome, defined by the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. The pathophysiology of SIRS involves a growing number of mediators including cytokines, bradykinin, eicosanoids, complement system, hydrolytic enzymes, low molecular weight peptides, adhesion molecules and free radicals (4 – 6). All these mediators show a broad amount of overlapping actions, crossreactions, redundancy and synergistic effects that make extremely complex the comprehension of this process. Cytokines are the main mediators involved in the progression of SIRS (7). In particular TNFa, IL-1b, IL-6 and IL-8 appear early in circulating blood in a classical sequence. However, the effects and generation of these cytokines cannot be properly understood without the contribution of other mediators, in particular oxygen-derived free radicals (OFR). These toxic mediators act in promoting the generation of cytokines by modulating the nuclear factors that regulate their synthesis (8), priming the endothelial cells by the induction of adhesion molecules involved in the recruitment of inflammatory cells (9), and finally producing additional tissue damage through their direct effect on different biomolecules (10). The broad spectrum of actions makes the OFR crucial actors in the triggering event of SIRS and the subsequent amplification of the proinflammatory cascade followed by the systemic response. In this paper, we shall review the current status on the role of these ubiquitous molecules in all the events leading to SIRS.
Oxygen Derived Free Radicals Most molecules have pairs of electrons in their outer orbitals, and the opposite spin of these pairs stabilizes each molecule. A classical definition of free radical is any species capable of independent existence that contains one or more unpaired electrons. Such unpaired electrons make the molecule highly reactive since it tends to react with other molecules
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to pair the single electron and thereby generate more stable species (11). The most abundant radical in biological systems is molecular oxygen (O2) and a number of oxygen-derived free radicals are also important. Superoxide anion (O27) and the hydroxyl radical (OH×) are particularly important in different process related with tissue injuries. Hydrogen peroxide (H2O2) is not a true free radical species, but constitutes a class of reactive oxygen metabolite that can be also highly toxic to tissue components. For this reason it is also used the term ‘Reactive oxygen species’ to include all these oxygen-derived toxic mediators (12). The toxicity of free radicals is related with the fact that these species, in particular the hydroxyl radical, can react with all the cell molecular components. This reaction generates, in turn, a second radical that interact with other molecules to continue the radical chain reaction. These chain reactions result in modifications and loss of function of proteins, breaks and crosslinking of DNA and lipid peroxidation affecting membrane fluidity and activity of membrane proteins (11). The potential deleterious effects of OFR are usually controlled by endogenous antioxidant mechanisms present in the cells. These mechanisms include enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (13). Other defense mechanisms involve the chain-breaking antioxidants, such as ascorbic acid, a-tocopherol and glu-
Figure 1. OFR as local cells activators. As a result of tissue damage, different sources of oxygen free radicals become activated. Mitochondria, xanthine oxidase and activated neutrophils produce reactive oxygen species. Subsequently, OFR underscore different signal transduction pathways (MAPKs and NFkB) activating effector molecules essential for cellular responses that include cytokine production. These cytokines trigger the systemic inflammatory response.
tathione, and strategies to keep any potential redox-active metals bound to proteins to minimize the hydroxyl radical formation (14). When the production of oxygen radicals exceeds the scavenging capacity of these enzymes, oxidative stress develops. In these conditions, the last line of defense is
Figure 2. OFR amplifying the inflammatory response: activated neutrophils produce OFR by the action of the membrane-associated NADPH oxidase. Xanthine oxidase released into the bloodstream constitutes another important source of OFR with systemic effects. In endothelial cells, OFR act inducing the expression of adhesion molecules and cytokines that promote the recruitment and adhesion of neutrophils and other inflammatory cells.
Figure 3. OFR as effectors of distant organ injury: when the generation of OFR exceeds the antioxidant capacity of the endogenous mechanisms, cell damage occurs due to the different direct effects of OFR in cell components but also strengthening the effect of other inflammatory mediators.
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the activation or repair processes designed to replace the damaged molecules or to correct the changes induced by the action of free radicals. Within the mitochondria, molecular oxygen is reduced to water during oxidative phosphorylation. However, about 1 – 5% of the oxygen escapes this conversion into water, thereby producing a number of toxic intermediates (15). Other endogenous sources of oxygen-derived free radicals are a number of oxidases that can, in certain circumstances, generate toxic oxygen metabolites. In particular, xanthine oxidoreductase plays an important role in different diseases (16). This enzyme catalyses the oxidation of hypoxanthine to xanthine, and then, the oxidation of xanthine to uric acid. The enzyme exists in two forms that catalyses the same reactions but the dehydrogenase form uses NAD + as electron acceptor while the oxidase form uses molecular oxygen and generates superoxide radical. Finally, the NADPH-dependent oxidase system of the membrane surface of neutrophils is a high efficient source of the superoxide radical generation related with the bactericidal function of these cells (17).
Free Radicals as Inductors of Cytokine Synthesis in SIRS Generation of cytokines is accepted to play a major role inducing inflammatory responses in general, and SIRS in particular (18). A key regulator of cytokine induction is the nuclear factor kB (NFkB). This factor constitutes a family of proteins which bind to DNA as homo- or heterodimers to activate the cytokine or stress genes synthesis. NFkB is present in the cytoplasm coupled to an inhibitor protein (IkB) that blocks the translocation to the nucleus. Under a number of stimuli, IkB becomes phosphorylated and degraded, thus allowing NFkB dimmers to translocate into the nucleus triggering the transcription of genes involved in the inflammatory response (19). Agents that activate NFkB include cytokines, mitogens and oxygen-derived free radicals (20). In fact, it has been reported that some of the beneficial effects of different antioxidants, such as N-acetylcysteine (21) and pyrrolidine dithiocarbamate (22), are related with their ability to inhibit NFkB activation. The role of free radicals as inductors of cytokine synthesis has been reported in different diseases that course with SIRS. Using experimental models of severe acute pancreatitis, different authors demonstrated that antioxidant treatments blocked NFkB activation and significantly improved local and systemic parameters of pancreatitis, mainly cytokine generation (23). Interestingly, Telek et al. (24) have demonstrated that the early acinar oxidative stress is co-localized with NFkB activation in pancreas. Then, it has been suggested that free radical-induced NFkB activation and the consequent cytokine synthesis may link the initial acinar cell injury with the systemic inflammatory response associated with severe acute pancreatitis. Similar results have been reported with other pathological conditions that lead to SIRS. Burn trauma triggers a cascade
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of cellular events involving nuclear translocation of NFkB (25). The finding that antioxidant vitamin therapy inhibited nuclear translocation of NFkB and decreased synthesis of inflammatory cytokines was paralleled by the finding of improved cardiac contractile function (an˜adir referencia). These data support the hypothesis that cellular oxidative stress is a critical step in burn-induced synthesis of inflammatory cytokines that finally results in cardiac injury. Nevertheless, it is unclear whether antioxidant vitamins given after burn trauma exerted their protective effects by quenching reactive oxygen metabolites, or by modulating NFkB (26). Other transcription factors that regulate inflammatoryrelated genes are also activated by oxidant stress. Phosphorylation of the MAP kinases family, including ERK, JNK and p38 kinases, could be induced by oxygen free radicals. Subsequently, these kinases lead to the activation of transcription factors that, as occurs with NFkB, regulate the synthesis of pro-inflammatory genes (8). In addition, the activation of MAP kinases could regulate the expression of different genes by their effect on the histone acetylation/phosphorylation. In this regard, it has been reported that histone acetylation plays a role in IL-8 and IL-6 gene expression, two cytokines closely related with SIRS (27). Increased expression of cytokines and other inflammatory genes is a mechanism with the ability to strongly amplify the initial cell response to tissue damage. When this amplification exceeds the regulatory mechanisms it turns a defensive mechanism as inflammation in a potentially lethal process.
Free Radicals as Endothelial Cell Activators in SIRS In addition to their role as initiator of local cytokine synthesis, oxygen free radicals could also act as important mediators of inflammatory responses leading to organ dysfunction and SIRS. The presence of circulating sources of free radicals in blood induces changes in the capilar endothelium of different organs far from the original site of injury (28). This is of importance because endothelial cells are simultaneously target and source of inflammatory mediators during the systemic inflammatory response. The systemic oxidant stress could activate endothelial cells that, in turns, express adhesion molecules and cell receptors making these cells more sensitive to the proinflammatory effects of circulating cytokines (5, 29). When the process advances, it becomes difficult to make distinctions between endothelial activation and endothelial dysfunction. A variety of clinical stimuli initiate an acute microvascular injury due to oxygen free radicals that contribute to a systemic inflammatory response. The key cellular participants are the polymorphonuclear neutrophils (PMN). Neutrophils produce reactive oxygen species while circulating, causing not only endothelial cell injury and damage but also activation and synthesis of more inflammatory mediators (30). For example, it has been reported that after injection of LPS, plateletendothelial cell adhesion is strongly induced as a consequence
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of endothelial cell and platelets activation. These adhesive interactions promote the leukocyte recruitment and thrombogenesis. This process has been significantly reduced by scavenging superoxide radical or in neutrophil NADPHoxidase deficient mice, indicating that free radicals generated by activated neutrophils act priming the endothelial cells (31). The systemic inflammatory response that occurs after surgical interventions, as cardiopulmonary bypass, is another clinical situation that evidences the activation of large areas of endothelium, and the margination and degranulation of neutrophils in a larger scale (32). Once adhered to the endothelium, neutrophils release proteases and oxygenderived free radicals responsible for much of the end-organ damage seen after cardiac operations. Nevertheless, neutrophils are not the only source of systemic free radical generation. During acute pancreatitis, Sanfey et al. (33) firstly demonstrated the role of xanthine oxidase as a local source of OFR in pancreas. Later the role of oxygen free radicals generated by xanthine oxidase in pancreatitis-associated SIRS have also been reported. In an experimental model of acute pancreatitis in rats, treatment with the xanthine oxidase inhibitor allopurinol prevented systemic organ failure associated with pancreatitis (34), underscoring the concept that generation of oxygen free radicals via xanthine oxidase represents a pivotal mechanism in the pathogenesis of acute pancreatitis. It appears that during pancreatitis, there is an increase in circulating xanthine oxidase due to pancreatic release, but also by extracellular mobilization (35). This mobilization occurs because, in addition to its intracellular location, xanthine oxidase is also associated to the polysaccharide chains of proteoglycans on the external endothelial cell membrane (36). During pancreatitis, some enzymes released by damaged pancreas acts on these polysaccharide chains, interfering the binding of xanthine oxidase to the endothelial cells, thus contributing to the increase observed in the plasma concentration of this enzyme. Circulating concentrations of xanthine, the substrate for the enzyme, are also increased due to the extended cell necrosis that occurs during pancreatitis. Simultaneous increases in xanthine and xanthine oxidase generate a circulating source of free radicals that induces the expression of P-selectin in endothelial cells of the lung, thus contributing to the systemic inflammatory process secondary to pancreatitis (37). Similar mechanism could be suspected in pathologies that imply extended cell necrosis.
Free Radicals Generated in Distant Organs It is known that neutrophils, once sequestered in distant organs as a result of the systemic inflammatory response to a local insult, generate oxygen free radicals as a part of their antimicrobial response (38). Nevertheless, it is important to take into account that other phagocytic cells, such as macrophages, also generate oxygen free radicals (39).
By far, NADPH oxidase-dependent free radical generation is the most important source of oxidant stress when phagocytic cells become activated (40). In these conditions, the antioxidant mechanisms are overhelmed and extended cell damage could easily occur. Additional sources of free radicals in target tissues are the enzymes xanthine oxidase, cytochrome p450 reductase, lipoxygenase, etc. from the damaged endothelial cells (11). Free radicals may act directly inducing changes in intracellular and extracellular molecules and then affecting the cellular viability, but also inducing apoptosis and exacerbation of the inflammatory process (41). The direct effects of free radicals on the cell components include alterations in proteins, DNA and lipids. Oxidation of proteins induces loss of function and makes them highly susceptible to degradation by proteases (42). Free radicals can alter the redox state of NAD + /NADH and NADP + / NADPH couples leading to profound changes in metabolic status of the cell. Cell membranes become damaged due to initiation of lipid peroxidation of polyunsaturated fatty acids with direct effects on membrane structure and fluidity, but also by damaging membrane components, including receptors, transporters and antigens (43). Another important target for free radicals is the DNA. Free radicals cleave and crosslink DNA strands, inducing mutations and loss of cell viability. But even when damage is less intense, single strand DNA breaks act inducing the activation of the nuclear enzyme polyADP-ribose synthetase. This enzyme initiates an energyconsuming, inefficient repair cycle by transferring ADP-ribose units to nuclear proteins, depleting NAD + and ATP pools and leading to cell dysfunction. In addition, among the nuclear proteins ADP-ribosilated by poly-ADP-ribose synthetase there are some nuclear factors that regulate the expression of more genes involved in the exacerbation of the inflammatory process, as P-selectin (44). Additional complications directly related to free radicals are the alterations in protease/antiprotease balance. Some protease inhibitors (a2-Macroglobulin or a1-protease inhibitor) are inactivated by neutrophil-derived oxidant species. This inactivation creates an environment favorable for the degradation of extracellular matrix by the action of gelatinases, collagenases and elastase (45). In these conditions, the progression and exacerbation of the inflammatory process is greatly increased. One of the initial observations pointing to the oxidant stress as a significant mechanism of lung injury during sepsis was obtained in expired breath condensates. In patients suffering from acute respiratory failure with focal pulmonary infiltrates H2O2 levels were significantly higher than in control patients (46). It is noteworthy the fact that H2O2 concentrations were greatest in patients with head injuries and sepsis, independent of the presence of pulmonary infiltrates. This observation suggested the participation of oxidants in sepsis but also in other forms of vital organ injury, such as trauma.
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Antioxidant Therapies During last years, a growing body of evidence supports the concept that oxidant stress occurs during the different stages of SIRS in the inflamed organs. Despite direct measurement of free radical generation is difficult, the oxidant/antioxidant balance has been assessed and different antioxidant therapies have been implemented, particularly in pathologies that course with a reduction in the total tissue antioxidant capacity, such as sepsis or burn trauma. Patients with SIRS exhibit decreased glutathione peroxidase activity (47) and an imbalance between superoxide dismutase and catalase activities (48). Consequently, a large amount of therapeutic interventions have been assayed attempting to restore a proper antioxidant status. The agents used for this purpose include N-acetylcysteine (NAC) (49, 50), a-tocopherol (51), allopurinol (34), selenium (52), deferroxamine (53), catalase and superoxide dismutase (54). Different combinations of these agents have also been used in order to improve their effects in different steps of the free radical generation chain (55). The efficacy of these interventions seems to be strongly dependent on the drug assayed, the time-course of the disease and the parameters analyzed. It is conceivable the existence of different therapeutic windows for each of the antioxidant approaches. In addition, it is important to take into account the fact that when SIRS occurs, there are different inflammatory pathways acting simultaneously. Thus, it is unlikely that interventions focused only in one of these mechanisms are enough to obtain clear therapeutic results. Combinations of antioxidants with inhibitors of cytokines could be, in theory, more useful for the treatment of SIRS.
CONCLUSIONS Localized inflammation is a physiological protective response which is generally tightly controlled by the body at the site of injury. Loss of this local control or an overly activated response results in an exaggerated systemic response that affects distant organs which is clinically identified as systemic inflammatory response syndrome (SIRS). Causes of SIRS include sepsis, acute pancreatitis, trauma and burns. In all of these processes, the production of oxygen free radicals has been reported to play a role as initiators, enhancers and damaging agents. Free radicals can act as a molecular trigger of the mechanism of inflammation after the initial insult. Oxidative stress mediates the activation of NFkB inducing in turn the transcription of certain genes promoting cytokine production. Release of these cytokines results in the enhancement of the inflammatory response. On a second step, free radicals generated into the bloodstream mainly from circulating neutrophils, but also from xanthine oxidase, act as activators of endothelial cells in
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distant organs. As a consequence, a second level of the inflammatory cascade is triggered by the induction of adhesion molecules and the generation of cytokines and other inflammatory mediators. Finally, free radicals generated by infiltrated neutrophils into distant organs act directly as noxious agents that react with molecular components, enhancing the inflammatory process and affecting cell viability. Altogether makes free radicals a particularly interesting therapeutic target in the different stages of the process, not only to prevent oxidant cell damage, but also modulating the inflammatory response. It is likely, however, that best results using antioxidant therapies will be obtained in combination with modulators of cytokines and other inflammatory pathways that become also activated during the progression of SIRS.
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