Multiple organ dysfunction syndrome (MODS) became a problem in intensive care units (ICUs) after improvements in hemodynamic support and fluid resuscitation led patients to survive the acute phase of shock and sepsis. Thirty years after its initial description (1), the mortality of MODS remains essentially unchanged. MODS still is the principal cause of morbidity and mortality for patients admitted to an ICU. The costs of its treatment are enormous (2, 3).
MODS has been documented to occur after a number of diverse clinical conditions, such as infection, shock, trauma, and pancreatitis. Thus, patients suffering from MODS comprise a heterogeneous population, which complicates research into its pathogenesis. Still, the development of rational interventions requires insight in the pathological processes involved. Elucidation of the mechanisms involved in the development of MODS will ultimately necessitate the collection of tissue samples and the performance of invasive procedures. These requirements greatly reduce the possibilities for research in human subjects. Therefore, an animal model for MODS is a necessary and valuable tool. In 1986, Goris and coworkers (4) first described a model that has subsequently been recognized as the one that best resembles human MODS. This review describes the model and aims to arrange the results reported in a variety of studies.
Zymosan is a substance derived from the cell wall of the yeast Saccharomyces cerevisiae. It is composed of polysaccharide chains of various molecular weights, containing approximately 73% polysaccharides, 15% proteins, and 7% lipids and inorganic components (5). When injected into animals, it induces inflammation by inducing a wide range of inflammatory mediators. These include activated components of the complement system (6), prostaglandins and leukotrienes (7), platelet aggregation factor (8), oxygen radicals (9), and lysosomal enzymes (10). Also, zymosan directly activates macrophages (11). Toll-like receptor (TLR)-2 has been shown to be involved in zymosan-induced signaling (12). After zymosan is phagocytosed, macrophages release lysosomal enzymes (13), reactive oxygen metabolites, arachidonic acid (14), and tumor necrosis factor-α (TNF-α) (15). Because zymosan is not degradable, phagocytosis by macrophages results in a prolonged inflammatory response. This effect can be enhanced by the use of mineral oil as a carrier.
THE ZYMOSAN-INDUCED GENERALIZED INFLAMMATION (ZIGI) MODEL
Most experimental models of critical illness, such as infusion of endotoxin or bacteria or cecal ligation and puncture, are essentially acute models for sepsis. Almost invariably, they are used to improve or investigate short-term mortality and organ failure. The observation period consists of hours rather than days. Because it usually requires at least 5 to 7 days after the initial event to fully develop MODS in critically ill patients, chronic models are likely to be more relevant to the human situation. To date, the ZIGI model is the only long-term experimental animal model for MODS.
Intraperitoneal injection of zymosan in a high dosage (0.8-1.0 mg/g body weight) in rats and mice results in a three-phasic illness. After the injection of zymosan, the animals develop acute peritonitis. They are very ill during the first 2 days, as reflected by ruffled fur, diarrhea, lethargic behavior, and a decrease in body weight. During this phase, the animals are leukopenic, and oxygen consumption (4), myeloperoxidase levels (indicating neutrophil recruitment) in lungs and peritoneum (16, 17), and endothelial permeability (18) are increased. Bacterial translocation to the peritoneal cavity and mesenteric lymph nodes is found regularly (19). The mortality in this phase is usually between 10% and 35%. Because early mortality suddenly increased dramatically a few years ago (up to 100%), most likely as the result of changing conditions within our central animal facility, we have introduced a small modification to the initial model (20). This modification consists of an aseptic intraperitoneal injection of 40 μg of lipopolysaccharide (LPS) 6 days before the intraperitoneal injection of zymosan in mice. LPS activates a variety of cell types, such as monocytes/macrophages, endothelial cells, and some epithelial cells (21). Triggering the immune system with a small dose of LPS prevents an excessive response to zymosan 6 days later because the mortality rate of the animals in the first days after zymosan returned to normal (below 30%).
In the second phase of the model (days 3-5), the condition of the surviving animals appears to return to normal, as reflected by the display of natural curiosity, grooming, smooth fur, and the disappearance of diarrhea. Body temperature is restored to normal, and the animals gain weight. There is no mortality in this phase. From approximately day 7 onward, the animals enter a MODS-like phase, characterized by lethargic behavior, breathing difficulties, progressive weight loss, and a substantial decrease in body temperature. Between days 7 and 14, the mortality is between 20% and 30%. Histopathological changes in various organs indicate a gradual development of a generalized inflammatory response with extensive tissue injury (22). Massive hemorrhages develop in the lungs. The liver displays progressive accumulation of macrophage-like and mononuclear cells, forming granuloma-like structures. The spleen displays great changes in red and white pulp with increased numbers of megakaryocytes and plasma-like cells (23). Organ damage in this phase is also reflected by an increase in the wet weight of lung, liver, and spleen (23), indicating tissue edema. Very recently, we have found that the activity of matrix metalloproteinases, which class of enzymes catalyzes connective tissue degradation, is upregulated during the development of organ damage (24). During the third phase, the course of body weight and body temperature-and, obviously, mortality-are quantitative measures of illness. Figure 1 shows the course of these parameters during a typical experiment. At the end of the experiment, organ weight or (semi)-quantitative histology yield good parameters for organ disease.
Initially, MODS was believed to occur only after a bacterial infection or endotoxemia. Zymosan causes an intense inflammatory response without administration of exogenous bacteria or modification of the normal bacterial flora. This allows examination of the possible role of bacterial translocation in the development of MODS. Studies in rats have shown that in the ZIGI model, bacterial translocation is common (19, 22, 25-28) but not essential for the development of organ damage. Using germ-free rats (4) and selective decontamination of the gastrointestinal tract of normal rats, Goris et al. (25) have demonstrated that zymosan is capable of inducing MODS in the absence of bacteria. In streptomycin-decontaminated rats, survival was 100% despite massive translocation of streptomycin-resistant enterobacteriacea (29). Streptomycin has been shown to prevent macrophage activation (30). Also, it has been reported that mice that are hyporesponsive to endotoxin remain only in a slightly better condition than endotoxin-sensitive mice (31), which suggests that endotoxin is not essential in the pathogenesis of MODS. Elimination of macrophages lowers the systemic toxic response (as indicated by the degree of conjunctivitis, ruffled fur, lethargy, and diarrhea) and subsequent mortality, despite the fact that systemic bacterial translocation is enhanced (32). Taken together, these observations support the hypothesis that, in this model, MODS is the result of a generalized inflammatory response rather than infection per se.
Because MODS is now believed to be the result of a generalized inflammatory response, increasing attention has been paid to the role of proinflammatory mediators in its pathophysiology. The (over)expression of these mediators, which include cytokines, complement factors, and reactive oxygen species, results in increased peripheral dilatation, leukocyte/endothelial cell activation, excessive microvascular permeability, and accelerated microvascular clotting (33). These responses contribute to the development of profound changes in the various organs, which may eventually lead to MODS (34, 35).
Zymosan induces secretion of TNF-α, interleukin (IL)-1β, IL-6, and IL-8 by macrophages (36). Three mechanisms are known by which zymosan can trigger cytokine secretion. First, normal serum contains immunoglobulin (Ig) G, which binds to zymosan (37). The complexes formed this way activate the classical pathway of the complement system, and may induce TNF-α release by cross-linking macrophage Fc receptors (38). Second, zymosan activates complement via the alternative pathway (39). The subsequent binding of C3b/iC3b to zymosan particles enables uptake of the particles via complement receptors on macrophages and granulocytes. Third, the binding of C3b to the zymosan surface results in increased conversion of C5 to C5a (40), which triggers TNF-α release (41). Whereas these pathways act synergistically to induce TNF-α release (42), the mechanisms by which other cytokines are induced by zymosan are less clear. IL-1β and IL-6 release by macrophages is partly dependent on exposure to TNF-α. A strong increase in the secretion of IL-8 is induced by phagocytosis of zymosan by monocytic cells (43).
In zymosan-induced organ damage, TNF-α appears to play an important role. Jansen et al. (44) found that plasma TNF-α and IL-6 concentrations were transiently increased during the first 24 h after administration of zymosan. After 8 days, a prominent peak of biologically inactive TNF-α was observed. There also was a significantly enhanced LPS-stimulated production of TNF-α by peritoneal cells over the entire experimental period. The plasma TNF levels did not correlate with the peritoneal macrophage TNF production levels, especially in the second phase of illness, when no plasma TNF could be detected. Peritoneal macrophage TNF production was very high. Volman et al. (45) found an increased expression of TNF-α, IL-1β, IL-6, IL-12, and interferon-γ (IFN-γ) mRNA in a time-dependent pattern in several organs. This increase was most pronounced for TNF-α in the lungs and liver. Moreover, in TNF-α/lymphotoxin-α knockout mice (20) and in TNF receptor p55 knockout mice (46), survival and clinical condition were significantly improved after zymosan challenge if compared with the respective wild-type controls. Also, intervention studies directed at TNF-α using a specific antibody (47), chlorpromazine (48), IL-10 (49, 50), and the alkaloid fangchinoline (51) have demonstrated mitigation of zymosan-induced MODS. This was reflected in improved survival, a lesser increase in organ weight, a less severe drop in body temperature and weight, improved pulmonary compliance, and reduced hemorrhage formation in the lungs. Although all these data suggest an important role for TNF-α in the development of organ damage, it is unlikely to be the only mediator responsible because interventions directed against TNF-α alone or even its complete absence could reduce but not prevent the symptoms of zymosan-induced MODS.
THE COMPLEMENT SYSTEM
Excessive complement activation has been proposed to play a role in MODS (52). Complement factor C5, participating in the classical and alternative pathway, is a potent polymorphonuclear neutrophil (PMN) chemoattractant. PMNs are capable of producing a variety of inflammatory mediators, including cytokines, oxygen radicals, proteases, and arachidonic acid metabolites, thereby possibly contributing to the tissue damage observed in MODS.
Nieuwenhuijzen et al. (53) injected C5-deficient mice and C5-sufficient mice with zymosan and observed a lower mortality and a less severe decrease in body temperature and body weight in the first, acute phase in the C5-deficient mice. Also, the C5-deficient mice scored better on a symptom scale of lethargy, conjunctivitis, diarrhea, and ruffled fur in this phase. However, deficiency of C5 could not prevent organ damage (assessed as the relative organ weights) in the late, MODS-like phase. Miller et al. (54) also injected C5-deficient mice and C5-sufficient mice with zymosan and found a lower mortality in both phases in C5-deficient mice. However, in a follow-up study (55), the same research group did not find significant differences in pulmonary neutrophil infiltration between the two types of mice in the first phase, although the absence of C5 caused a decrease in circulating neutrophil levels.
In vivo studies with complement-modulating substances have also been performed. Ivanovska et al. (56) observed that administration of complement-inhibiting bisbenzyisoquinoline alkaloids to zymosan-treated mice yielded a lower mortality and a lower percentage of mice with injury of liver, kidney, and spleen. The latter was assessed from the presence of macroscopically observed fibrosis, solid accretions around these organs, foci of inflammation on renal membranes, and enlargement of the spleen.
Taken together, these studies suggest a certain involvement of complement factors in the development of murine MODS. However, because the number of studies is limited and the results are not unequivocal, it remains to be established if their role is essential and causative.
The release of oxidants by activated phagocytic cells can result in severe cell damage, most notably the peroxidation of cell membrane lipids. The lipid peroxidation process is associated with impaired cell membrane function and decreased adenosine triphosphate production, eventually leading to cell lysis and increased vascular permeability. Because of their cytotoxic effects, reactive oxygen and nitrogen species have been implicated in the pathogenesis of MODS (33, 34). Numerous studies have been undertaken to study the role of these substances in the ZIGI model.
The occurrence of lung and liver lipid peroxidation was found to correlate well with the triphasic illness. Lipid peroxidation is elevated in the first (57, 58) and the third phase (58) of illness. The production capacity of superoxide (O2−) and nitric oxide (NO) by peritoneal macrophages increases from day 7 onward and thus coincides with the occurrence of organ damage (59). Also, several studies have shown the presence of nitrotyrosine, a biomarker of the reactive nitrogen species peroxynitrite, in the course of the ZIGI model (60-63). Demling et al. (64, 65) reported an increased oxidant activity in the lung and a reduced antioxidant capacity in the liver.
Intervention studies directed at counteracting oxidant stress have also been performed. Van Bebber et al. (66) administered a combination of superoxide dismutase and catalase to rats treated with zymosan and found that, although lipid peroxidation was significantly decreased, mortality and organ damage remained unchanged. Because the rats were sacrificed 48 h after zymosan treatment, data are limited to the first, acute phase. Long-term administration of hydroxyl scavengers (mannitol, dimethyl sulfoxide, and dimethyl thiourea) did not improve the course of body temperature and body weight or the respiratory rate, organ weights, or mortality (29). Mainous et al. (27) found that pretreatment of rats and mice with allopurinol or ibuprofen, which are inhibitors of oxygen-derived free radical production, provided protection against bacterial translocation 6 h after zymosan injection and improved the survival rate, as measured after 7 days. Tempol, a small molecule that permeates biological membranes and scavenges superoxide anions and other free radicals, attenuated organ damage, as observed histologically in lung, liver, and intestine, and subsequent mortality in a study with rats (63). Cuzzocrea et al. (67) reported that intraperitoneal injection of N-acetylcysteine, a glutathione precursor, prevented the development of peritonitis and reduced peroxynitrite formation in a dose-dependent manner when given to zymosan-shocked rats. In addition, this intervention was effective in preventing the development of lung and intestinal injury and neutrophil infiltration. in vitro studies have demonstrated that oxidative injury in various cell types is related in part to DNA single-strand breakage and the subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS). (68). Massive ADP ribosylation of nuclear proteins by PARS can result in cellular energy depletion and injury (69) and, ultimately, organ damage. Several studies have shown that inhibition of PARS prevents neutrophil recruitment and reduces microscopically visible organ injury elicited by intraperitoneal injection of zymosan (70-72).
An enzyme that has received special attention regarding tissue damage is inducible NO synthase (iNOS). It is induced by cytokines and LPS and generates NO, a reactive nitrogen species that directly and indirectly may induce tissue damage during critical illness (73). NO is also produced by the constitutive isoforms of NOS, but only in relatively small amounts that are thought to be harmless, although of great importance to normal physiology (73). Cuzzocrea et al. (74, 75) have reported experiments that suggest a causative role for NO in zymosan-induced organ damage. Administration of L-NAME, a nonselective NOS inhibitor, attenuated zymosan-induced acute peritonitis in rats (74, 75). Also, iNOS knockout mice showed a lower mortality and a lesser degree of microscopically visible organ damage and neutrophil infiltration in the lungs, liver, and intestine than wild-type mice (61). Also, administration of aminoguanidine, a selective iNOS inhibitor, to wild-type mice had similar effects. However, these beneficial effects in aminoguanidine-treated mice and iNOS knockout mice could not be confirmed by Volman et al. (76). This apparent discrepancy might be explained by the fact that the latter authors examined the course of illness for at least 14 days, thus essentially investigating MODS after a chronic systemic inflammation. In contrast, Cuzzocrea et al. (74, 75) limited their observations to the first 48 h after zymosan administration, thus effectively studying nonseptic shock.
Taken together, it is clear that in the course of the ZIGI model, there is increased oxidant activity. Still, intervention studies aimed to suppress oxidant stress have not demonstrated complete protection against the development of MODS. This means that although oxidants certainly contribute to organ damage, other mechanisms must do so as well.
INTERVENTIONS DIRECTED AT MULTIPLE MEDIATORS
Because it appears unlikely that MODS is the result of the overexpression of a single mediator, interventions directed at multiple mediators may be expected to yield better results than those aimed at a single compound. Although dietary fish oil is believed to possess anti-inflammatory effects, intervention studies with dietary fish oil did not prevent MODS and did not reduce the expression of TNF-α and IL-6 (77, 78). Cuzzocrea et al. (62) reported the effects of hyperbaric oxygen therapy on multiple organ failure induced by zymosan in the rat. Although the precise molecular mechanisms remain unclear, it appeared that hyperbaric oxygen therapy exerts potent anti-inflammatory effects on systemic inflammation and effectively prevents the development of lung, liver, and intestinal injury. However, the experiment was ended after 72 h, when the degree of organ damage was only modest.
Tyrosine kinase inhibitors can reduce the formation and/or effects of TNF-α and IL-1β, the expression of iNOS and cyclooxygenase-2, and the activation of the transcription factor NF-κB (79, 80). Dugo et al. (81) studied the effects of the tyrosine kinase inhibitor tyrphostin AG126. This compound apparently attenuates the severity of MODS and reduces the mortality induced by zymosan. Still, Volman et al. did not find any beneficial effects of pentoxifylline, a substance that, at least in vitro, can reduce the expression of TNF-α, IL-1β, and IL-6 (T.J.H. Volman, R.J.A. Goris, and T. Hendriks, unpublished data).
Inhibition of NF-κB appears to be a promising approach in preventing the development of zymosan-induced MODS. Cuzzocrea et al. (82) found that inhibition of calpain I, which is an indirect way of preventing NF-κB activation, results in a lesser degree of inflammatory organ damage and a lower mortality during zymosan-induced MODS in rats. In apparent contrast, recent experiments in our laboratory failed to demonstrate any beneficial effects on morbidity and mortality of pyrrolidine dithiocarbamate, a nonspecific NF-κB inhibitor, in zymosan-treated mice (T.J.H. Volman and T. Hendricks, unpublished data).
CONCLUSIONS AND FUTURE DIRECTIONS
Figure 2 summarizes the mechanisms that are currently thought to contribute to the development of MODS. The ZIGI model has contributed significantly to our understanding of its pathophysiology, especially in the areas that are highlighted in the scheme. However, as in any animal model, it has its limitations. Animal models are suitable for investigating the mechanisms of disease. They are also necessary for the preclinical testing of potential therapeutic agents. However, it remains difficult to extrapolate the results of such studies to clinical practice because, for instance, the study population in animal studies is very homogenous (same sex and age, inbred population, etc.), whereas patient populations usually are very heterogenous. This does not in any way diminish the fact that animal studies can yield valuable indications for treatment options and, if an agent is proven successful in multiple animal models, there is a reasonable chance that it will be effective in patients as well. In the past, many efforts have been undertaken to identify the single mediator that causes most or all of the trouble in generalized inflammation. It now appears that MODS is unlikely to be the result of the overexpression of a single mediator. Intervention studies directed at blocking a single mediator, or a single process, have been successful in quite a number of cases but did not result in a complete disappearance of MODS-like symptoms. Therefore, interventions directed at multiple mediators currently seem the most promising approach. A major problem in performing these studies is discovering or designing agents that can block or modulate multiple mediators in a specific way. For instance, inhibiting the expression of multiple proinflammatory cytokines by inhibiting NF-κB seems a logical approach, but so far very few specific NF-κB inhibitors have been available for use in vivo. Next to this practical problem, there appears to be a great risk that inhibition of NF-κB will have harmful side effects, such as apoptosis of tissues and an impaired defense to bacteria (83).
Thus far, studies directed at multiple mediators have been performed using protocols that were unspecific, and the mechanisms of actions hardly understood, which makes it difficult to draw definite conclusions from these studies. Hopefully, far more specific interventions will become possible in the near future. This will improve the quality of the studies and will further improve our understanding of the underlying pathophysiology of MODS.
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