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ILAR Journal V40(4) 1999
Animal Models of Inflammation
Matthew L. Steinhauser, Steven L. Kunkel, and Cory M. Hogaboam
| All authors are from the Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, where Matthew L. Steinhauser, B.S., is a Research Assistant, Steven L. Kunkel, Ph.D., is an Endowed Professor, and Cory M. Hogaboam, Ph.D., is an Assistant Professor. |
Clinical Significance of Sepsis
Sepsis is quite common, with more than 100,000 cases annually in the United States alone (Bmn-Buisson and others 1995; Seidenfeld and others 1986). Ultimately 25 to 35% of all septic episodes end in death, and those patients experiencing septic peritonitis display a much higher mortality rate of 60 to 80% (Bone and others 1992; Holzheimer and others 1991; Parrillo and others 1990). Two general diagnostic criteria define sepsis: (1) Septic patients display systemic inflammatory response syndrome (SIRSb, which is generally characterized by a state of severe, systemic endothelial cell inflammation. (2) Septic patients must also have documented evidence of infection (American College of Chest Physicians/Society of Critical Care Medicine 1992; Bone 1991). Although microorganisms and microor-ganism-derived products are important contributors to the disease state, the clinical manifestations of sepsis usually stem from intense cellular interactions associated with systemic inflammation (Brigham and Meyrick 1986; Goris and others 1985; Nuytinck and others 1988). The generalized activation of the immune system also has physiological implications. The most common symptoms of sepsis are hy-potension, coagulopathy, fever or hypothermia, tachycardia, tachypnea, tissue injury, and multiorgan dysfunction. In addition, sepsis often induces a state of immunosuppression (Bone and others 1992). Consequently, the host displays a predisposition to the development of nosocomial infection, particularly bacterial infection of the lung (Brun-Buisson and others 1995; Montgomery and others 1985). Not only is pneumonia more common in patients with sepsis, but also those septic patients that develop complicating pneumonia display mortality rates as high as 90% (Niederman and Fien 1990; Seidenfeld and others 1986).
Despite significant advances in antibiotic development, intensive care unit technology, and mechanical ventilatory support, sepsis-related mortality remains unacceptably high. The limited capacity of present medical technology to effectively treat sepsis and septic-induced disorders presumably reflects an insufficient understanding of the mechanisms of sepsis pathogenesis. Thus, extensive research into the septic response has occurred to gain a more complete understanding of the endogenous mediators that initiate and maintain or regulate the inflammatory responses leading to the syndrome.
Pathogenesis of Sepsis
Sepsis is initiated by the presence of microbial organisms or their components. Lipopolysaccharide, for exampleIa major cell wall component of Gram-negative bacterial organisms--can alone instigate many of the pathophysiological events that occur within the host during a septic episode (Remick and others 1990). The septic response, like many other pathological disease processes, depends on an organized series of molecular and cellular events that participate in a complex network of cell signaling and activation. Various chemical signals mediate elaborate cell-to-cell communication cascades that are responsible for the initiation, maintenance, and resolution of disorders like sepsis. The list of mediators responsible for the coordination of these communication networks includes reactive nitrogen and oxygen metabolites, lipids, nucleotides, peptides, and polypeptides. The latter class of immune molecules contains a large group of important mediators collectively termed cytokines, which are active communication signals that influence cell activation events via autocrine, paracrine, or endocrine pathways. Furthermore, the various activities for which cytokines are responsible -- including cellular activation, chemotaxis, cell differentiation, augmentation of phagocytosis, and induction of cell proliferation -- dictate the progression of immune/inflammatory responses (Kunkel 1997; Strieter and others 1993).
During the onset of sepsis, microbial components and byproducts induce the production of the early-response, pro-inflammatory cytokines, which are tumor necrosis factor (TNF1)-a and interleukin (IL1)- 1b. These two cytokines have been shown to mediate directly or indirectly the hemodynamic and inflammatory changes characteristic of sepsis (Remick and others 1990). Furthermore, TNF and IL-1 initiate a proinflammatory cascade, resulting in the production of other proinflammatory cytokines like IL-6, interferon (IFN1)-g, IL-12, and various chemokines (which are a subclass of cytokines with chemotactic and activating properties). In general, the proinflammatory cytokine cascade effects a wide range of events including activation of resident immune cell populations at the infection site and early infiltration of phagocytic polymorphonuclear cells or neutrophils and mononuclear phagocytes. Although the threat of bacterial colonization during sepsis necessitates compartmentalized inflammatory responses at the site of active infection, an overexuberant proinflammatory cytokine response can result in the release of inflammatory cytokines into circulation, followed by systemic immune cell activation, hemodynamic instability, and end-organ injury. Thus, the host relies on the action of antiinflammatory mediators, like soluble TNF and IL-1 receptors (sTNFr and IRAP), IL-10, and IL-4, to rein in the often overzealous proinflammatory response during sepsis (Blackwell and Christman 1996; Bone 1991). Although it is clear that endogenous antiinflammatory mediators are required for the host to achieve proper disease resolution, this compensatory antiinflammatory response contributes to the state of immunoparalysis often observed in septic patients. Ultimately, many of those septic patients that survive the acute hyperinflammatory response experience this state of immunoparalysis in which they are highly susceptible to lethal secondary infections.
Modeling Sepsis
Endotoxin is widely considered to be an important inducer of the septic response, and it follows that its administration to a healthy host can cause physiological symptoms reminiscent of sepsis. Thus, many studies have attempted to recreate sepsis syndrome in animals by bolus injection or continuous infusion of endotoxin, either intraperitoneally or intravenously. Although the response to endotoxin varies widely depending on the dose, site, and timing of administration, the primary intent of any endotoxin-based model is to mimic the physiological symptoms associated with sepsis. However, this approach to modeling ignores one of the fundamental diagnostic guidelines for sepsis--that septic patients have evidence of bacterial infection. Although endotoxin models may be valuable tools for investigating well-defined, physiological variables during sepsis, they are poor settings for therapeutic evaluation. This discrepancy between the patho-genesis of endotoxemia and human clinical sepsis likely explains the failure of endotoxin models in predicting the therapeutic potentiality of TNF and IL-1 neutralization strategies. Although studies with endotoxemia models showed significant benefit associated with neutralizing the biological activity of proinflammatory cytokines like IL-1 and TNF, these therapies failed in humans suffering from sepsis (Abraham and others 1995, 1998; Fisher and others 1994, 1996). Although some of the preclinical trials with TNF and IL- 1 soluble receptors used models based on a bolus infusion of live bacteria, it has since been shown that this model acts as a toxic shock model rather than bacterial sepsis (Bagby and others 1991).
The most clinically relevant models of sepsis attempt to recreate the physiological symptoms of sepsis concurrent with an active bacterial infection. Humans seldom face a sudden exposure to large numbers of bacteria. Thus, the common scenario in clinical cases of sepsis is one in which some focus of infection seeds the body with bacteria. Of the various bacterial sepsis models, our laboratory employs the cecal ligation and puncture (CLP1) model of sepsis because of its resemblance to clinical sepsis. As previously described (Walley and others 1996; Wichterman and others 1980), sepsis is induced by opening the abdominal cavity of mice, ligating the distal one third of the cecum, and finally puncturing the ligated cecum with a needle. This operation results in a slow leak of fecal material into the peritoneal cavity, inducing a focused peritonitis that often leads to bacteremia. The manner in which CLP induces sepsis and the subsequent pathological progress of CLP-induced disease mirror many clinical cases of sepsis, especially those scenarios in which the slow leakage of bowel contents induces a septic response. Examples include postsurgical trauma, inflammatory bowel disease, and bowel ischemia. Furthermore, the subsequent response to cecal products that leak into the peritoneal cavity resembles that described for septic patients, in that the CLP model produces delayed and prolonged proinflammatory cytokine expression. Perhaps most importantly, the CLP model meets the two general diagnostic criteria for sepsis: The mice display systemic inflammation akin to the human systemic inflammatory response syndrome, and they experience an active microbial infection.
Most of the sepsis models mentioned above can be recreated in a variety of mammalian species including primates, dogs, pigs, rats, guinea pigs, and mice. Each species presents different advantages, depending on the type and purpose of the experiments. Many experiments, for instance, must be done using large animal models. However, small animal species provide a more cost-effective and practical alternative for studies requiring large numbers of animals (Fink and Heard 1990). Many laboratories (including ours) use mice to model sepsis, because this species provides additional advantages over other small mammals. Specifically, various technologies are available to investigators using mice for sepsis experimentation. A large spectrum of murine-specific monoclonal and polyclonal antibodies are available for use in protein detection assays (enzyme-linked immuno-sorbent assays), immunohistochemical protein localization, and immunoneutralization experiments. In addition, a large number of different genetically defined and genetically engineered mouse strains are available for disease modeling. Finally, there has been a recent explosion in the development of transgenic and "knock out" mice, which can be invaluable in the characterization of molecular mechanisms of septic pathology.
Cytokines in Sepsis
As mentioned above, a septic response is triggered upon exposure to microbes or microbial products, resulting in the initiation of a proinflammatory cytokine cascade. Although numerous cytokines have been implicated in the pathogen-esis of sepsis, TNF, IL-I, IL-6, and IL-8 have been most strongly associated with disease progression (Blackwell and Christman 1996). TNF and IL-1 in particular have received much attention as the most proximal endogenous mediators of the proinflammatory cytokine cascade. TNF and IL- 1 are released shortly after exposure to bacterial products, with peak production occurring within 2 hr after initiation of sepsis (Cannon and others 1990; Hesse and others 1988). Together these potent inflammatory agonists directly or indirectly mediate the hemodynamic and inflammatory changes that typify sepsis syndrome (Remick and others 1990). In fact, the infusion of either cytokine into a healthy host can alone cause many of the pathophysiological symptoms observed during a clinical bout of sepsis (Chapman and others 1987; Dinarello 1991; Selby and others 1987; Smith and others 1990; van der Poll and others 1990).
The extensive characterization of in vivo and in vitro properties of these proinflammatory cytokines strengthens their assigned role as the primary initiators of the typical septic inflammatory reaction. Although both TNF and IL-1 can directly contribute to polymorphonuclear maturation, trafficking, and activation (Dinarello 1991; Moser and others 1989; Munro and others 1989; van der Poll and others 1992; Wewers and others 1990), these early-response cytokines serve a fundamental role in the progression to septic shock and/or multiorgan dysfunction by initiating the proinflam-matory cascade. TNF and IL- 1 both stimulate the release of a gamut of downstream proinflammatory mediators (Blackwell and Christman 1996; Bone 1991; Dinarello 1997; Tracey and Cerami 1993; van der Poll and Lowry 1995). In sum, this body of data casts TNF and IL-1 as pivotal mediators of the septic response, inasmuch as the production of these two cytokines facilitates the release of many proinflammatory agonists participating in the cascade, ultimately leading to multiorgan dysfunction and death.
Because of the central role TNF and IL- 1 appear to play in the proinflammatory cascade that leads to septic pathology, many early cytokine manipulation therapies targeted these two mediators. The neutralization of either IL-1 or TNF in models of septic shock resulted in a substantial reduction in systemic inflammation and mortality (Beutler and others 1985; Dinarello and Thompson 1991; Tracey and others 1987). However, later experiments using models of bacterial sepsis cast IL- 1 and TNF as important mediators of host defense (Eskandari and others 1992; O'Reilly and others 1992). Similarly, clinical trials aimed at neutralizing the biological activity of TNF or IL-1 failed to improve the outcome of sepsis in human patients (Abraham and others 1995, 1998; Cohen and Carlet 1996; Fisher and others 1994, 1996).
While IL-12 has classically been regarded as a pivotal stimulus of Th1-type T cell-mediated immune responses (Brunda 1994), recent studies have identified IL-12 as an important cytokine mediator during septic inflammatory events (Hazelzet and others 1997; Heinzel and others 1994; Mancuso and others 1997; Wysocka and others 1995; Zisman and others 1997a). Although IL-12 has been shown to enhance the cytolytic activity of cytotoxic T lymphocytes and natural killer (NK1) cells and to stimulate the proliferation of activated T and NK cells (Brunda 1994), IL-12's most important function during a septic inflammatory reaction may be the stimulation of cytokine production from NK and T cells. More specifically, IL-12 can induce the production of IFN-g by NK and T cells (Gazzinelli and others 1993; Heinzel and others 1994). As a hallmark cytokine of the innate immune response, IFN-g upregulates human leukocyte antigen-DR expression, stimulates macrophage and neutrophil microbicidal activity, and primes macrophages for enhanced TNF and IL-1 synthesis. Thus, IL-12's most profound contribution to the septic inflammatory milieu may be the indirect activation of inflammatory cells via the upregulation of IFN-y production.
Although both IL-12 and IFN-g clearly function as pro-inflammatory mediators and likely contribute to the deleterious hyperinflammatory state that typifies SIRS, the function of these cytokines in sepsis appears complex. Not surprisingly, studies with models of endotoxin-induced septic shock have implicated IL-12 and IFN-g as deleterious mediators of septic pathology. The neutralization of IL- 12 and subsequently IFN-g in the context of endotoxemia resulted in substantial improvements in mortality associated with shock, suggesting that the inflammatory properties of these cytokines are inappropriate during sepsis (Wysocka and others 1995; Zisman and others 1997a). The roles of IL-12 and IFN-g during sepsis are less clear. During responses characterized by systemic inflammatory reactions to bacterial infection, IL-12 and IFN-g clearly play important roles, as their neutralization in various infection models results in reduced bacterial clearance and increased infection-induced mortality (Chehimi and Trinchieri 1994; Flynn and others 1995; Gazzinelli and others 1993; Greenberger and others 1996; Heinzel and others 1993; Stevenson and others 1995; Young and Hardy 1995). Furthermore, experiments with models of bacterial sepsis suggest a vital function for endogenously produced IL-12 and IFN-g. IFN-g clearly serves a protective role in a model of fecal peritonitis, as IFN-y receptor-deficient mice experience increased mortality (Zantl and others 1998). Similarly, observations using a neonatal murine sepsis model caused by group B streptococci suggested that IL- 12 neutralization induced lethality by facilitating bacterial infection (Mancuso and others 1997). Moreover, our laboratory has shown that endogenous IL-12 production is required for the containment of bacteria and prevention of mortality associated with CLP-induced sepsis (Steinhauser and others 1999b). IL-12 and IFN-g clearly serve an important role during bacterial sepsis, probably functioning to contain bacterial infection. These data further support the contention that the pro-inflammatory cascade during sepsis is a vital host response.
Although various proinflammatory cytokines contribute to the inflammatory cascade that produces septic pathology, various cytokines also display antiinflammatory properties, serving to counterbalance an overzealous proinflammatory state. IL-10 in particular has been implicated as the primary endogenous modulator of the lethal inflammatory response during sepsis, which drives the compensatory antiinflammatory response. The importance of IL-10 production during sepsis has been well established in various sepsis models (Gerard and others 1993; Howard and others 1993; van der Poll and others 1995; Walley and others 1996). The neutralization of IL-10 in models of endotoxin shock and bacterial sepsis results in exaggerated proinflammatory cytokine expression and death. Conversely, the administration of IL-10 to mice with endotoxemia or bacterial sepsis confers significant therapeutic protection. The vital role of IL-10 during a septic response has been attributed to this cytokine's ability to suppress the production of proinflammatory cytokines, including TNF-a, IL-I, and IFN-g (Cassatella and others 1993; Fiorentino and others 1991; Grunig and others 1997; Kasama and others 1994). Furthermore, IL-10 appears to promote a state of inflammatory cell deactivation, as evidenced by its repression of macrophage and neutrophil phagocytic and bactericidal activities (Bogdan and others 1991; de Vries 1995; Howard and others 1992; Laichalk and others 1996; Oswald and others 1992; Randow and others 1995; Strassmann and others 1994). Although IL-10 is clearly required to control and resolve the inflammatory cascade during sepsis, this antiinflammatory cytokine can become deleterious during a severe infection. The endogenous production of IL- 10 has been implicated in disease-induced mortality associated with various infection models (Bermudez and Champsi 1993; Greenberger and others 1995). In the CLP model specifically, we have shown that a shift toward increased IL-10 production concomitant with decreased IL-12 and IFN-g production after the immunoneutralization of IL-12 reduced bacterial containment in the peritoneum and increased mortality. Moreover, we have shown that endogenous IL-10 production during murine CLP-induced sepsis results in a predisposition to nosocomial pneumonia, which is among the most common lethal manifestations of sepsis syndrome (Steinhauser and others 1999a). These data suggest that IL-10 is a major contributor to the state of immunoparalysis after the initial septic hyperinflammatory response; and the use of antiinflammatory/immunosuppressive cytokines like IL-10 during sepsis may involve a high risk of complications associated with increased susceptibility to infection.
Cytokines have emerged as vital initiators and propagators of the inflammatory response that typifies sepsis. Although the production of prominent proinflammatory cytokines like TNF, IL-l, IL-12, and IFN-g clearly results in much of the tissue pathology and deleterious physiological symptoms associated with sepsis, this cascade appears to be an important host-defense response. Furthermore, data collected thus far clearly call into question future drugs targeting the integral members of the proinflammatory cascade.
Chemokines in Sepsis
Chemokines are a class of cytokines originally described as leukocyte chemoattractants. Recently, however, these small
proteins have been shown to function in the regulation of anglogenesis, fibrinogenesis, and immune/inflammatory responses and as inflammatory/immune cell activators (Mackay 1997; Rollins 1997). The two best understood classes of chemokines are the C-X-C and C-C families, named for the distinctive cysteine residue motifs observed in these molecules. More recently, however, the C and C-XXX-C chemokine families have been described (Klm and Broxmeyer 1999). Several chemokines are clearly upregulated during sepsis, as increased levels of IL-8, macrophage inflammatory protein (MIP1)- 1a, MIP- 1b, monocyte chemotactic protein (MCP1)- 1, and MCP-2 appear to correlate with the diagnosis of the disease in human patients (Bossink and others 1995; Damas and others 1997; Hamano and others 1998; Marie and others 1997; O'Grady and others 1999). Moreover, our laboratory has shown that the chemokines MCP-1 (originally known as JE), MIP-1a, and MIP-2 are produced during CLP-induced sepsis (Walley and others 1997). Although various studies have implicated chemokines as members of the septic cytokine cascade, very little is known about the specific roles of chemokines in sepsis (Table 1). To this end, our laboratory has shown that during CLP-induced sepsis, the specific neutralization of the C-X-C chemokine MIP-2 results in reduced neutrophil infiltration of the peritoneal cavity, which correlates with a marked reduction in mortality (Walley and others 1997). Although this reduction in neutrophil recruitment after MIP-2 neutralization is likely related to this molecule's chemotactic properties, MCP- 1 (a CC chemokine) appears to display immunomodulatory properties in an acute inflammatory response. Interestingly, during endotoxin-induced septic shock, the exogenous administration of the CC chemokine MCP-1 confers significant therapeutic advantage (Zisman and others 1997b). During endotoxin challenge, MCP-1 appears to be operating therapeutically by facilitating increased IL-10 production concomitant with decreased IL-12 and TNF production, suggesting that MCP-1 may facilitate a shift from a hyperinflammatory state to a compensatory antiinflamma-tory response. Although MCP-1 appears to display systemic immunomodulatory properties during the septic response to endotoxin challenge, in CLP-induced sepsis, MCP- 1 administration results in a significant increase in inflammatory cell infiltration of the peritoneum (Figure 1). In addition to its potent chemotactic properties, MCP-1 has been shown to activate macrophage phagocytic and bactericidal activity (Nakano and others 1994). This combination of immuno-stimulatory and immunomodulatory properties may make MCP-1 an attractive therapeutic molecule for the treatment of bacterial sepsis. Furthermore, these data open the possibility that more chemokines may display unique combinations of regulatory properties during sepsis, including the capacity to shift focus from an SIRS-like hyperinflammatory state to a compensatory antiinflammatory response.
With the apparent failure of cytokine manipulation therapies targeting integral members of the proinflammatory cascade, chemokines may emerge as viable therapeutic targets. Two aspects of chemokine function may make these small proteins especially viable targets for therapeutic manipulation: (1) Chemokines appear to be more distal participants in the proinflammatory cascade. Whereas TNFa and IL-1 production appear to peak to 1 to 4 hr after the initiation of a septic response (Cannon and others 1990; McAllister and others 1994; Michie and others 1988), our laboratory has shown that the chemokines MCP-1, MIP-1a, and MIP-2 peak approximately 24 hr after the initiation of CLP-induced sepsis (Walley and others 1997). This temporal delay suggests the possibility of inflammatory manipulations without drastically altering cytokine balance. Additionally, because most septic patients present after the initiation of the septic response, distal mediators may present realistic targets for therapy in a clinical setting. (2) Although the list of identified chemokines now exceeds 50, each chemokine appears to feature a distinct functional profile. By definition, chemokines are chemotactic agents; however, each chemokine may also display a unique spectrum of nonchemotactic functions, including cellular activation and/or regulation, angiostatic or angiogenic capabilities, and pro-/antifibrinogenic properties. Thus, specific chemokine manipulations may enable far more focused effects on the disease process, without derailing what appears to be an essential sequence of inflammatory events (Figure 2).
Conclusion
During sepsis there appears to be a balance, albeit precarious, between pro- and antiinflammatory cytokines. Although the proinflammatory cascade clearly drives much septic-induced pathology, studies using models of bacterial sepsis clearly indicate that the inflammatory response is required for the containment of infection. Chemokines, however, are more distal mediators of the septic response that also display unique functional profiles. Thus, manipulation of specific chemokine levels during a septic episode may promote disease resolution without leaving the patient susceptible to infection. Animal models (especially those that mimic human bacterial sepsis like the CLP model) will play an essential role in deciphering the role of chemokines in sepsis and in evaluating the therapeutic potential of chemokine manipulations during septic progression.
1 Abbreviations used in this article: CLP, cecal ligation and puncture; IFN, interferon; IL, interleukin; MCP, monocyte chemotactic protein; MIP, mac-rophage inflammatory protein; NK, natural killer; SIRS, systemic inflammatory response syndrome; TNF, tumor necrosis factor.
Acknowledgment
We thank Robin Kunkel for her artistic help.
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Table 1 Contribution of chemokines to the septic milieu: Summary of those chemokines known to be produced during murine and/or human sepsisa
| Therapeutic manipulation? | ||||
| Human | Mouse | Human | Animal model | |
| MCPb-1 | MCP-1/ JE/ MCAFb | Yes | Murine endotoxemia; primate bacteremia | MCP-1 protein therapy improves survival in murine endotoxemia; MCP-1 neutralization reduces survival in murine bacterial sepsis (CLPb) |
| MCP-2 | MCP-2 | Yes | Primate bacteremia | ? |
| MIPb-1a | MIP-1a | Yes | Murine endotoxemia; murine bacterial sepsis (CLP) | ? |
| MIP-Ib | MIP-Ib | Yes | Murine endotoxemia; murine bacterial sepsis (CLP) | ? |
| RANTESb | RANTES | ? | Murine endotoxemia | ? |
| ILb-8 | MIP-2 | Yes | Murine bacterial sepsis (CLP); murine/rabbit endotoxemia | IL-8 neutralization improves survival in rabbit endotoxin shock; MIP-2 neutralization improves survival in murine CLP |
| GROb-a | KC | ? | Murine bacterial sepsis | ? |
| IPb-10 | IP-10 | ? | Murine bacterial sepsis | ? |
| ? | LIXb | ? | Murine endotoxemia | ? |
b bMCP, monocyte chemotactic protein; MCAF, monocyte chemattractant and activating factor; CLP, cecal ligation and puncture; MIP, macrophage inflammatory protein; RANTES, regulated upon activation in normal T cells; IL, interleukin; GRO, growth-related ongogene; IP, interferon-inducible protein; LIX, lipopolysaccharide-inducible CXC chemokine.
Figure 1 Administration of monocyte chemotactic protein (MCP)-1 to mice with cecal ligation and puncture (CLP)-induced sepsis causes increased accumulation of macrophages and neutrophils within the peritoneal cavity. MCP-1 (500 mg) was given by intraperitoneal injection immediately after CLP surgery. Cell populations were determined from peritoneal washes taken from mice 4 hr after CLP surgery. *p<0.05 as determined by Bonferroni t test.
Figure 2 Schematic depicting the hypothesized paradigm of the role of cytokines and chemokines in sepsis. ANTI = antiinflammatory cytokines; PRO = proinflammatory cytokines, ainterleukin (aIL)- 10/aIL- 1/atumor necrosis factor (aTNF) denotes cytokine specific neutralization, whether it be with antibodies, soluble receptors, or receptor antogonists. JE, original name for monocyte chemotactic protein-1.
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