PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Chem Res Toxicol. Author manuscript; available in PMC Aug 17, 2010.
Published in final edited form as:
PMCID: PMC2787782
NIHMSID: NIHMS136600
Macrophages and Inflammatory Mediators in Chemical Toxicity: A Battle of Forces
Debra L. Laskin, Ph.D.
Debra L. Laskin, Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854;
Macrophages function as control switches of the immune system, providing a balance between pro- and anti-inflammatory responses. To accomplish this, they develop into different subsets: classically (M1) or alternatively (M2) activated macrophages. Whereas M1 macrophages display a cytotoxic, proinflammatory phenotype, much like the soldiers of The Dark Side of The Force in the Star Wars movies; M2 macrophages, like Jedi fighters, suppress immune and inflammatory responses and participate in wound repair and angiogenesis. Critical to the actions of these divergent or polarized macrophage subpopulations is the regulated release of inflammatory mediators. When properly controlled, M1 macrophages effectively destroy invading pathogens, tumor cells and foreign materials. However, when M1 activation becomes excessive or uncontrolled, these cells can succumb to The Dark Side, releasing copious amounts of cytotoxic mediators that contribute to disease pathogenesis. The activity of M1 macrophages is countered by The Force of alternatively activated M2 macrophages which release anti-inflammatory cytokines, growth factors and mediators involved in extracellular matrix turnover and tissue repair. It is the balance in the production of mediators by these two cell types that ultimately determines the outcome of the tissue response to chemical toxicants.
For most of my early scientific career, when I considered the role of macrophages in tissue injury, it was their dark side that intrigued me; after all, the movie Star Wars was on everyone’s mind and there were increasing numbers of publications supporting the idea that by releasing cytotoxic mediators that contribute to injury and disease, macrophages were very much like the Death Star. But over the last two decades, as more information has accumulated from my own laboratory and others, it has become clear that the contribution of macrophages and the mediators they release to chemically-induced tissue injury is much more complex. There is in fact, another side to macrophage functioning: suppression of inflammation and wound repair. Thus, the outcome of the response to tissue injury depends on the balance between the two opposing forces of macrophages. Furthermore, it appears that the multiplicitous functions of macrophages are not mediated by a single homogeneous population of cells. But in order to set the stage for this discussion, it is first necessary to provide some background on macrophages and inflammatory mediators they release.
Macrophages are mononuclear phagocytes derived from bone marrow precursors. These cells differentiate into monocytes which circulate in the blood. The majority of monocytes (>95%) localize in tissues and mature into macrophages where they develop specialized functions depending on the needs of the tissue. Thus, in the liver, resident macrophages or Kupffer cells develop a high phagocytic capacity, while in the lung, alveolar macrophages acquire the capacity to release large quantities of highly reactive cytotoxic oxidants. Macrophages are key players in the innate immune response. Through the process of phagocytosis, they function as scavengers, ridding the body of worn-out cells and debris, as well as viruses, bacteria, apoptotic cells and some tumor cells (1). Macrophages are also one of the most active secretory cells in the body releasing a vast array of mediators that regulate all aspects of host defense, inflammation and homeostasis including enzymes, complement proteins, cytokines, growth factors, eicosanoids and oxidants. In addition, they are considered professional antigen presenting cells, one of the major cell types involved in initiating specific immune responses of T lymphocytes.
Accumulating evidence suggests that the diverse biological activity of macrophages is mediated by functionally distinct subpopulations that are phenotypically polarized by their microenvironment and by exposure to inflammatory mediators (Table 1). These divergent macrophage subpopulations are broadly classified into two major groups: classically activated M1 macrophages and alternatively activated M2 macrophages. M1 macrophages are activated by type I cytokines like interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα), or after recognition of pathogen associated molecular patterns or PAMPs (e.g., lipopolysaccharide [LPS], lipoproteins, dsRNA, lipoteichoic acid) and endogenous “danger” signals (e.g., heat shock proteins, HMGB1). Alternatively activated M2 macrophages are further subdivided into M2a (activated by interleukin [IL]-4 or IL-13), M2b (activated by immune complexes in combination with IL-1β or LPS) and M2c (activated by IL-10, transforming growth factor-β [TGFβ] or glucocorticoids). M1 macrophages exhibit potent microbicidal activity, and release IL-12, promoting strong Th1 immune responses. In addition, they exert anti-proliferative and cytotoxic activities, which is due in part to the release of reactive oxygen and nitrogen species and proinflammatory cytokines (e.g., TNFα, IL-1, IL-6) (2, 3). It is the M1 population that is thought to contribute to macrophage-mediated tissue injury (2, 48). In contrast, M2 macrophages support Th2-associated effector functions. M2 macrophages release IL-10 and exert selective immunosuppressive activity, and inhibit T-cell proliferation. M2 macrophages also play a role in the resolution of inflammation through phagocytosis of apoptotic neutrophils, reduced production of pro-inflammatory cytokines, and increased synthesis of mediators important in tissue remodeling, angiogenesis, and wound repair. Similar functions are exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumorigenic role. It should be noted, however, that classification of macrophages into these two groups (M1 and M2) oversimplifies the complex functional activity of these cells. Macrophage activation is in fact a dynamic process; thus the same cells may initially take part in proinflammatory and cytotoxic reactions and later participate in the resolution of inflammation and wound healing (4, 9). This suggests that macrophages undergo progressive functional changes as a result of alterations in their microenvironment (2, 10, 11).
Table 1
Table 1
Activated Macrophage Subpopulations
The concept that macrophages accumulating in tissues in response to injury or infection have a “Dark Side” and can contribute to disease pathogenesis predated the first Star Wars movie by nearly one hundred years. Initially proposed in the late 19th century by one of the “fathers” of modern immunology, Eli Metchnikoff recognized that stimulated phagocytes might be capable of doing harm (12). He described the inflammatory process as a “salutary reaction against some injurious influence” and postulated that “ferments” released by cells at the site of inflammation might be capable of damaging host tissues (13, 14). Over the last century, this concept has been refined as the functions of macrophages in many disease processes have been better elucidated. It is now well established that cytotoxic and proinflammatory mediators released by activated macrophages can contribute to the pathophysiological responses initiated by diverse xenobiotics in many different tissues [reviewed in (15)]. Thus, there are numerous examples in the literature describing the contribution of cytotoxic mediators released by macrophages to injury and disease in the liver, lung, skin and brain. For the purposes of this review, however, the discussion will focus on the liver, the major organ of drug and xenobiotic metabolism.
Some of the earliest experimental evidence linking macrophages with chemically-induced hepatotoxicity is based on histologic examination of livers collected from animals treated with toxic chemicals. Thus, after treatment of rodents with hepatotoxic doses of acetaminophen, carbon tetrachloride, phenobarbital or endotoxin, increased numbers of macrophages are observed in the liver. Moreover, the specific location of the cells in the liver lobule correlates with areas that subsequently exhibit damage (15, 16). In a number of experimental models, data clearly demonstrate that macrophages accumulating in tissues following exposure to toxicants become activated, and contribute to liver injury [reviewed in (15, 17, 18)]. The pathogenic process appears to involve the release of cytotoxic, matrix degrading and proinflammatory mediators by these cells (see further below). That macrophages contribute to tissue injury is most clearly evident from findings that toxicity is directly correlated with their functional status. Accordingly, when macrophage cytotoxic/inflammatory activity is blocked with hydrocortisone or synthetic steroids, hepatotoxicity induced by acetaminophen and carbon tetrachloride is ameliorated (1922). Similarly, the accumulation of macrophages in the liver and subsequent toxicity of these xenobiotics is abrogated in rodents by pretreatment with macrophage inhibitors such as gadolinium chloride (GdCl3) or dextran sulfate (2330). Protection against early damage induced by acetaminophen has also been reported in animals depleted of macrophages by pretreatment with liposome-encapsulated dichloromethylene diphosphonate (clodronate) (31). Both GdCl3 and clodronate liposomes also prevent liver damage induced by allyl alcohol, endotoxin, fumonisin, thioacetamide, cadmium chloride, concanavalin A and diethyldithiocarbamate (3242). The importance of macrophages in the pathogenesis of liver injury is also exemplified by findings that activation of these cells can augment tissue damage induced by hepatotoxicants. Thus, pretreatment of rodents with Toll-like receptor agonists such as LPS or polyinosinic:polycytidylic acid (poly I:C) which induce macrophage accumulation and activation in the liver, results in an exaggerated hepatotoxic response to acetaminophen, carbon tetrachloride, halothane, trovafloxacin, galactosamine and Corynebacterium parvum (4348).
A question arises, however, as to the nature of the macrophage population mediating the hepatotoxic response. As indicated above, recent studies suggest that these cells possess a classically activated or M1 macrophage phenotype. Consistent with this idea are findings that M1 macrophages are activated to release reactive oxygen species (ROS), reactive nitrogen species (RNS), hydrolytic enzymes, lipid mediators, and proinflammatory cytokines, each of which has been implicated in hepatotoxicity [reviewed in (15)]. Moreover, abrogating the production of these proinflammatory mediators by depleting cytotoxic liver macrophages using GdCl3 or dextran sulfate correlates with protection against liver injury induced by a variety of hepatotoxicants (2426, 30, 31, 33, 36, 37, 4954).
In parallel to the forces of The Dark Side, classically activated M1 macrophages contribute to tissue injury by unleashing a deadly barrage of dark side energy which is in the form of cytotoxic and proinflammatory mediators. Most notable are ROS and RNS, which have been implicated in tissue injury induced by a variety of toxicants. ROS and RNS are produced in significant quantities by macrophages via enzyme catalyzed reactions and during mitochondrial respiration. Whereas the generation of low levels of ROS and/or RNS under tonic conditions functions to regulate a number of cellular signaling pathways including kinases, transcription factors, metabolic enzymes and proteases, during acute inflammatory responses, these mediators function to destroy invading pathogens and foreign materials. Evidence suggests that uncontrolled or excessive production of ROS and/or RNS by resident macrophages and inflammatory leukocytes contributes to oxidative and nitrosative stress and consequent tissue injury. Many biological molecules including lipids, proteins, and DNA are targets for modification by reactive species resulting in diverse pathologic consequences. For instance, peroxidation of membrane lipids by ROS can lead to the release of arachidonic acid and the generation of additional proinflammatory mediators including prostaglandins, thromboxanes, and leukotrienes. ROS can also react with cellular lipids to generate lipid peroxides and cytotoxic reactive aldehydes (55). Recent studies have also identified several novel products generated as a consequence of ROS and RNS modification of biological molecules, including nitrated alkenes, nitrosothiols, S-glutathionylation, and nitrotyrosine [reviewed in (56, 57)]. Elucidating the signaling properties of these new biomolecules currently represents an area of intense investigation with reference to a wide range of pathologies.
Macrophage-derived ROS and RNS have been implicated in the pathogenesis of liver injury induced by hepatotoxicants such as acetaminophen, galactosamine, endotoxin, carbon tetrachloride, 1,2,-dichlorobenzene and alcohol (25, 43, 52, 5873). Macrophages accumulating in the liver of animals treated with various hepatotoxicants have been reported to release excessive quantities of ROS and RNS (34, 58, 62, 67, 70, 7476). Moreover, stimulation of macrophages to produce additional oxidants exacerbates liver injury. This has been observed in rodents administered vitamin A, Corynebacterium parvum, latex beads or poly I:C, which activate macrophages in the liver to produce ROS and augment injury induced by hepatotoxicants such as endotoxin, acetaminophen, carbon tetrachloride and galactosamine (43, 47, 60, 65, 77, 78). Conversely, hepatotoxicity induced by galactosamine and 1,2-dichlorobenzene, as well as carbon tetrachloride and vitamin A, is abrogated by methyl palmitate, an effective inhibitor of oxidative metabolism in liver macrophages (43, 60, 61, 64). Protection is also observed in various models of hepatotoxicity using agents that function to reduce levels of ROS and oxidative stress including allopurinol, hemin, ethyl pyruvate, glutathione, N-acetylcysteine, chondroitin-4-sulfate, ascorbate, N-acetyl-l-cysteine, Cu, Zn-superoxide dismutase (SOD1) and oleanolic acid (30, 35, 59, 60, 68, 69, 71, 7985). Moreover, mice over-expressing antioxidants such as SOD1 or extracellular glutathione peroxidase (GPX1) are protected from liver injury induced by acetaminophen (86, 87). Similar hepatoprotection has also been produced by administration of a nonpeptidyl mimetic of manganese SOD (SOD2), as well as by extracellular SOD (SOD3) gene therapy (8890). Surprisingly, SOD1−/− mice have also been reported to be resistant to acetaminophen- induced hepatotoxicity (86); however, this appears to be due to reduced CYP2E1 activity and altered cellular redox balance. A question arises as to the nature of the ROS involved in hepatotoxicity and its cellular origin. The findings that mice lacking NADPH oxidase, the major enzyme mediating the generation of superoxide anion by macrophages, do not display altered sensitivity to acetaminophen, suggest that this reactive oxygen intermediate is not a critical mediator of macrophage induced hepatotoxicity in this model (91). It may be that the contribution of macrophage-derived superoxide anion to tissue injury is dependent on the hepatotoxicant and the extent to which other inflammatory mediators are produced in the tissue.
The role of RNS in hepatotoxicity also appears to depend on the toxicant. Thus, whereas with some toxicants, hepatoprotective effects are observed in mice with a targeted disruption of the inducible nitric oxide synthase (iNOS) gene or in mice treated with an iNOS inhibitor (30, 52, 62, 63, 66, 73, 9294), with others, liver injury is exacerbated (9598). A comparable protective effect has been observed in the liver during ischemia/reperfusion by blocking arginase activity which raises nitric oxide levels (99). It has also been reported that nitric oxide donors protect against hepatotoxicity induced by acetaminophen (100). Thus, it appears that nitric oxide, or secondary oxidants generated from nitric oxide (e.g., peroxynitrite), may be cytotoxic or protective depending on quantities of these mediators produced in the tissue, as well as levels of superoxide anion present, and the extent to which tissue injury is mediated by ROS (101).
Another group of mediators that contribute to macrophage-mediated cytotoxicity and tissue injury are proinflammatory cytokines including TNFα, IL-1, and IL-6, as well as chemokines such as CXCL8 (IL-8), CXCL2 (MIP-2) and CCL2 (MCP-1) [reviewed in (15)]. These proteins can induce damage directly in target tissues and/or indirectly by recruiting and activating additional leukocytes, a process that amplifies the inflammatory response. Most notable among the pro-inflammatory cytokines is TNFα which has been implicated not only in the pathogenesis of septic shock and inflammatory tissue injury, but also in the regulation of apoptosis, acute-phase protein gene expression, and cytochrome P450 activity (15, 102105). TNFα also stimulates the release of other cytotoxic and immunoregulatory mediators including IL-1, IL-6, platelet activating factor, colony-stimulating factor, prostaglandins, ROS and RNS from macrophages and neutrophils which can augment tissue injury (12, 106, 107). Hepatic injury induced by alcohol, endotoxin, acetaminophen, carbon tetrachloride, cadmium, galactosamine and aflatoxin is characterized by excessive production of TNFα(73, 84, 97, 108118). Moreover, hepatotoxicity induced by a number of these agents is abrogated by administration of antibodies to TNFα or a TNF receptor antagonist, and is suppressed in mice lacking TNFα or TNFR1 (45, 97, 108111, 116, 119122). These findings demonstrate that TNFα is indeed a critical mediator of macrophage-induced liver injury.
Just as in Star Wars, where there was a balancing force to counter the machinations of The Dark Side; The Jedi, guardians of peace and justice; so it is that there is a tissue protective role for macrophages. This activity is mediated by M2 macrophages that accumulate at injured sites later in the inflammatory process; these cells function to restore homeostasis by down regulating M1 cells and the production of cytotoxic inflammatory mediators, and by stimulating tissue repair (4, 10). Through the release of various cytokines and growth factors, M2 macrophages also stimulate angiogenesis, stabilize new matrix components, and induce fibroblasts and macrophages to synthesize extracellular matrix proteins (4, 5, 123126). M2 macrophages have been reported to be immunosuppressive in animal models of multiple sclerosis, rheumatoid arthritis and lung inflammation (127129). Moreover, in the liver, depleting or blocking activation or recruitment of M2 macrophages into inflammatory sites delays repair and/or exacerbates injury and the development of fibrosis induced by hepatotoxicants such as acetaminophen, carbon tetrachloride and cadmium (6, 27, 37, 118, 130135).
M2 macrophages, like the Jedi, have specialized field gear for their missions of defense and repair. In macrophages, these include an ability to release inflammatory mediators and growth factors such as TNFα, IL-6, IL-10, IL-18 binding protein and TGFβ, as well as various eicosanoids. These mediators counteract cytotoxic and proinflammatory events and promote tissue regeneration either directly or indirectly by inducing the production of additional anti-inflammatory, growth promoting and angiogenic mediators including IL-4, IL-13, lipoxins, resolvins, protectins and vascular endothelial cell growth factor (VEGF) (27, 136, 137). Following hepatotoxicant exposure, expression of protective proteins including IL-4, IL-10, IL-13, TNFα TGFβ and VEGF increases in the liver (27, 63, 73, 84, 115, 138142). Additionally, upregulation of these mediators protects against chemically-induced hepatotoxicity, while blocking their activity causes an exaggerated response. For example, administration of IL-13 protects mice from lethal endotoxemia, while treatment of animals with anti-IL-13 antibodies exacerbates acetaminophen-induced hepatotoxicity and significantly reduces survival (73, 140). Similarly, in mice treated with IL-10, acetaminophen-induced liver injury is ameliorated, while carbon tetrachloride and acetaminophen induced hepatotoxicity is exaggerated in IL-10 or IL-13 knockout mice, and in IL-4/IL-10 double knockout mice (73, 139, 141). The exaggerated hepatotoxic response is associated with increased production of cytotoxic mediators including ROS, RNS, TNFα, IFNγ and/or various chemokines.
Within the Star Wars story there were individuals such as Anakin Skywalker who struggled with which side of The Force they chose to follow. TNFα appears to possess a similar dichotomous behavior, as it plays a dual role in hepatotoxicity. For TNFα, this is most likely related to the timing of its release in tissues. Thus, when released early after injury by M1 macrophages, it functions as a proinflammatory and cytotoxic cytokine, while TNFα released later in the inflammatory response by M2 macrophages plays an essential role in antioxidant defense and in the initiation of tissue repair (143). This latter activity is due to the ability of TNFα to function as a potent mitogen, stimulating hepatocyte proliferation following acute injury (144146). TNFα also stimulates macrophages and other cells to produce mediators important in wound healing, including TGFβ, connective tissue growth factor, VEGF, matrix metalloproteinase-9, IL-6, and chemokines such as CCL2, CXCL8 and CXCL1 (103, 147). These findings, together with the observations that knockout mice lacking the gene for TNFα or TNF receptor 1 (TNFR1) are significantly more sensitive to liver injury induced by acetaminophen or carbon tetrachloride than their wild type counterparts, demonstrates the importance of TNFα in repair of damaged tissue (113116, 148).
Over the past few years controversy has arisen over the protective versus pathologic role of liver macrophages in hepatotoxicity. Probably the most notable example of this controversy is related to acetaminophen-induced liver injury. Whereas in some studies it has been reported that blocking macrophages protects against liver injury, in others, exaggerated hepatotoxicity is observed. These divergent findings most likely reflect the distinct macrophage subpopulations responding at different times during the course of liver injury and repair. As described above, evidence suggests that macrophages play a dual role in the pathogenic response to hepatotoxicants such as acetaminophen. Whereas initially, classically activated macrophages displaying an M1 phenotype respond to injury by releasing cytotoxic and proinflammatory mediators which contribute to tissue injury, subsequently, alternatively activated M2 macrophages emigrate into injured sites and release mediators that down regulate inflammation (e.g., IL-10) and initiate tissue repair (e.g., VEGF, TNFα, and TGFβ) Although these macrophage populations are described as phenotypically distinct, they more likely represent extremes on a dynamic continuum of macrophages with varying functional capacities determined by changes in the cytokine milieu in the inflammatory microenvironment. Thus, the extent to which any given macrophage population contributes to or protects against tissue injury depends on the stage in the pathogenic process it encounters, and the specific cytokines and inflammatory mediators generated. In this context, using the same agent to block or delete macrophages may have different consequences depending on when the agent is administered and which macrophage population is targeted.
Another factor that contributes to conflicting findings on the role of macrophages in acetaminophen-induced hepatotoxicity is the method used to eliminate macrophages or to suppress their activity. For the most part, two major approaches have been used: GdCl3 and clodronate containing liposomes. Gadolinium is a rare earth metal that is taken up by macrophages of the reticuloendothelial system (149). Early studies suggested that GdCl3 functions in vivo by blocking phagocytosis and preventing macrophages from becoming activated, an effect thought to be due to competitive inhibition of calcium mobilization (150153). Subsequently, it was shown that GdCl3 exerts its effects by selectively eliminating large highly phagocytic Kupffer cells, and/or provoking a switch in their phenotype or acinar distribution (53, 154, 155). In control animals, the most active Kupffer cells are located in the periportal regions of the liver lobule (156, 157). After GdCl3 administration, these cells are localized mainly in centrilobular regions of the liver and are primed to participate in tissue repair (154, 155). The observation that these macrophages express immature monocyte/macrophage markers suggests that GdCl3 stimulates extrahepatic recruitment of cells from blood and bone marrow precursors (154). It is noteworthy to mention that after GdCl3 treatment of animals, macrophages localized in centrilobular regions of the liver continue to release TNFα which, as described above, plays a key role in repair of damaged liver (138, 155, 158). Furthermore, these cells are relatively resistant to a second challenge with GdCl3. These findings, together with reports that Kupffer cell production of ROS and RNS is reduced after GdCl3 administration, while IL-10 is unaffected, indicate that GdCl3 targets M1 macrophages, and that macrophages remaining in the liver are of the M2 phenotype (24, 25, 27, 35, 53). This is also supported by findings that hepatocyte proliferation is either increased or unaffected by GdCl3 treatment of animals (159, 160).
Another method utilized to assess the role of Kupffer cells in chemical toxicity is administration of liposomes containing clodronate. Intravenous administration of these liposomes results in depletion of macrophages in the liver via apoptosis (159). In contrast to the selective depletion of larger macrophages in periportal regions of the liver by GdCl3, both larger Kupffer cells and smaller ones in midzonal and centrilobular regions are eliminated by clodronate liposomes (6, 27, 118, 161163). Studies on the kinetics of macrophage repopulation in the liver after clodronate liposome administration have shown that macrophages do not begin to reappear for at least 7 days (164). In contrast to macrophages repopulating the liver after GdCl3, these cells originate from a macrophage precursor pool in the liver, rather than directly from bone marrow derived monocytes, and are phenotypically more mature (6, 165, 166). Furthermore, production of macrophage colony stimulating factor in the liver plays a crucial role in their differentiation, maturation and proliferation (167). The fact that administration of clodronate liposomes prevents acetaminophen-induced increases in protective molecules such as TNFα, IL-6, IL-10, and IL-18 binding protein in the liver supports the idea that M2 cells are a major target of clodronate liposomes (27, 118).
In summary it is apparent that in the acetaminophen-induced hepatotoxicity model, GdCl3 and clodronate liposomes target distinct macrophage subpopulations which likely accounts for conflicting findings on the role of macrophages in the pathogenic process. Thus, while GdCl3 preferentially targets cytotoxic M1 macrophages for elimination, clodronate liposomes mainly target M2 macrophages. This idea is consistent with reports that elimination of macrophages using GdCl3 protects against acetaminophen-induced hepatotoxicity, while liver injury is exacerbated in animals treated with clodronate liposomes (24, 25, 27, 28, 30, 31, 118, 131).
Popular culture is often used as allegorical material in the teaching of modern philosophy. Indeed, there have been numerous philosophical treatises discussing the ever-present power of The Force and its more seductive Dark Side. The consistent conclusion of these writings is that The Dark Side, as well as opposing the Jedi, is a necessary consequence of The Force in terms of cosmic balance. It is reasonable to extend this allegory to the phenotypic forms of macrophages. In this way, although we may tend to think of the M1 macrophage as evil and the M2 macrophage as good, as they are involved in injury and repair, respectively, it may be more accurate to view them as two sides of the same coin, just as Darth Vader and Anakin Skywalker represent the two sides of The Force in one individual. Thus, it is not so much that M1 and M2 macrophages have opposing actions at inflammatory sites; rather there is a complex interplay between the two phenotypes that is necessary for an appropriate response to a toxic insult. Without doubt, macrophages are an important cellular component of the nonspecific host defense system. These are the primary cells responsible for protecting the body from the damaging effects of invading pathogens and toxins. Although their presence in the body is clearly essential for appropriate immunological defense and wound repair, an imbalance in macrophage activation may in fact contribute to tissue injury. It is likely that the extent to which macrophages contribute to injury or participate in tissue repair depends on the balance of their phenotypic experience and the timing of their appearance in the liver. Aberrations in the relative responsiveness of these cells leading to an imbalance between production of proinflammatory and anti-inflammatory mediators may be important in determining the final outcome of the pathogenic response to toxicants.
Acknowledgments
Supported by NIH Grants GM034310, ES004738, CA132624, AR055073 and ES005022. Special thanks to Andrew J. Gow for helpful comments, suggestions and allegories.
1. Zhang X, Mosser DM. Macrophage activation by endogenous danger signals. J Pathol. 2008;214:161–178. [PMC free article] [PubMed]
2. Edwards JP, Zhang X, Frauwirth KA, Mosser DM. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol. 2006;80:1298–1307. [PMC free article] [PubMed]
3. Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, Meerschaut S, Beschin A, Raes G, De Baetselier P. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology. 2006;211:487–501. [PubMed]
4. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol. 2008;181:3733–3739. [PubMed]
5. Duffield JS. The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci (Lond) 2003;104:27–38. [PubMed]
6. Holt MP, Cheng L, Ju C. Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol. 2008;84:1410–1421. [PubMed]
7. Liu Y, Stewart KN, Bishop E, Marek CJ, Kluth DC, Rees AJ, Wilson HM. Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo. J Immunol. 2008;180:6270–6278. [PubMed]
8. Trujillo G, O’Connor EC, Kunkel SL, Hogaboam CM. A novel mechanism for CCR4 in the regulation of macrophage activation in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2008;172:1209–1221. [PubMed]
9. Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N, Dormont D, Gras G. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol. 2005;142:481–489. [PubMed]
10. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci. 2008;13:453–461. [PubMed]
11. Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol. 2004;76:509–513. [PMC free article] [PubMed]
12. Gordon S. The macrophage: past, present and future. Eur J Immunol. 2007;37(Suppl 1):S9–17. [PubMed]
13. Metchnikoff E. Lectures on the comparative pathology of inflammation (Reprint) Dover Publications; New York: 1968. p. 10.
14. Metchnikoff E. Immunity in infective disease (Reprint) Johnson Reprint Company; New York: 1968. pp. 76–180.
15. Laskin DL, Gardner CR. Nonparenchymal cells, inflammatory macrophages, and hepatotoxicity. In: Kaplowitz N, DeLeve LD, editors. Drug-Induced Liver Disease. Informa Healthcare; New York: 2007. pp. 159–184.
16. Laskin DL. Nonparenchymal cells and hepatotoxicity. Semin Liver Dis. 1990;10:293–304. [PubMed]
17. Gardner CR, Laskin DL. Sinusoidal cells in liver injury and repair. In: Sahu SC, editor. Hepatotoxicity: From Genomics to In Vitro and In Vivo Models. John Wiley & Sons; West Sussex: 2007. pp. 341–370.
18. Laskin DL, Pendino KJ. Macrophages and inflammatory mediators in tissue injury. Annu Rev Pharmacol Toxicol. 1995;35:655–677. [PubMed]
19. Lloyd SA, Franklin MR. Modulation of carbon tetrachloride hepatotoxicity and xenobiotic-metabolizing enzymes by corticosterone pretreatment, adrenalectomy and sham surgery. Toxicol Lett. 1991;55:65–75. [PubMed]
20. Madhu C, Klaassen CD. Protective effect of pregnenolone-16 alpha-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters. Toxicol Appl Pharmacol. 1991;109:305–313. [PubMed]
21. Madhu C, Maziasz T, Klaassen CD. Effect of pregnenolone-16 alpha-carbonitrile and dexamethasone on acetaminophen-induced hepatotoxicity in mice. Toxicol Appl Pharmacol. 1992;115:191–198. [PubMed]
22. Sudhir S, Budhiraja RD. Comparison of the protective effect of Withaferin-‘A’ and hydrocortisone against CCl4 induced hepatotoxicity in rats. Indian J Physiol Pharmacol. 1992;36:127–129. [PubMed]
23. Edwards MJ, Keller BJ, Kauffman FC, Thurman RG. The involvement of Kupffer cells in carbon tetrachloride toxicity. Toxicol Appl Pharmacol. 1993;119:275–279. [PubMed]
24. Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology. 1995;21:1045–1050. [PubMed]
25. Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson JA. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology. 1999;30:186–195. [PubMed]
26. Muriel P, Alba N, Perez-Alvarez VM, Shibayama M, Tsutsumi VK. Kupffer cell inhibition prevents hepatic lipid peroxidation and damage induced by carbon tetrachloride. Comp Biochem Physiol C Toxicol Pharmacol. 2001;130:219–226. [PubMed]
27. Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW, Pohl LR. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol. 2002;15:1504–1513. [PubMed]
28. Ito Y, Bethea NW, Abril ER, McCuskey RS. Early hepatic microvascular injury in response to acetaminophen toxicity. Microcirculation. 2003;10:391–400. [PubMed]
29. Muriel P, Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J Appl Toxicol. 2003;23:103–108. [PubMed]
30. Abdel-Zaher AO, Abdel-Rahman MM, Hafez MM, Omran FM. Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage. Toxicology. 2007;234:124–134. [PubMed]
31. Goldin RD, Ratnayaka ID, Breach CS, Brown IN, Wickramasinghe SN. Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol. 1996;179:432–435. [PubMed]
32. Przybocki JM, Reuhl KR, Thurman RG, Kauffman FC. Involvement of nonparenchymal cells in oxygen-dependent hepatic injury by allyl alcohol. Toxicol Appl Pharmacol. 1992;115:57–63. [PubMed]
33. Iimuro Y, Yamamoto M, Kohno H, Itakura J, Fujii H, Matsumoto Y. Blockade of liver macrophages by gadolinium chloride reduces lethality in endotoxemic rats--analysis of mechanisms of lethality in endotoxemia. J Leukoc Biol. 1994;55:723–728. [PubMed]
34. Ishiyama H, Ogino K, Hobara T. Role of Kupffer cells in rat liver injury induced by diethyldithiocarbamate. Eur J Pharmacol. 1995;292:135–141. [PubMed]
35. Liu P, McGuire GM, Fisher MA, Farhood A, Smith CW, Jaeschke H. Activation of Kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia. Shock. 1995;3:56–62. [PubMed]
36. Koop DR, Klopfenstein B, Iimuro Y, Thurman RG. Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1. Mol Pharmacol. 1997;51:944–950. [PubMed]
37. Yamano T, DeCicco LA, Rikans LE. Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: role of Kupffer cells and inflammatory cytokines. Toxicol Appl Pharmacol. 2000;162:68–75. [PubMed]
38. Harstad EB, Klaassen CD. Gadolinium chloride pretreatment prevents cadmium chloride-induced liver damage in both wild-type and MT-null mice. Toxicol Appl Pharmacol. 2002;180:178–185. [PubMed]
39. Andres D, Sanchez-Reus I, Bautista M, Cascales M. Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity. Expression of metallothionein and HSP70. Biochem Pharmacol. 2003;66:917–926. [PubMed]
40. He Q, Kim J, Sharma RP. Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride. Toxicology. 2005;207:137–147. [PubMed]
41. Henrich D, Lehnert M, Herzog C, Niederlaender S, Relja B, Conzelmann L, Marzi I. Differential effects of GdCl3- or MDP treatment on rat liver microcirculation and gene expression in the hepatic non-parenchymal cell fraction in LPS shock. Microcirculation. 2008;15:427–439. [PubMed]
42. Nakashima H, Kinoshita M, Nakashima M, Habu Y, Shono S, Uchida T, Shinomiya N, Seki S. Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice. Hepatology. 2008;48:1979–1988. [PubMed]
43. Al-Tuwaijri A, Akdamar K, Di Luzio NR. Modification of galactosamine-induced liver injury in rats by reticuloendothelial system stimulation or depression. Hepatology. 1981;1:107–113. [PubMed]
44. Cheng L, You Q, Yin H, Holt M, Franklin C, Ju C. Effect of polyI:C cotreatment on halothane-induced liver injury in mice. Hepatology. 2009;49:215–226. [PMC free article] [PubMed]
45. Dejager L, Libert C. Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice. Cytokine. 2008;42:55–61. [PubMed]
46. Galanos C, Freudenberg MA, Reutter W. Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci U S A. 1979;76:5939–5943. [PubMed]
47. Ganey PE, Luyendyk JP, Maddox JF, Roth RA. Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chem Biol Interact. 2004;150:35–51. [PubMed]
48. Kalabis GM, Wells PG. Biphasic modulation of acetaminophen bioactivation and hepatotoxicity by pretreatment with the interferon inducer polyinosinic-polycytidylic acid. J Pharmacol Exp Ther. 1990;255:1408–1419. [PubMed]
49. Fujita S, Arii S, Monden K, Adachi Y, Funaki N, Higashitsuji H, Furutani M, Mise M, Ishiguro S, Kitao T, et al. Participation of hepatic macrophages and plasma factors in endotoxin-induced liver injury. J Surg Res. 1995;59:263–270. [PubMed]
50. Sauer JM, Hooser SB, Badger DA, Baines A, Sipes IG. Alterations in chemically induced tissue injury related to all-trans-retinol pretreatment in rodents. Drug Metab Rev. 1995;27:299–323. [PubMed]
51. Vollmar B, Ruttinger D, Wanner GA, Leiderer R, Menger MD. Modulation of Kupffer cell activity by gadolinium chloride in endotoxemic rats. Shock. 1996;6:434–441. [PubMed]
52. Michael SL, Mayeux PR, Bucci TJ, Warbritton AR, Irwin LK, Pumford NR, Hinson JA. Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity. Nitric Oxide. 2001;5:432–441. [PubMed]
53. Kono H, Fujii H, Asakawa M, Yamamoto M, Maki A, Matsuda M, Rusyn I, Matsumoto Y. Functional heterogeneity of the Kupffer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin. J Surg Res. 2002;106:179–187. [PubMed]
54. Hatano M, Sasaki S, Ohata S, Shiratsuchi Y, Yamazaki T, Nagata K, Kobayashi Y. Effects of Kupffer cell-depletion on Concanavalin A-induced hepatitis. Cell Immunol. 2008;251:25–30. [PubMed]
55. Adibhatla RM, Hatcher JF. Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. BMB Rep. 2008;41:560–567. [PMC free article] [PubMed]
56. Gow AJ, Farkouh CR, Munson DA, Posencheg MA, Ischiropoulos H. Biological significance of nitric oxide-mediated protein modifications. Am J Physiol Lung Cell Mol Physiol. 2004;287:L262–268. [PubMed]
57. Laskin JD, Heck DE, Laskin DL. Nitric oxide pathways in toxic responses. In: BB, TM, TS, editors. General and Applied Toxicology. John Wiley & Sons Ltd; UK: 2009. (In press)
58. Arthur MJP, Bentley IS, Tanner AR, Saunders PK, Millward-Sadler GH, Wright R. Oxygen-derived free radicals promote hepatic injury in the rat. Gastroenterology. 1985;89:1114–1122. [PubMed]
59. Chiu H, Brittingham JA, Laskin DL. Differential induction of heme oxygenase-1 in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in the rat: effects of hemin and biliverdin. Toxicol Appl Pharmacol. 2002;181:106–115. [PubMed]
60. elSisi AE, Earnest DL, Sipes IG. Vitamin A potentiation of carbon tetrachloride hepatotoxicity: role of liver macrophages and active oxygen species. Toxicol Appl Pharmacol. 1993;119:295–301. [PubMed]
61. elSisi AE, Hall P, Sim WL, Earnest DL, Sipes IG. Characterization of vitamin A potentiation of carbon tetrachloride-induced liver injury. Toxicol Appl Pharmacol. 1993;119:280–288. [PubMed]
62. Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, Laskin JD, Laskin DL. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology. 1998;26:748–754. [PubMed]
63. Gardner CR, Laskin JD, Dambach DM, Sacco M, Durham SK, Bruno MK, Cohen SD, Gordon MK, Gerecke DR, Zhou P, Laskin DL. Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase: Potential role of tumor necrosis factor-α and interleukin-10. Toxicol Appl Pharmacol. 2002;184:27–36. [PubMed]
64. Guanawardhana L, Mobley SA, Sipes IG. Modulation of 1,2-dichlorobenzene hepatotoxicity in the Fischer-344 rat by a scavenger of superoxide anions and an inhibitor of Kupffer cells. Toxicol Appl Pharmacol. 1993;119:205–213. [PubMed]
65. Hendriks HF, Horan MA, Durham SK, Earnest DL, Brouwer A, Hollander CF, Knook DL. Endotoxin-induced liver injury in aged and subacutely hypervitaminotic A rats. Mech Ageing Dev. 1987;41:241–250. [PubMed]
66. Hinson JA, Bucci TJ, Irwin LK, Michael SL, Mayeux PR. Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice. Nitric Oxide. 2002;6:160–167. [PubMed]
67. Ito Y, Abril ER, Bethea NW, McCuskey RS. Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice. Am J Physiol Gastrointest Liver Physiol. 2004;286:G60–67. [PubMed]
68. Nakae D, Yamamoto K, Yoshiji H, Kinugasa T, Maruyama H, Farber JL, Konishi Y. Liposome-encapsulated superoxide dismutase prevents liver necrosis induced by acetaminophen. Am J Pathol. 1990;136:787–795. [PubMed]
69. Shiratori Y, Kawase T, Shiina S, Okano K, Sugimoto T, Teraoka H, Matano S, Matsumoto K, Kamii K. Modulation of hepatotoxicity by macrophages in the liver. Hepatology. 1988;8:815–821. [PubMed]
70. Shiratori Y, Tanaka M, Hai K, Kawase T, Shiina S, Sugimoto T. Role of endotoxin-responsive macrophages in hepatic injury. Hepatology. 1990;11:183–192. [PubMed]
71. Sugino K, Dohi K, Yamada K, Kawasaki T. Changes in the levels of endogenous antioxidants in the liver of mice with experimental endotoxemia and the protective effects of the antioxidants. Surgery. 1989;105:200–206. [PubMed]
72. Takeyama Y, Kamimura S, Kuroiwa A, Sohda T, Irie M, Shijo H, Okumura M. Role of Kupffer cell-derived reactive oxygen intermediates in alcoholic liver disease in rats in vivo. Alcohol Clin Exp Res. 1996;20:335A–339A. [PubMed]
73. Yee SB, Bourdi M, Masson MJ, Pohl LR. Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol. 2007;20:734–744. [PubMed]
74. Laskin DL, Pilaro AM. Potential role of activated macrophages in acetaminophen hepatotoxicity. I. Isolation and characterization of activated macrophages from rat liver. Toxicol Appl Pharmacol. 1986;86:204–215. [PubMed]
75. Alric L, Orfila C, Carrere N, Beraud M, Carrera G, Lepert JC, Duffaut M, Pipy B, Vinel JP. Reactive oxygen intermediates and eicosanoid production by Kupffer cells and infiltrated macrophages in acute and chronic liver injury induced in rats by CCl4. Inflamm Res. 2000;49:700–707. [PubMed]
76. Jaeschke H, Knight TR, Bajt ML. The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett. 2003;144:279–288. [PubMed]
77. Grun M, Liehr H, Grun W, Rasenack U, Brunswig D. Influence of liver-RES on toxic liver damage due to galactosamine. Acta Hepatogastroenterol (Stuttg) 1974;21:5–15. [PubMed]
78. Raiford DS, Thigpen MC. Kupffer cell stimulation with Corynebacterium parvum reduces some cytochrome P450-dependent activities and diminishes acetaminophen and carbon tetrachloride-induced liver injury in the rat. Toxicol Appl Pharmacol. 1994;129:36–45. [PubMed]
79. Jaeschke H. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther. 1990;255:935–941. [PubMed]
80. Shiratori Y, Tanaka M, Umihara J, Kawase T, Shiina S, Sugimoto T. Leukotriene inhibitors modulate hepatic injury induced by lipopolysaccharide-activated macrophages. J Hepatol. 1990;10:51–61. [PubMed]
81. Balanehru S, Nagarajan B. Protective effect of oleanolic acid and ursolic acid against lipid peroxidation. Biochem Int. 1991;24:981–990. [PubMed]
82. Odaka Y, Takahashi T, Yamasaki A, Suzuki T, Fujiwara T, Yamada T, Hirakawa M, Fujita H, Ohmori E, Akagi R. Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction. Biochem Pharmacol. 2000;59:871–880. [PubMed]
83. Nakahira K, Takahashi T, Shimizu H, Maeshima K, Uehara K, Fujii H, Nakatsuka H, Yokoyama M, Akagi R, Morita K. Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity. Biochem Pharmacol. 2003;66:1091–1105. [PubMed]
84. Dambach DM, Durham SK, Laskin JD, Laskin DL. Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol. 2006;211:157–165. [PubMed]
85. Campo GM, Avenoso A, Campo S, Nastasi G, Traina P, D’Ascola A, Rugolo CA, Calatroni A. The antioxidant activity of chondroitin-4-sulphate, in carbon tetrachloride-induced acute hepatitis in mice, involves NF-kappaB and caspase activation. Br J Pharmacol. 2008;155:945–956. [PubMed]
86. Lei XG, Zhu JH, McClung JP, Aregullin M, Roneker CA. Mice deficient in Cu, Zn-superoxide dismutase are resistant to acetaminophen toxicity. Biochem J. 2006;399:455–461. [PubMed]
87. Mirochnitchenko O, Weisbrot-Lefkowitz M, Reuhl K, Chen L, Yang C, Inouye M. Acetaminophen toxicity. Opposite effects of two forms of glutathione peroxidase. J Biol Chem. 1999;274:10349–10355. [PubMed]
88. Ferret PJ, Hammoud R, Tulliez M, Tran A, Trebeden H, Jaffray P, Malassagne B, Calmus Y, Weill B, Batteux F. Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse. Hepatology. 2001;33:1173–1180. [PubMed]
89. Laukkanen MO, Leppanen P, Turunen P, Tuomisto T, Naarala J, Yla-Herttuala S. EC-SOD gene therapy reduces paracetamol-induced liver damage in mice. J Gene Med. 2001;3:321–325. [PubMed]
90. Venugopal SK, Wu J, Catana AM, Eisenbud L, He SQ, Duan YY, Follenzi A, Zern MA. Lentivirus-mediated superoxide dismutase1 gene delivery protects against oxidative stress-induced liver injury in mice. Liver Int. 2007;27:1311–1322. [PubMed]
91. James LP, McCullough SS, Knight TR, Jaeschke H, Hinson JA. Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic Res. 2003;37:1289–1297. [PubMed]
92. Bianchi M, Ulrich P, Bloom O, Meistrell M, Zimmerman GA, Schmidtmayerova H, Bukrinsky M, Donnelley T, Bucala R, Sherry B, Manogue KR, Tortolani AJ, Cerami A, Tracey KJ. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol Med. 1995;1:254–266. [PMC free article] [PubMed]
93. Venkatraman A, Shiva S, Wigley A, Ulasova E, Chhieng D, Bailey SM, Darley-Usmar VM. The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice. Hepatology. 2004;40:565–573. [PubMed]
94. Aram G, Potter JJ, Liu X, Torbenson MS, Mezey E. Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration. Hepatology. 2008;47:2051–2058. [PubMed]
95. Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AJ, Simmon RL. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L- arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol. 1990;48:565–569. [PubMed]
96. Harbrecht BG, Billiar TR, Stadler J, Demetris AJ, Ochoa J, Curran RD, Simmons RL. Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol. 1992;52:390–394. [PubMed]
97. Morio LA, Chiu H, Sprowles KA, Zhou P, Heck DE, Gordon MK, Laskin DL. Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol. 2001;172:44–51. [PubMed]
98. Wright CE, Rees DD, Moncada S. Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res. 1992;26:48–57. [PubMed]
99. Jeyabalan G, Klune JR, Nakao A, Martik N, Wu G, Tsung A, Geller DA. Arginase blockade protects against hepatic damage in warm ischemia-reperfusion. Nitric Oxide. 2008;19:29–35. [PMC free article] [PubMed]
100. Liu J, Li C, Waalkes MP, Clark J, Myers P, Saavedra JE, Keefer LK. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. Hepatology. 2003;37:324–333. [PubMed]
101. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87:315–424. [PMC free article] [PubMed]
102. Lacour S, Gautier JC, Pallardy M, Roberts R. Cytokines as potential biomarkers of liver toxicity. Cancer Biomark. 2005;1:29–39. [PubMed]
103. Dinarello CA. Historical insights into cytokines. Eur J Immunol. 2007;37(Suppl 1):S34–45. [PMC free article] [PubMed]
104. Wullaert A, van Loo G, Heyninck K, Beyaert R. Hepatic tumor necrosis factor signaling and nuclear factor-κB: effects on liver homeostasis and beyond. Endocr Rev. 2007;28:365–386. [PubMed]
105. Tayal V, Kalra BS. Cytokines and anti-cytokines as therapeutics--an update. Eur J Pharmacol. 2008;579:1–12. [PubMed]
106. Aggarwal BB, Shishodia S, Takada Y, Jackson-Bernitsas D, Ahn KS, Sethi G, Ichikawa H. TNF blockade: an inflammatory issue. Ernst Schering Res Found Workshop. 2006:161–186. [PubMed]
107. Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149–160. [PubMed]
108. Hishinuma I, Nagakawa J, Hirota K, Miyamoto K, Tsukidate K, Yamanaka T, Katayama K, Yamatsu I. Involvement of tumor necrosis factor-α in development of hepatic injury in galactosamine-sensitized mice. Hepatology. 1990;12:1187–1191. [PubMed]
109. Czaja MJ, Xu J, Alt E. Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterology. 1995;108:1849–1854. [PubMed]
110. Kayama F, Yoshida T, Elwell MR, Luster MI. Role of tumor necrosis factor-α in cadmium-induced hepatotoxicity. Toxicol Appl Pharmacol. 1995;131:224–234. [PubMed]
111. Barton CC, Barton EX, Ganey PE, Kunkel SL, Roth RA. Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha. Hepatology. 2001;33:66–73. [PubMed]
112. Ishida Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N. A pivotal involvement of IFN-γ in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J. 2002;16:1227–1236. [PubMed]
113. Chiu H, Gardner CR, Dambach DM, Brittingham JA, Durham SK, Laskin JD, Laskin DL. Role of p55 tumor necrosis factor receptor 1 in acetaminophen-induced antioxidant defense. Am J Physiol Gastrointest Liver Physiol. 2003;285:G959–966. [PubMed]
114. Chiu H, Gardner CR, Dambach DM, Durham SK, Brittingham JA, Laskin JD, Laskin DL. Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice. Toxicol Appl Pharmacol. 2003;193:218–227. [PubMed]
115. Gardner CR, Laskin JD, Dambach DM, Chiu H, Durham SK, Zhou P, Bruno M, Gerecke DR, Gordon MK, Laskin DL. Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1. Potential role of inflammatory mediators. Toxicol Appl Pharmacol. 2003;192:119–130. [PubMed]
116. Ishida Y, Kondo T, Tsuneyama K, Lu P, Takayasu T, Mukaida N. The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice. J Leukoc Biol. 2004;75:59–67. [PubMed]
117. Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, Jaeschke H. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 2006;216:98–107. [PubMed]
118. Campion SN, Johnson R, Aleksunes LM, Goedken MJ, van Rooijen N, Scheffer GL, Cherrington NJ, Manautou JE. Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function. Am J Physiol Gastrointest Liver Physiol. 2008;295:G294–304. [PubMed]
119. Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI. Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 1995;133:43–52. [PubMed]
120. Simeonova PP, Gallucci RM, Hulderman T, Wilson R, Kommineni C, Rao M, Luster MI. The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol Appl Pharmacol. 2001;177:112–120. [PubMed]
121. Harstad EB, Klaassen CD. Tumor necrosis factor-alpha-null mice are not resistant to cadmium chloride-induced hepatotoxicity. Toxicol Appl Pharmacol. 2002;179:155–162. [PubMed]
122. Kruglov AA, Kuchmiy A, Grivennikov SI, Tumanov AV, Kuprash DV, Nedospasov SA. Physiological functions of tumor necrosis factor and the consequences of its pathologic overexpression or blockade: mouse models. Cytokine Growth Factor Rev. 2008;19:231–244. [PubMed]
123. Anderson CF, Mosser DM. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol. 2002;72:101–106. [PubMed]
124. Gratchev A, Guillot P, Hakiy N, Politz O, Orfanos CE, Schledzewski K, Goerdt S. Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3. Scand J Immunol. 2001;53:386–392. [PubMed]
125. Guruvayoorappan C. Tumor versus tumor-associated macrophages: how hot is the link? Integr Cancer Ther. 2008;7:90–95. [PubMed]
126. Song E, Ouyang N, Horbelt M, Antus B, Wang M, Exton MS. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol. 2000;204:19–28. [PubMed]
127. Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation. J Clin Invest. 2002;109:41–50. [PMC free article] [PubMed]
128. Magnus T, Chan A, Grauer O, Toyka KV, Gold R. Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation. J Immunol. 2001;167:5004–5010. [PubMed]
129. van Lent PL, Licht R, Dijkman H, Holthuysen AE, Berden JH, van den Berg WB. Uptake of apoptotic leukocytes by synovial lining macrophages inhibits immune complex-mediated arthritis. J Leukoc Biol. 2001;70:708–714. [PubMed]
130. Abshagen K, Eipel C, Kalff JC, Menger MD, Vollmar B. Kupffer cells are mandatory for adequate liver regeneration by mediating hyperperfusion via modulation of vasoactive proteins. Microcirculation. 2008;15:37–47. [PubMed]
131. Campion SN, Tatis-Rios C, Augustine LM, Goedken MJ, van Rooijen N, Cherrington NJ, Manautou JE. Effect of allyl alcohol on hepatic transporter expression: zonal patterns of expression and role of Kupffer cell function. Toxicol Appl Pharmacol. 2009;236:49–58. [PubMed]
132. Dambach DM, Watson LM, Gray KR, Durham SK, Laskin DL. Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology. 2002;35:1093–1103. [PubMed]
133. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65. [PMC free article] [PubMed]
134. Hogaboam CM, Bone-Larson CL, Steinhauser ML, Matsukawa A, Gosling J, Boring L, Charo IF, Simpson KJ, Lukacs NW, Kunkel SL. Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C–C chemokine receptor 2. Am J Pathol. 2000;156:1245–1252. [PubMed]
135. Ishida Y, Kondo T, Kimura A, Tsuneyama K, Takayasu T, Mukaida N. Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury. Eur J Immunol. 2006;36:1028–1038. [PubMed]
136. Gabay C, Porter B, Guenette D, Billir B, Arend WP. Interleukin-4 (IL-4) and IL-13 enhance the effect of IL-1beta on production of IL-1 receptor antagonist by human primary hepatocytes and hepatoma HepG2 cells: differential effect on C-reactive protein production. Blood. 1999;93:1299–1307. [PubMed]
137. Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid mediators. Annu Rev Pathol. 2008;3:279–312. [PMC free article] [PubMed]
138. Rai RM, Loffreda S, Karp CL, Yang SQ, Lin HZ, Diehl AM. Kupffer cell depletion abolishes induction of interleukin-10 and permits sustained overexpression of tumor necrosis factor alpha messenger RNA in the regenerating rat liver. Hepatology. 1997;25:889–895. [PubMed]
139. Louis H, Van Laethem JL, Wu W, Quertinmont E, Degraef C, Van den Berg K, Demols A, Goldman M, Le Moine O, Geerts A, Deviere J. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology. 1998;28:1607–1615. [PubMed]
140. Matsukawa A, Hogaboam CM, Lukacs NW, Lincoln PM, Evanoff HL, Strieter RM, Kunkel SL. Expression and contribution of endogenous IL-13 in an experimental model of sepsis. J Immunol. 2000;164:2738–2744. [PubMed]
141. Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, Shah AG, Pohl LR. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology. 2002;35:289–298. [PubMed]
142. Donahower B, McCullough SS, Kurten R, Lamps LW, Simpson P, Hinson JA, James LP. Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am J Physiol Gastrointest Liver Physiol. 2006;291:G102–109. [PubMed]
143. Schwabe RF, Brenner DA. Mechanisms of liver injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 2006;290:G583–589. [PubMed]
144. Diehl AM. Cytokine regulation of liver injury and repair. Immunol Rev. 2000;174:160–171. [PubMed]
145. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10:45–65. [PubMed]
146. Yamada Y, Kirillova I, Peschon JJ, Fausto N. Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A. 1997;94:1441–1446. [PubMed]
147. Cosgrove BD, Cheng C, Pritchard JR, Stolz DB, Lauffenburger DA, Griffith LG. An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha. Hepatology. 2008;48:276–288. [PubMed]
148. Bruccoleri A, Gallucci R, Germolec DR, Blackshear P, Simeonova P, Thurman RG, Luster MI. Induction of early-immediate genes by tumor necrosis factor alpha contribute to liver repair following chemical-induced hepatotoxicity. Hepatology. 1997;25:133–141. [PubMed]
149. Dean PB, Niemi P, Kivisaari L, Kormano M. Comparative pharmacokinetics of gadolinium DTPA and gadolinium chloride. Invest Radiol. 1988;23(Suppl 1):S258–260. [PubMed]
150. Lazar G. The reticuloendothelial-blocking effect of rare earth metals in rats. J Reticuloendothel Soc. 1973;13:231–237. [PubMed]
151. Husztik E, Lazar G, Parducz A. Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol. 1980;61:624–630. [PubMed]
152. Kim SG, Choi SH. Gadolinium chloride inhibition of rat hepatic microsomal epoxide hydrolase and glutathione S-transferase gene expression. Drug Metab Dispos. 1997;25:1416–1423. [PubMed]
153. Lazar G. Effect of reticuloendothelial stimulation and depression on rare earth metal chloride-induced splenic calcification and fatty degeneration of the liver. Experientia. 1973;29:818–819. [PubMed]
154. Martin S. Changes in Kupffer cell phenotype and acinar location induced by intravenous gadolinium chloride. In: Knook D, Wisse E, editors. Cells of the Hepatic Sinusoid. Kupffer Cell Foundation; The Netherlands: 1993. pp. 168–170.
155. Rai RM, Zhang JX, Clemens MG, Diehl AM. Gadolinium chloride alters the acinar distribution of phagocytosis and balance between pro- and anti-inflammatory cytokines. Shock. 1996;6:243–247. [PubMed]
156. Bautista AP, Meszaros K, Bojta J, Spitzer JJ. Superoxide anion generation in the liver during the early stage of endotoxemia in rats. J Leukoc Biol. 1990;48:123–128. [PubMed]
157. Jaeschke H, Bautista AP, Spolarics Z, Spitzer JJ. Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia. Free Radic Res Commun. 1991;15:277–284. [PubMed]
158. Webber EM, Bruix J, Pierce RH, Fausto N. Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology. 1998;28:1226–1234. [PubMed]
159. Naito M, Nagai H, Kawano S, Umezu H, Zhu H, Moriyama H, Yamamoto T, Takatsuka H, Takei Y. Liposome-encapsulated dichloromethylene diphosphonate induces macrophage apoptosis in vivo and in vitro. J Leukoc Biol. 1996;60:337–344. [PubMed]
160. Leung L, Johnson M, Glauert H. Effect of gadolinium chloride-induced Kupffer cell inactivation on liver regeneration in rats. Environ Nutri Inter. 1997;1:13–22.
161. Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol. 1992;52:296–302. [PubMed]
162. Bautista AP, Spolarics Z, Jaeschke H, Smith CW, Spitzer JJ. Antineutrophil monoclonal antibody (1F12) alters superoxide anion release by neutrophils and Kupffer cells. J Leukoc Biol. 1994;55:328–335. [PubMed]
163. van Rooijen N, van Kesteren-Hendrikx E. “In vivo” depletion of macrophages by liposome-mediated “suicide” Methods Enzymol. 2003;373:3–16. [PubMed]
164. Van Rooijen N, Kors N, vd Ende M, Dijkstra CD. Depletion and repopulation of macrophages in spleen and liver of rat after intravenous treatment with liposome-encapsulated dichloromethylene diphosphonate. Cell Tissue Res. 1990;260:215–222. [PubMed]
165. Kraal G, Rodrigues H, Hoeben K, Van Rooijen N. Lymphocyte migration in the spleen: the effect of macrophage elimination. Immunology. 1989;68:227–232. [PubMed]
166. Yamamoto T, Naito M, Moriyama H, Umezu H, Matsuo H, Kiwada H, Arakawa M. Repopulation of murine Kupffer cells after intravenous administration of liposome-encapsulated dichloromethylene diphosphonate. Am J Pathol. 1996;149:1271–1286. [PubMed]
167. van Rooijen N, Sanders A. Elimination, blocking, and activation of macrophages: three of a kind? J Leukoc Biol. 1997;62:702–709. [PubMed]