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Nitric Oxide in Liver Inflammation and Regeneration Paloma Martin-Sanz,1 Sonsoles Hortelano,1 Nuria A. Callejas,1 Nora Goren,1 Marta Casado,1 Miriam Zeini,1 and Lisardo Bosc´a1,2 Received October 2001; accepted August 1, 2002
Hepatocytes express and release inflammatory mediators after challenge with bacterial cell wall molecules and proinflammatory cytokines. Nitric oxide synthase-2 (NOS-2) is expressed under these conditions and the high-output NO synthesis that follows contributes to the inflammatory response in this tissue and participates in the onset of several hepatopathies. However, in the course of liver regeneration, for example, after partial hepatectomy, NOS-2 is expressed at moderate levels and contributes to inhibit apoptosis and to favor progression in the cell cycle until the organ size and function are restored. The mechanisms involved in the regulation of NOS-2 expression under these conditions are revised. Key words: Nitric oxide; transcription factors; liver inflammation; liver regeneration; apoptosis.
INTRODUCTION In the aftermath of liver injury by toxic and xenobiotic compounds, or after surgical resection of portions of tissue, up to 2/3 of partial hepatectomy, the liver initiates a series of reactions intended to reestablish its function (Diez-Fernandez et al., 1997; Fausto, 1999, 2000; Fausto et al., 1995; Greenbaum et al., 1998; Hortelano et al., 1995; Lee, 2001; Michalopoulos and DeFrances, 1997; Taub, 1998). This process is accomplished by the expression of genes that contribute to the maintenance of the hepatic-dependent homeostasis in the organism and that inhibit apoptosis and promote cell growth (Camargo et al., 1997; Campbell et al., 2001; Clavien, 1997; Cressman et al., 1996; Michalopoulos and DeFrances, 1997; Yamada et al., 1998). Indeed, the ability of mammalian hepatocytes to proliferate after acute partial hepatectomy (PH) is a useful model for the study of synchronized cell proliferation of highly differentiated tissues, and provides a good system for the in vivo characterization of the factors involved in the control of cell growth and arrest in response to pathophysiological stimuli (DeAngelis et al., 2001; Debonera et al., 2001; Diehl and Rai, 1996; Fausto, 1999, 2000; Hortelano et al., 1995). Moreover, a remarkable characteristic of this regenerative process is the capacity of the liver to grow until the organ function is fully restored (Mojena et al., 2001; Sakamoto et al., 1999; Scotte et al., 1997; Streetz et al., 2001; Webber et al., 1998). Experimental evidence suggests that the expression of Type 2 nitric oxide synthase (NOS-2), the high output NO synthesizing enzyme participates actively in the course of liver inflammation, as well as in different regenerative processes, providing a signaling 1 Instituto
de Bioqu´ımica (Centro Mixto CSIC-UCM), Facultad de Farmacia, Universidad Complutense, Madrid, Spain. 2 To whom correspondence should be addressed at Instituto de Bioqu´ımica, Facultad de Farmacia, 28040 Madrid, Spain. E-mail:
[email protected] 325 C 2002 Plenum Publishing Corporation 0885-7490/02/1200-0325/0 °
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network that modulates several transduction pathways involved in the resolution of the inflammatory process and in liver regeneration. The physiopathological roles mediated by this NO is reviewed. INFLAMMATION Mammalian hepatocytes well respond in vivo and in vitro to most of the proinflammatory cytokines and bacterial cell wall molecules, promoting the expression of genes that mediate the inflammatory response. In this way, hepatocytes express NOS-2 and acutephase proteins, but fail to induce COX-2, an enzyme that is present in Kupffer cells treated with proinflammatory stimuli (Fig. 1). Indeed, fetal, neonatal, regenerating, and dedifferentiated hepatocytes retain the ability to express COX-2 (Fig. 2), and the potential role for the prostaglandins released under these conditions remains to be established (Casado et al., 2001; DeWitt, 1991; Galea and Feinstein, 1999; Goss et al., 1993; Martin-Sanz et al., 1998). Moreover, some of the cytokines locally produced after liver injury are good inducers of the expression of NOS-2, and a high NO release has been measured under these conditions (Curran et al., 1989; Diaz-Guerra et al., 1997; Galea and Feinstein, 1999). In addition to this, induction of NOS-2 in liver has been detected in the course of several hepatic dysfunctions such as hyperdynamic circulation, chemical aggression or during septic shock. Therefore, the expression of this gene appears to be a widely established response of the damaged organ (Clemens, 1999; Diez-Fernandez et al., 1997; Guidotti et al., 2000; Hierholzer et al., 1998; Hortelano et al., 1995; Kaplowitz, 2000; Morikawa et al., 1999). The sequence and structure of NOS-2 in rodents and humans is well conserved. However, this is not the case of the promoter region that regulates its expression and therefore, the activity because the main control of this enzyme is at the transcription level (MacMicking et al., 1997; Taylor and Geller, 2000; Xie et al., 1993). In rodents, a 1.8-kb fragment of the promoter region of the murine NOS-2 gene (Fig. 3) has been cloned (Xie et al., 1993). This sequence contains consensus motifs for the binding of at least 24 transcriptional factors, including 2 copies of NF-κB, 2 copies of AP-1, 10 copies of IFN-γ response elements (γ -IRE), 3 copies of the γ -activated site, and 2 copies of the IFN-stimulated response element. Analysis of the transcriptional activity of this promoter using deletional mutants revealed the essential role of the κB motifs in the control of NOS-2 expression (Diaz-Guerra et al., 1996; Velasco et al., 1997). Therefore, the study of the mechanisms leading to NF-κB activation is of great interest to establish the pathways that control NOS-2 expression in the course of several liver dysfunctions. NF-κB consists of a heterodimeric complex composed of two subunits of the NF-κB/c-Rel family, usually p50 and p65, that are retained in the cytoplasm as an inactive complex through the interaction with IκB inhibitory proteins (Baeuerle, 1998; Baeuerle
Figure 1. Isolated hepatocytes express inflammatory mediators such as acute phase proteins and NOS-2, but not COX-2, in response to proinflammatory stimuli or infection by hepatitis B virus. Under these conditions, the hepatocytes remain in the G0 phase of the cell cycle.
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Figure 2. COX-2 is not expressed in postnatal hepatocytes. Hepatocytes obtained from livers of animals of the indicated age were stimulated with LPS and proinflammatory stimuli and the levels of expression of NOS-2 and COX-2 were determined. In parallel, C/EBPα was determined as a transcription factor impairing COX-2 inducibility. Partial hepatectomy was carried out in animals aged 3 months.
and Baichwal, 1997). A specific regulation by extracellular factors of the IκBα and IκBβ isoforms has been reported in liver, which in turn defines the duration of NF-κB activation (Velasco et al., 1997). Regarding the function of the NO synthesized by hepatocytes under inflammatory conditions it appears to exert a protection against apoptosis, in particular,
Figure 3. A schematic representation of the promoter region of mNOS-2 is shown. The cooperation between transcription factors activated in response to IFN-γ , and the distal κB site is depicted (A). NF-κB is activated in response to different cell stresses, ranging from ionizing radiation to bacterial lipopolysaccharide, and is required, although is not sufficient for the expression of NOS-2 and other genes related to inflammation (B).
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TNF-α induced apoptotic death, and also by inhibiting different steps of procaspase activation, as well as caspase activity (Eustice et al., 1991; Glockzin et al., 1999; Kim et al., 1997; Li and Billiar, 1999a,b). Other effects of NO on hepatocyte function have been discussed elsewhere (Nussler et al., 1995; Pastor et al., 1995; Schoen et al., 2001; Titheradge, 1999).
PARTIAL HEPATECTOMY The study of liver regeneration is a well-established research area of interest both from the pathophysiological and experimental points of view (Michalopoulos and DeFrances, 1997). One of the models to accomplish the regenerative process is through the surgical resection of a major portion of liver (about 75% of liver mass). In that case, the remnant liver initiates a series of timed responses intended first to favor cell growth and to inhibit apoptosis, and then to stop hepatocyte proliferation once the liver function is fully restored (Casado et al., 2001; Fausto, 1999, 2000; Taub, 1998). Under these conditions, liver regeneration is accomplished through the synchronous entry of the hepatocytes into the cell cycle, exhibiting a peak of DNA synthesis at 24 hr after PH, followed by mitosis 6– 14 hr later, depending on the animal species. The studies on liver regeneration have stressed the relevance of a cooperative signaling in the commitment for cell growth (Fig. 4). This is the result of the occurrence of a specific time-course pattern of release of cytokines, growth factors, and hormones until the recovery of the hepatic function (Fausto, 2000; Michalopoulos and DeFrances, 1997). The nature of the factors and early signals involved in the recruitment of cells to entry in the cell-cycle division has been characterized from a biochemical, pharmacological, and genetic point of view, following PH in several animal models: The current view about the process of regeneration is based on the existence of a dynamic balance between positive and negative controls (Fig. 4). In this regard, most of the changes of the expression of immediate-early genes that follow after PH (Clemens, 1999; Debonera et al., 2001; Gallucci et al., 2000) trigger the expression of proteins that directly participate in the control of liver regeneration, either by promoting cell growth or
Figure 4. Positive and negative stimuli governing hepatocyte proliferation. Moderate concentrations of NO contribute to improve hepatocyte viability by preventing stimuli-dependent apoptosis (adapted from Michalopoulos and DeFrances, 1997).
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arrest (Michalopoulos and DeFrances, 1997) or by favoring the restoration of blood flow and diffusion of extracellular factors that mediate the synchronized regenerative process (Hollenberg et al., 2000; Kumins et al., 1997). For this reason, stress has been focused on the identification of cytokines and hormones that promote (hepatocyte growth factor, TGF-α, prolactin, glucagon) or inhibit (TGF-α) hepatocyte growth both in vivo and in primary cultures of cells from hepatectomized animals (Michalopoulos and DeFrances, 1997). Moreover, in the remnant liver, the balance of the cytokines released after PH, either by the hepatocytes (i.e., TGF-α) or by nonparenchymal cells (Kupffer and Ito cells), is translated into the hepatocyte in signals (second messengers) that produce the biochemical changes responsible for the regenerative process. Therefore, it is conceivable that the precise moments in which cytokines are produced, and the existence of comodulatory interactions between them, play a critical role in the exit from the usual transcriptionally active G0 /G1 growth arrest phase to the acquaintance for progression through the cell cycle. A rapid release of TNF-α (Gallucci et al., 2000) and IL-6 (Clavien, 1997) has been observed after PH, and this is followed by NF-κB activation in the liver remnant (Fig. 5). NF-κB is required for the inhibition of apoptosis, through mechanisms not well defined (Bellas et al., 1997; Lavon et al., 2000; Rosenfeld et al., 2000; Taub, 1998), and for the expression of genes that control the regenerative process downstream this point, among them NOS-2 (Hortelano et al., 1995). Several groups reported that NOS-2 is effectively induced in the remnant liver of partially hepatectomized mice, but this response is quantitatively lower than those elicited in animals suffering septic shock, in terms of NO synthesis. Moreover, the expression of NOS-2 is transient and the enzyme is active because NO synthesis is detected in vivo using electron paramagnetic resonance (EPR) techniques (Obolenskaya et al., 1994a,b). This NO release, because of the expression of NOS-2 and occurring between 4–18-hr post-PH, seems to be delivered and consumed exclusively in the liver. This conclusion is supported by the observation of a total absence of nitrosylated hemoglobin in the blood that emerges directly from the liver. These data are very different from those obtained in the in vivo LPS-induced endotoxemia, where the formation of a nitrosylated hemoglobin in lysed erythrocytes, and a huge increase in nitrite concentration in plasma
Figure 5. Release of proinflammatory cytokines (TNF-α and IL-6) to the serum in animals that underwent 2/3 PH. The NF-κB activity was determined at the indicated times by electrophoretic mobility shift assays using an oligonucleotide probe containing the distal κB motif of the murine NOS-2 promoter.
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are clearly detected (Fry, 2000; Szabo and Billiar, 1999; Titheradge, 1999; Yamashita et al., 2000). Moreover, after PH, both hepatic NOS activity and levels of NOS mRNA have been exclusively detected in the liver, indicating that this is a local effect (Hortelano et al., 1995). However, the relative contribution of each liver cell type (Kupffer and hepatocytes, and possibly endothelial cells) to the total NOS activity and NO synthesis seems to be different; Kupffer cells, although less abundant than hepatocytes, produce much more NO than the hepatocytes when cultured under similar conditions. However, because NO may easily diffuse through the cells, the origin of this molecule is not critical for the ability to promote intracellular changes in neighboring cells. Type 2 nitric oxide synthase levels are mainly controlled at the transcription level (Diaz-Guerra et al., 1996), and because of the synchrony of the regenerative process after PH it is conceivable a homogeneous wave of activation of transcription factors is responsible for the expression of this gene. Activation of NF-κB has been reported by various groups as an essential requirement for NOS-2 transcription (Diaz-Guerra et al., 1997). In the remnant liver after PH, NF-κB activation occurs at the start of the regenerative process (as soon as 30-min post-PH; Fig. 5), and rapidly falls in the following hours. According to these data, it might be concluded that this early and quantitatively important activation of NF-κB is sufficient for the turn-on of NOS-2 transcription, which exhibits a peak of mRNA levels 4 hr after PH, and the corresponding peak of NOS-2 protein at 8 hr. Apparently, there is a unique peak of NF-κB activation and NOS-2 expression, although NO synthesis has been detected at times longer than 24 hr (Obolenskaya et al., 1994a,b). The early synthesis of TNF-α in regenerating liver, as well as the network interaction of inflammatory molecules released after PH has been established, and a central role in the control of the early events in the regeneration process has been proposed for them (Knight et al., 2000; Yamada et al., 1998). In agreement with this suggestion, TNF-α stimulates DNA synthesis in primary cultures of hepatocytes, and plays a positive role in the early event post-PH. Concerning the origin of TNF-α, Kupffer cells seem to be the main contributors to its synthesis in the liver. Regarding the potential role for the NO released after PH, several targets have been suggested ranging from modulation of protein function via S-nitrosylation reactions, to systemic effects on blood flow (Clemens, 1999; Debonera et al., 2001). In addition to this, it has been described a role for NO in the regulation of the cell cycle as reflected by the important changes of the pattern of ploidy during the regenerative process. In this regard, several effects of NO in the regulation of hepatic functions have been reported: changes of the rate of hepatic protein synthesis (Hortelano et al., 1995) and the control of mitochondrial respiration. Indeed, using pharmacological and genetic approaches, this role of NO on regeneration can be analyzed (Fig. 6): Inhibition of NO synthesis with selective NOS-2 inhibitors resulted in an enhanced superoxide production by liver and in an altered ploidy pattern in the remnant tissue at 24-hr post-PH (Hortelano et al., 1995; Rosenfeld et al., 2000; Vos et al., 1997). Moreover, NO has proved to be an important regulator of IκB function, and in this way, it can prevent NF-κB activation once its synthesis is turned on (Diaz-Guerra et al., 1997). In this aspect, NF-κB activation is largely delayed (at least 3 hr after PH) in animals previously treated with dexamethasone, a condition in which IκB activity is upregulated and NOS-2 expression repressed. In addition to this, PH experiments in animals with disrupted NOS-2 gene or overexpressing TGF-β, which impairs NOS-2 expression, exhibit an impaired liver regeneration (Rai et al., 1998). The same defect was
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Figure 6. Experimental models to assess the involvement of NO in liver regeneration after 2/3 PH. Impairment or defective regeneration was observed in animals treated with NOS-2 inhibitors (1400W, aminoguanidine, L-NIL), glucocorticoids (dexamethasone), and NF-κB inhibitors (lactacystine, MG132). Similar results were obtained in animals lacking NOS-2.
observed in animals lacking TNF-α receptor I (Knight et al., 2000; Yamada et al., 1998), carrying a development regulated IκBα transgene or transduced with adenovirus-mediated IκBα expression (Rosenfeld et al., 2000; Taylor et al., 1999). Interestingly, animals deficient of p50 exhibit a normal regenerative process (DeAngelis et al., 2001). Several revisions of the regenerating process deduced from animals genetically altered are available (Fausto, 1999; Huang and Fishman, 1996). It has been also proposed that NO is involved in the process of vascular readaptation after PH, preventing the blood-flow collapse resulting from the liver resection and favoring a general permeability throughout the organ, as well as inducing the expression of specific metabolic responses required to initiate the recovery of hepatic function. Several reports confirm the important role of NO in the process of vascularization, angiogenesis, and permeabilization of tissues (Hickey et al., 1997; Hierholzer et al., 1998; Hollenberg et al., 1999, 2000; Kumins et al., 1997). In summary, a contribution for NO in the process of liver regeneration after PH can be proposed (Fig. 7).
Figure 7. Schematic representation of the priming effect exerted by NO and PGs on liver regeneration after PH.
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