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Fortin, Carl F.*; McDonald, Patrick P.*; Fülöp, Tàmàs; Lesur, Olivier*‡

doi: 10.1097/SHK.0b013e3181c0f068
Review Article

Sepsis is exceedingly burdensome for hospital intensive care unit caregivers, and its incidence, as well as sepsis-related deaths, is increasing steadily. Sepsis is characterized by a robust increase in NO production throughout the organism that is driven by iNOS. Moreover, NO is an important factor in the development of septic shock and is synthesized by NOS, an enzyme expressed by a variety of cells, including vascular endothelium, macrophages, and neutrophils. However, the effects of NO on leukocyte functions, and the underlying mechanisms, are relatively unknown. Thus, the present review focuses on the effects of NO and its derivatives on cells of the immune system. Experimental evidences discussed herein show that NO induces posttranslational modifications of key proteins in targeted processes with the potential of deterring cellular physiology. Consequently, the manipulation of NO distribution in septic patients, used in conjunction with conventional treatments aimed at restoring normal immune functions, may represent a valuable therapeutic strategy.

*Pulmonary Division and Groupe de Physiopathologie Respiratoire, Université de Sherbrooke; Biogerontology Laboratory, Research Center on Aging, Sherbrooke Geriatric University Institute; and Medical Intensive Care Unit, CHU Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Received 13 Apr 2009; first review completed 28 Apr 2009; accepted in final form 23 Jul 2009

Address reprint requests to Olivier Lesur, MD, Pulmonary Division and Groupe de Physiopathologie Respiratoire, and Medical Intensive Care Unit, CHU Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Quebec, Canada J1H 5N4. E-mail:

The author Fortin is a recipient of a Doctoral Award Scholarship from the Canadian Institutes of Health Research.

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An extended survey conducted between 1979 and 2000 in the United States concluded that the incidence of sepsis and the number of sepsis-related deaths rose at a rate of 8.7% per year during this interval, and that the number of hospitalizations for severe sepsis has almost doubled in the 1993 to 2003 period (1, 2). Sepsis is also a major health concern worldwide (3-10). Inasmuch, the acute phase of sepsis is burdensome for hospital caregivers in intensive care units. Septic patients receive extensive treatments during prolonged periods and have their hospital stay extended by 2 to 3 weeks, mainly in the intensive care unit ward, with a mean stay of 15.7 days (11). Moreover, the average individual cost of a septic patient has been estimated at US $22,100 in the United States, which, on an annual basis, amounts to US $16.7 billion for all septic patients (12). Recent estimates in the United States reported 750,000 sepsis cases annually, of which almost 50% received intensive care (12). In addition, the incidence and mortality of sepsis are increasing with patient age (i.e., increased >100-fold with age for the former and increased 4-fold for the latter) (12). Further compounding the problem is that Gram-positive bacteria and fungal organisms have increasingly replaced Gram-negative bacteria as common causes leading to sepsis (1).

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The avid reader is directed to the final report of the 2001 International Sepsis Definitions Conference for complete definitions of sepsis (13). Briefly, sepsis is the clinical syndrome defined by the presence of both infection and systemic inflammatory response, which is the presence of systemic inflammation occurring in the presence of an infection. However, systemic inflammatory response can also occur in the absence of infection such as in patients with burns, trauma, pancreatitis, and other diseases. The primary sites of infection leading to sepsis are, beginning with the most common, the respiratory tract, intra-abdominal space, and the urinary tract (14-17). Severe sepsis refers to "systemic invasive" sepsis complicated by organ dysfunction(s), potentially leading to multiple organ dysfunction and failure syndrome (MODS). Severe sepsis is, in fact, the clinical representation of an extreme and combined proinflammatory and anti-inflammatory state (18). Septic shock is a state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes and requiring vasopressive-supporting drugs.

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NO is synthesized by NOS along the pathway leading from l-arginine to l-citrulline and is produced by the vascular endothelium, macrophages, and neutrophils, among others (19). It is now recognized as a major second messenger in cell biology because newly synthesized NO, acting locally, enters nearby cells by diffusion, where it activates cytosolic guanylate cyclase, leading to the formation of cyclic GMP (cGMP) in target cells (19). In vascular smooth muscle, elevated levels of cGMP lead to altered protein phosphorylation, which is associated with smooth muscle and vascular relaxations (20). There are three recognized isoforms of NOS: eNOS; nNOS, and iNOS. Two of these isoforms, eNOS and nNOS, are Ca2+-dependent and constitutively expressed, whereas iNOS is Ca2+-independent, and its expression is induced by cytokines or inflammatory mediators in most cell types. The combination of NO and superoxide anion (O2-), which is derived from NADPH oxidase, results in the production of reactive nitrogen species such as peroxynitrite (ONOO-) (21). Peroxynitrite is a potent oxidizing agent that can contribute to nitrosylation of proteins, including iNOS itself, as well as oxidization of biological molecules such as amino and nucleic acids (21, 22). It is known that peroxynitrite is produced by neutrophils and macrophages after LPS stimulation (23) and contributes to the immunosuppression of leukocytes during sepsis (24-26). It is thought that a large portion of NO-mediated effects are the result of peroxynitrite action on signal transduction molecules (21).

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NO is a major factor regulating microvascular homeostasis under normal conditions. In the vascular endothelium, the regulation of blood flow is principally mediated by eNOS-produced NO (27). Inflammatory stimuli (LPS, IL-1β, macrophage migration inhibitory factor [MIF], or IL-6) are known to alter microvascular homeostasis owing in part to iNOS-produced NO (28-30). Furthermore, alteration of microvascular homeostasis is thought to lead to heterogeneity in tissue perfusion, a phenomenon observed both in experimental and human sepsis (31-33). Such alterations also deflect blood flow away from needy microvascular units (33), which is a leading factor of tissue hypoxia (34), and, eventually, a contributive one to MODS. On one hand, iNOS-induced NO has also been associated with acute lung injury in the context of cecal ligation and puncture (CLP)-induced sepsis in C57Bl/6 mice (35); on the other hand, septic iNOS-/- mice developed more lung apoptosis (36). Although data were contradictory regarding this point, it was reasoned that the inhibition of NO synthesis in a context of sepsis could improve clinical outcome. At first, the inhibition of iNOS was shown to reverse LPS- or TNF-α-induced hypotension in animal models (37, 38). These results were subsequently replicated in humans (39, 40), and it was further described that NO inhibition led to increases in arterial pressure, systemic and pulmonary vascular resistance, and decreased cardiac output (41). However, despite an observed improvement in vascular tone, the overall clinical condition was not improved, and mortality remained high (41-43). Nevertheless, a recent survey of preclinical and clinical data reveal that experimental NO supplementation is associated with a favorable outcome in various models of animal sepsis (44). Interestingly, administration of exogenous NO before, or after, induction of sepsis has beneficial effects on mortality and tissue injury such as microscopic intestinal lesions (44). Finally, NO production in the early phases of sepsis is likely to contribute, together with respiratory burst, to efficient microbial clearance by phagocytic cells, especially because respiratory burst and NO-derived mediators have well-known antimicrobial activities (45-47). Therefore, such clearance in the early phases of sepsis is likely to explain why a nonspecific inhibitor of iNOS was found to be detrimental in a clinical trial (48). The beneficial and detrimental roles of NO in the pathophysiology of sepsis have been depicted previously (49), and some aspects of this are represented in Figure 1.

Fig. 1

Fig. 1

In the following sections, the potential alterations caused by NO on leukocyte functions will be further examined because these alterations have often been overlooked in the current model of sepsis pathophysiology. This is of particular interest especially because sepsis is associated with decreased leukocyte functions, and immunosuppression in survivors of sepsis, in experimental models, and in septic patients (50, 51). By illustrating the dual effect of sepsis on the immune system, it is our hope that this review may contribute in sparking new interests in the study of sepsis pathophysiology.

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Neutrophils migrate rapidly to the site of infection where they are activated in response to specific structures on microbial pathogen surfaces, as well as by various classes of inflammatory mediators, including cytokines and chemokines. Once on site, the neutrophils attempt to clear the site of pathogens by phagocytosis and the generation of reactive oxygen species such as H2O2 (52). Reactive oxygen species and NO are not only involved in bacterial killing (45) but are also linked to tissue damage, increased vascular permeability, and organ injury (53, 54). Neutrophils have been found to be resistant to constitutive apoptosis in human sepsis (55, 56) and septic rats (57). In both instances, C5a, PI3-K, as well as IFN-γ, IL-2, IL-15, granulocyte-macrophage- and granulocyte-colony stimulating factor were reported to play a major role in the prolongation of neutrophil survival (56, 57). Alterations induced by sepsis on the functions of neutrophils and other leukocytes are shown in Table 1.

Table 1

Table 1

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An exogenous source of NO, sodium nitroprusside, is able to enhance the secretion of TNF-α by neutrophils when used in conjunction with LPS or IFN-γ by mechanisms independent of cGMP or increased mRNA (58), thereby suggesting that NO may act as a secretagogue on neutrophils. In the early phase of sepsis, NO is known to increase neutrophil phagocytosis (59). In contrast, in the latter phase of sepsis, neutrophil adhesion, rolling, migration, oxidative, and microbicidal activities are decreased by NO in various animal (60) and human (61-68) models. Emerging insights have recently arisen in connection with this NO-mediated decrease in neutrophil function. Indeed, the impaired migration of neutrophils observed in sepsis has been shown to result in part from NO-mediated down-regulation of CXCR2, a chemokine receptor (69). Furthermore, peroxynitrite, an NO-derived oxidizing and nitrating compound, is involved in the migratory failure of neutrophils in sepsis by yet undefined mechanisms (25). Recent studies, however, have shed some insight into the processes involved in neutrophil migration failure induced by NO donors such as peroxynitrite and 3-morpholinosydnonimine (70-72). Incubation of neutrophils with NO donors nitrosylates actin, thereby impeding its polymerization, and in turn, cell migration and phagocytosis (70, 72), thus providing a likely explanation for the neutrophil migration failure observed in sepsis. In addition, NO donors have been found to induce the nitration of signaling proteins, thereby reducing total tyrosine phosphorylation after activation of neutrophils by N-formyl-methionine-leucine-phenylalanine (fMLP) or phorbol myristic acid ester (71). Conversely, peroxynitrite has been found to be a potential priming agent for respiratory burst by human neutrophils (73). A low dose of peroxynitrite (300 μM) was shown to enhance superoxide anion production by phorbol myristic acid ester or fMLP, as well as induce expression of cell surface proteins by a mechanism involving tyrosine nitration (73). Alterations induced by NO, or by NO donors, on leukocytes are shown in Table 2.

Table 2

Table 2

The previously described observations are in keeping with the fact that neutrophils have both protective and detrimental effects on the outcome of sepsis, as shown in a rat model of CLP-induced sepsis (74). Neutrophil depletion before CLP has been found to result in substantial increases in bacteremia, with no evidence of attenuated liver or renal dysfunction (74). By comparison, neutrophil depletion 12 h after CLP resulted in a dramatic reduction in bacteremia, in liver and renal dysfunction, and in sharp reductions in serum levels of several cytokines (IL-1β, IL-6, IL-1β, TNF-α, and IL-2), as well as in improved survival (74). The increased levels of cytokines in late sepsis may be related to earlier findings describing that exogenous NO augments TNF-α secretion by human neutrophils (58). Moreover, Skidgel et al. (75) observed an increase in NO-mediated macrophage inflammatory protein (MIP) 2 in response to Escherichia coli challenge in mice. Interestingly, in their settings, NO had almost no role in the activation of nuclear factor (NF)-κB (75), akin to the failure of exogenous NO to induce TNF-α mRNA expression in neutrophils (58). These observations suggest that the NO-mediated increase in cytokine levels in sepsis does not involve the activation of transcription factors in leukocytes, thereby evoking potentially new therapeutic targets such as the use of secretion inhibitors. This is in striking contrast with other cell types where, for instance, Sparkman and Boggaram (76) found that NO induced IL-8 gene expression in H441 lung epithelial cells via a cGMP-independent mechanism. Alternatively, acute-phase serum proteins could be responsible for increased cytokine levels in late sepsis because serum amyloid A has been shown to induce the release of TNF-α, IL-1β, and IL-8 in human neutrophils (77). The use of a proteasome inhibitor (thereby impairing NF-κB activation), in combination with antibiotics, was reported to significantly improve the outcome of septic mice (78).

Whatever the case may be, it remains puzzling that neutrophils seem to secrete cytokines in late sepsis (74), whereas other functional responses are decreased by NO under the same condition (60-68). This is further complicated by findings showing a possible secretagogue effect of NO on neutrophils in early sepsis (58, 75). Overall, these results are very intriguing and stress the need for further investigation into the effects of NO on cytokine secretion by neutrophils in early and late sepsis.

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Within the innate immunity, resident macrophages and infiltrating monocytes provide immediate defense against foreign pathogens and coordinate leukocyte infiltration (79, 80). Macrophages collaborate with, and educate, T and B cells to initiate the immune response through cell-cell interactions and various mediators such as cytokines, chemokines, enzymes, arachidonic acid metabolites, and reactive radicals (80). Thus, macrophages play an essential role in triggering, instructing, and terminating the adaptive immune response, depending on the functional phenotypes they acquire as a consequence of tissue-derived signals.

For circulating monocytes, the progression of sepsis severity leads to decreased human leukocyte antigen (HLA)-DR expression (81, 82). Additionally, this decreased expression is linked to poor outcome for septic patients (82). Furthermore, monocytes from septic patients have been shown to have a significantly reduced production of cytokines (TNF-α, IL-1β, and IL-12) and were unable to acquire high levels of CD80 and CD86 molecules or be rescued from apoptosis by CD40L (84). Consequently, CD40L-activated monocytes from septic patients were unable to induce CD4+ lymphocyte proliferation and secretion of IFN-γ (83). Moreover, investigation of the chemokine fractalkine (CXC3CL1) and its receptor (CX3CR1) on monocytes from septic patients have shown that CX3CR1 expression is down-regulated, and that monocytes are unresponsive upon fractalkine challenge (84). Although sepsis induces monocyte apoptosis in humans and rabbits (85, 86), these studies revealed that survivors exhibit increased monocyte apoptosis linked to a lower secretion of serum TNF-α relatively to nonsurvivors (85, 86).

To our knowledge, the effect of macrophage depletion on the course of sepsis has yet to be tested. A recent study, however, showed that sepsis induces a major depletion of immature macrophages in a mouse model of sepsis (87). Furthermore, a prospective study conducted with rat macrophages incubated with serum from septic patients did reveal some alterations in rat macrophage function (66). In particular, secretion of TNF- and IL-1β was increased when rat macrophages were incubated with serum of septic patients but not with serum from healthy volunteers (66). Moreover, rat macrophages displayed a decreased phagocytic capacity upon addition of serum from septic patients into the medium (66). These findings suggest that alterations in macrophage number and function may be of importance in sepsis-induced immune suppression.

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Evidences showing altered functions of monocytes/macrophages by NO in sepsis are less abundant than for neutrophils. Nevertheless, NO has been found to inhibit monocyte adhesion to porcine aortic endothelial cell monolayers and chemotaxis stimulated by fMLP, whereas it failed to influence cell surface expression of CD11b/CD18 (62). In addition, an exogenous source of NO, sodium nitroprusside, inhibited fMLP-induced monocyte migration and increased cGMP concentrations (61). Moreover, NO donors have been found to cause a transitory inhibition of cell respiration and a 50% reduction in cellular adenosine triphosphate in T lymphocytes and monocytes, leading to an inhibition of cell proliferation and cytokine (IL-2, IL-4, IL-5, and IFN-γ) secretion (65). The effect of NO donors has been tested on monocyte differentiation into immature dendritic cells, and the results suggest that NO affects DC differentiation and maturation (63). Finally, monocyte-derived dendritic cell functions are impaired by NO as shown by a decrease in CD23-triggered cytokine secretion (MIP1-α and IL-6) in IL-4- or GM-CSF-matured monocytes (67).

On the other hand, there is evidence that NO and peroxynitrite, an NO-derived mediator, play a role in the physiological functions of monocytes and macrophages. In whole blood, peroxynitrite induces IL-8 mRNA expression and stimulates IL-8 release by human leukocytes (64, 68). Peroxynitrite also induces cytokine secretion (TNF-α and IL-6) in human macrophages through a NF-κB-dependent mechanism (88). Furthermore, in monocytes, the LPS-induced expression of tissue factor, which induces intravascular coagulation in sepsis (89, 90), is mediated by previous formation of peroxynitrite (24). These results suggest that because leukocytes produce peroxynitrite after LPS stimulation (23, 64), the high amount of NO observed in sepsis could exert adverse effects on normal autocrine peroxynitrite signaling by promoting NO tolerance. In this regard, it was found that, although NO inhibits NF-κB activation in rat vascular smooth muscle cells, peroxynitrite exposure leads to sustained NF-κB activity (91). This phenomenon is reminiscent of endotoxin tolerance, where sustained endotoxin concentrations lead to desensitization of cells and blunted responsiveness (92). Likewise, it is known that IRAK-M inhibits the TLR/IRAK pathway during endotoxin tolerance (93, 94), and an NO donor was found to induce a sustained IRAK-M mRNA and protein expression in monocytes (95). In addition, insights obtained from other experimental settings helped shed some light into the mechanistic aspects contributing to these alterations. Cell lysates from RAW 264.7 cells incubated with 1 mM peroxynitrite resulted in the nitration of several proteins in the range of 60 to 250 kDa (96). The authors identified one of the nitrated proteins as p85, the regulatory subunit of phosphatidylinositol 3-kinase, a key enzyme involved in the signal transduction cascades initiated by many agonists, including growth factors (96). In addition, in a macrophage cell line, induction of iNOS resulted in tyrosine-nitration of cellular proteins and in the presence of nitrated tyrosine residues in STAT1, leading to a reduction in phospho-STAT1 after IFN-γ stimulation (97). Interestingly, the upper kinase Jak2 had its activity impaired but displayed no nitrated tyrosine residues (97), suggesting that NO and derivatives could negatively impact cellular signaling by other means than nitration. Peroxynitrite also induces the nitration of tyrosine residues on peroxisome proliferators-activated receptor γ in a macrophage cell line; however, the authors did not asses the functional consequences of this nitration (98). Moreover, 3-morpholinosydnonimine-derived peroxynitrite was found to induce apoptosis in monocytes by activation of caspase 3 and caspase 9, bcl-2 depletion, as well as accumulation of proapoptotic proteins (99). This is likely due to the potentially detrimental defects in signaling transduction induced by tyrosine nitration of Rac and Lyn, among others (99). Further studies are clearly needed to fully characterize the physiology of macrophages in a state of NO-induced tolerance in sepsis models.

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Dendritic cells (DCs) are the most potent antigen-presenting cells known and play a key role in T- and B-cell activation by antigen presentation and production of cytokines and chemokines. Dendritic cells participate in either Th1 or Th2 cell responses depending on factors such as activating stimulus and presentation of pathogen-derived antigens (100, 101).

Dendritic cells are lost by apoptosis from the spleen and lymph nodes (87, 102), late after the onset of sepsis, in mouse models and in septic patients (103-105). This loss of DCs, however, occurs after CD4+ T-cell activation (106). Nonetheless, in a mouse model of CLP-induced sepsis, it was demonstrated that DCs from septic mice were unable to secrete IL-12, even upon stimulation with CpG or LPS and CD40L, but, were capable to release high levels of IL-1β in late sepsis (107). In the same study, the remaining DCs showed a reduced capacity for allogeneic T-cell activation, associated with decreased IL-2 synthesis, in late sepsis (107). Furthermore, DCs from septic mice demonstrated an impaired capacity to release proinflammatory and Th1-promoting cytokines (TNF-α, IFN-γ, and IL-12) in response to bacterial stimuli in late sepsis (108). On the contrary, these DCs secreted higher levels of IL-1β in late sepsis (108), suggesting a potential role for DCs in the immune suppression observed in sepsis. Despite that, CD86 and CD40, costimulatory molecules for T-cell activation, are up-regulated on the surface of DCs in sepsis (107, 108). No experimental evidences have shown that the other costimulatory molecules are increased by sepsis on the surface of DCs. Up-regulation of IL-1β secretion and costimulatory molecule expression on DCs suggest a potential ability to induce T-cell energy in late sepsis. In contrast, DCs seem to function normally in early sepsis because they secrete normal amounts of IL-12 (107). Together, these observations support the notion that DCs contribute to the altered immune response observed in late sepsis in nonhuman models.

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To the best of our knowledge, NO-mediated effects on DCs in the context of sepsis have not been described to date. Nevertheless, some experimental evidences from in vitro studies suggest that sepsis-induced excess NO could alter DC function in a subset-specific manner. For instance, it was found that NO protects immature DCs from the apoptogenic effects of large amounts of E. coli and LPS through cGMP formation and stimulation of the cGMP-dependent protein kinase (109). Furthermore, addition of an NO donor, S-nitrosoglutathione, to monocyte-derived DCs (whether matured by LPS or soluble CD40 ligand) was shown to lead to a decreased capacity to activate naive allogeneic T cells, owing in part to a reduced expression of CD86 (110). In contrast, S-nitrosoglutathione led to a strong Th1 polarization with an accompanying increase in IFN-γ and TNF-α release, but a decrease in IL-1β secretion (110). Adding further intricacy to the matter, NO favors the polarization of plasmacytoid dendritic cells toward a Th2 phenotype (111). In fact, plasmacytoid dendritic cells secrete less cytokines (IFN-γ, TNF-α, and IL-6) after exposure to NO; however, they up-regulate their CD40L surface expression and, consequently, promote the differentiation of naive CD4+ T cells into a Th2 phenotype upon stimulation with TLR9 ligand (CpG) (111). Experimental evidences regarding possible alterations of DC function in the context of sepsis and NO excess is thus warranted, especially because DCs are key players in both innate and adaptive immunity.

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During sepsis, it is known that lymphocytes exhibit accelerated apoptosis, loss of phagocytic function, and unbalanced cytokine secretion (e.g., decreased secretion of TNF-α and IL-6 but increased secretion of IL-1β) during sepsis (102, 112, 113). Furthermore, in a mouse model of sepsis induced by live E. coli, a large proportion of both CD4+ and CD8+ T cells was found to be activated within 1 day after E. coli infection (114). The role of αβ T cells in the pathophysiology of sepsis has been confirmed by experiments with T-cell-efficient mice (114-116). These studies indicate that mice depleted of αβ T cells were more resistant to mortality in an acutely lethal model of CLP (115) or in sepsis induced by injection of E. coli (114). Authors observed that improved survival of T-cell-deficient mice was associated with decreased proinflammatory cytokines (IL-6 and MIP-2) (114, 115), with less hypothermia, and an improved acid-base balance (115).

In the case of γδ T cells, their depletion in a mice model of CLP-induced sepsis resulted in decreased survival 10 days after the onset of sepsis, as well as in altered plasma cytokine levels (increased IL-6 and IFN-γ but slightly decreased IL-1β), in tissue damage and in bacteremia (117). However, other groups (115, 118) have reported conflicting findings whereby depletion of γδ T cells in a mouse model of sepsis either resulted in a sharp increase in survival 7 days after the onset of sepsis by CLP surgery (118) or had no significant effect on survival (115). The observed discrepancies between these reports may be the result of differences in the severity of sepsis models used. Although all the aforementioned models use CLP-induced sepsis, the survival rates differ widely among the three models, ranging from 45% (117) to 0% (115). Interestingly, it is only when a nonacutely lethal CLP model is used that γδ T cells seem to play a role in sepsis (117, 118). These results strengthen the need for further research to assert the role of γδ T cells in sepsis, and that the severity of sepsis, indicated by survival rate of the CLP model used, may influence the contribution of these cells in this pathophysiology.

Additionally, it was recently found that number of T reg cells and soluble CD25 plasma levels are increased in septic patients (119), although T reg cells did not contribute to mortality in a murine CLP-induced model of sepsis (120). Therefore, it seems that the various lymphocyte subsets contribute differentially to the severity and mortality of sepsis. Furthermore, it was recently found that CD4 knockout mice were more susceptible to CLP-induced sepsis within the first 30 h than CD8 knockout and wild-type mice (116) possibly because of the loss of IL-1β secretion and helper functions of Th2 cells. This increased mortality was, in addition, linked to increased bacteremia and IL-6 concentration in plasma (116).

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Although there are, to our knowledge, no studies showing the effect of NO on lymphocyte function in the context of sepsis, there are indications of such effects in other contexts that could thus represent important mechanisms contributing to their decreased function in sepsis. Recently, CD8+ T cells were found to undergo nitration of tyrosines in the TCR-CD8 complex, through reactive oxygen species and peroxynitrite, in the context of cancer-induced tolerance (121). As a result, these cells were unable to bind a specific peptide presented by the major histocompatibility complex but were responsive to nonspecific stimulation (121). Moreover, it is known that NO and peroxynitrite can impair the proliferation of activated T cells (122, 123) by mechanisms involving the inhibition of activation-induced protein phosphorylation by nitration of tyrosines residues and by priming for apoptosis (123). In keeping with this observation, Kong et al. (124) found that tyrosine phosphorylation of a pentadecameric peptide representing a tyrosine phosphorylation site of p34cdc2 (a kinase implicated in cell cycle regulation and normally phosphorylated by Lck) was disrupted because of peroxynitrite-promoted nitration of this tyrosine residue. Moreover, NO-mediated inhibition of T-cell proliferation was associated with the inhibition of caspase activity by reversible S-nitrosylation (125). These results suggest that NO-induced alteration of substrates that are important in lymphocyte physiology could represent a major factor underlying the decrease of their functions in sepsis and the ensuing immunosuppression observed in sepsis survivors.

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This review presents documented evidences that elevated NO concentrations observed in sepsis are detrimental for normal leukocyte functions, as summarized in Table 1 and Table 2. Paradoxically, iNOS-derived NO influences the physiological functions of most leukocytes and is implicated in phagocytic, antimicrobial, and tumoricidal activities (122, 126, 127). One of the features of sepsis is endotoxin tolerance (128), and in light of this review, a similar NO-induced tolerance must also be taken into account in the pathophysiology of sepsis. Furthermore, an additional feature of sepsis is that surviving patients (or animals in experimental sepsis models) are temporarily immunodepressed (129), owing, in part, to mechanisms involving epigenetic changes at the nucleosomal level (51, 130). Eventually, these epigenetic changes can lead to decreased HLA-DR mRNA and protein levels as well as surface expression in human monocytes (131, 132). It is therefore possible that these epigenetic changes, which would presumably lead to tolerance, are driven by NO or NO-derived mediators because it is known that peroxynitrite oxidizes nucleic acids and induces DNA repair mechanisms (21). Finally, depletion of lymphocytes and neutrophils can improve survival rates in models of sepsis (albeit with different kinetics), in part by decreasing proinflammatory cytokine concentrations in serum. The experimental evidences discussed herein show that NO is potentially implicated in this phenomenon. Therefore, manipulation of NO distribution in septic patients, used in conjunction with other therapies aimed at restoring normal immune functions, may represent a valuable therapeutic strategy.

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Neutrophils; monocytes; macrophages; dendritic cells; lymphocytes; cytokines

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