CYTOKINES IN NECROTIZING ENTEROCOLITIS : Shock (original) (raw)
INTRODUCTION
Necrotizing enterocolitis (NEC) is well recognized among neonatologists and pediatric surgeons as one of the most devastating intra-abdominal emergencies in the newborn infant, particularly those of very low birth weight. The primary feature of NEC is bowel wall inflammation with necrosis, often leading to perforation, and the necessity of emergent surgical exploration or decompression. Necrotizing enterocolitis mainly affects infants in neonatal intensive care units and has variable incidence both within and between countries. In the United States, it has been reported that between 1% and 7.7% of all neonatal intensive care unit admissions or 10% of very low-birth-weight infants are affected. Full-term infants account for only 5% to 25% of cases (1).
Many groups have focused their research on NEC, including its epidemiology, pathophysiology, and potential therapeutic modalities. Although the cause of NEC is not fully understood, most would agree that several risk factors play a role. These risk factors include intestinal ischemia, colonization by pathological bacteria, and excess protein in the intestinal lumen(2). Specimens of NEC intestine invariably show inflammation, ischemic necrosis, and bacterial overgrowth, with evidence of reparative changes such as epithelial regeneration and fibrosis (3). Therapy is therefore directed at modulating these factors.
There are several focuses of study regarding NEC and its potential therapy, including attenuation of bacterial overgrowth by supplementing different intestinal flora and maintaining breast-milk feedings instead of transitioning to cow s milk. Despite great advances in these areas, the underlying cause of intestinal necrosis rests with gut ischemia and the subsequent reperfusion injury associated with it. The cytokine pathway directly leads to intestinal ischemia, shock, and subsequent multisystem organ failure, and therefore understanding this inflammatory cascade is crucial in attempting to attenuate the destructive properties of the disease.
Many studies have been performed and published on individual cytokines, but a concise review of the supporting studies for NEC does not exist. The purpose of this manuscript, therefore, is to review the current literature supporting the involvement of the cytokine cascade with NEC.
MODELS
There are a number of accepted models used to study NEC and the cytokine cascade. These models serve to create necrotic bowel in animals to simulate that in the newborn child. It is certainly conceivable that severe intestinal ischemia leads to an overwhelming inflammatory cascade, but most feel that there is evidence to support that the inflammatory cascade actually can cause intestinal ischemia. One such model supporting this theory uses varying degrees of lipopolysaccharide (LPS), platelet-activating factor (PAF), and tumor necrosis factor (TNF) to create intestinal ischemia. Lipopolysaccharide is thought to mimic the bacterial overgrowth in the intestinal lumen, and the PAF and TNF cause a hypotensive response and shock. In addition, intestinal inflammation tends to be less severe after sudden occlusion of the arterial circulation from thrombotic disease as compared with when devitalization of the bowel is gradual (4).
Many animal models can simulate NEC, but often do not contain the aspect of prematurity that is seen in human NEC. A model first described in 1972 by Barlow et al. (5) more physiologically resembles what is seen in human NEC. The model entails removing rat pups from the maternal uterus, exposing them to maternal milk, and stressing them with asphyxia, gram-negative bacterial colonization, and artificial formula feedings. After a few days of life, the rat pups began to exhibit signs of NEC, including intestinal distension and bloody diarrhea.
Other models have been described that do not physiologically resemble human NEC, but aid in the study of the disease process. These include inducing hypoxia for 5 min followed by 10 min with 100% oxygen (6), hypoxia for 50 s followed by cold exposure at 4°C for 10 min (7-9), rebreathing into a bag for 3 to 5 min (10), superior mesenteric artery clamping with or without intraluminal injection of PAF (11, 12), intra-arterial injection of TNF (13), and creating severe hypoxemia by placing rats into 100% nitrogen or moderate hypoxemia by placing them into a 10% oxygen atmosphere (4).
Finally, a rat model has been described by Chan et al. (14) who created intestinal ischemia by increasing intraluminal pressure above the mean arterial pressure. Loops of terminal ileum were harvested from 1- and 3-month-old rats. The loop was injected with Escherichia coli, and the intraluminal pressure was increased using a normal saline infusion set. The loops were placed back in the abdomen, and after 24 h, they were reassessed. Necrotizing enterocolitis occurred in 100% of rats in which the intraluminal pressure was greater than mean arterial pressure and that received a dose of E. coli in the bowel lumen.
In addition to in vivo animal models, various in vitro models have been created. These are usually intestinal-derived cell lines such as Caco-2, which is a human colon carcinoma cell line. Inflammatory stimulants, such as LPS and interleukin (IL) 1β, can be added to cell cultures which can then be analyzed by ELISA to determine the presence or absence of specific cytokines (15). In addition, the cells themselves can be studied with regard to permeability, viability, and electrical charge after addition of certain stimulants or creation of hypoxic environments.
CYTOKINES
The cytokine pathway (Fig. 1) plays a pivotal role in the development of NEC. The ischemic episode that results from the inflammatory cascade and the resulting reperfusion injury inevitably lead to the characteristic symptoms of NEC. It is the hypothesis of Hsueh et al. (4) that an initial insult such as hypoxia or infection leads to intestinal mucosal damage. After formula feeding, intestinal bacteria attach to the immature mucosa eliciting production of several cytokines, including PAF and TNF-α. The important work of Cetin et al. (16) has shown that bacterial products such as LPS also slow enterocyte reparative factors by inhibiting new enterocyte migration to sites of injury. This leads to local leak of mucosa, entry of bacteria, triggering of the inflammatory cascade, vasoconstriction, and finally ischemia and intestinal wall necrosis (Fig. 2) (4). Left unchecked and without support, NEC can lead to acidosis, shock, multisystem organ failure, and, eventually, death.
Inflammatory cascade. The inflammatory cascade results in the secretion of multiple proinflammatory and counterregulatory cytokines that eventually lead to the generation of toxic metabolites and destruction of the intestinal mucosa.
Model of NEC. Hypoxia or other injury results in mild mucosal injury. The addition of formula feeding causes increased gut bacteria which now has a nidus of attachment and penetration into the gut. The inflammatory cascade is activated by the bacterial invasion, oxygen radicals are generated, and damage to the gut ensues.
The protective effect of probiotics, defined as bacteria that contribute to intestinal balance, has also been studied greatly. Probiotics tend to enhance the intestinal mucosal protective barrier (17), and several clinical trials have shown a decrease in the incidence of NEC with their administration (18, 19). Furthermore, studies have shown that probiotics aid in promoting a TH1 immune response by upregulating IgA and downregulating IgE (20). The addition of probiotics also increases the production of IL-6 and TNF-α, thereby directly affecting the cytokine milieu within the intestine (21).
Proinflammatory cytokines
Tumor necrosis factor α
Tumor necrosis factor α, a prominent member of the cytokine cascade, has been studied greatly. It is released from macrophages, monocytes, lymphocytes, and other cells and serves to increase the production of IL-1, as well as to elicit leukocyte migration, angiogenesis, fever, and the acute-phase response (22). Tumor necrosis factor α is also in the apoptotic pathway and has been associated with the onset of shock (23). The final effects of TNF-α during shock depend on the TNF receptor with which it interacts (24).
Previous studies have shown that TNF-α is increased in NEC (25-27) and drastically increases the production of matrix metalloproteinases (MMPs), which are proteolytic enzymes capable of degrading the extracellular matrix (28). In experimental models, TNF-α-induced release of these MMPs from mucosal mesenchymal cells caused tissue injury. Furthermore, TNF-α antibodies have been shown to block this cascade, as well as subsequent tissue injury (29). Studies have shown that TNF-α specifically upregulates stromelysin 1 (28), MMP-9 and MMP-12 in macrophages (30, 31), and MMP-19 in epithelial cells (32), thereby leading to extracellular matrix breakdown and tissue destruction. Pender et al. (33) have shown that very small concentrations of stromelysin 1 can degrade fetal gut explants in as little as 24 h.
The natural inhibitors of MMPs are the tissue inhibitors of metalloproteinases (TIMPs). The extracellular activity of MMPs is regulated by the TIMPs, which incidentally are produced by the same cells that secrete the MMPs (34). Pender et al. have determined that TIMP-1 is upregulated in NEC along with other metalloproteinases, possibly suggesting that NEC results from an imbalance in destructive versus protective factors and that, despite intraluminal necrosis, the gut is trying to repair itself (34). This theory is quite logical as Ballace et al. (3) have reported that 68% of the patients from their 10-year experience had evidence of intestinal reparative changes at surgical exploration.
Pender et al. (28) also showed an increased level of TNF-α DNA transcripts in NEC samples compared with controls, but an overall decreased number of transcripts compared with other inflammatory bowel syndromes. Furthermore, studies of the effects of Kupffer cells in the liver by Halpern et al. (35) suggest that the majority of the TNF-α found in the gut lumen comes from Kupffer cells. This was shown by inhibiting Kupffer cells with gadolinium chloride and observing decreased TNF-α transcripts in the intestinal lumen. Taken together, these data may suggest that TNF-α plays a less significant role in the inflammatory cascade associated with NEC as compared with other intestinal inflammatory conditions.
TNF-α therefore is a proinflammatory cytokine, capable of increasing other cytokines in the inflammatory cascade. Upregulation of the inflammatory cascade results in eventual ischemia of the intestine. In NEC, tissue damage is partially a result of activation of the MMP pathway, which in turn induces necrosis of the intestine.
Interleukin 1
Interleukin 1 is a cytokine released from macrophages and other antigen-presenting cells. It has two components, namely, IL-1α, a cell-associated protein, and IL-1β, the secretory molecule. Interleukin 1 promotes the inflammatory response, is stimulated by TNF-α (22), and is often attributed to the onset of fever, increased endothelial leukocyte adhesion, phagocyte activation, and lymphocyte costimulation (36). Interleukin 1β has also been shown to activate the IL-8 gene(37), thereby increasing the neutrophil population at the site of inflammation. Due to these properties, IL-1 has been noted to play a pivotal role in the systemic inflammatory response syndrome (SIRS), which can lead to sepsis and multisystem organ failure if not corrected (38). It is therefore no surprise that so many infants with NEC develop shock and that so many studies have focused on IL-1.
Interleukin 1β has previously been shown to be present in tissue from patients with inflammatory bowel disease (IBD) (39) and in intestinal specimens of infants with NEC (40). Studies have also shown that circulating monocytes from patients with IBDs produce an increased amount of IL-1β when stimulated (41). Despite these previous reports, IL-1β was not consistently elevated in infants with NEC in a study by Edelson et al. (42) They reported that, in upward of 40% of patients with clinical NEC, no detectable amount of IL-1β was present. This phenomenon is not completely understood; however, the study by Edelson et al. measured serum concentrations of IL-1β, whereas other groups analyzed messenger RNA (mRNA) transcripts from archived pathological specimens. The difference in their results may suggest that IL-1β is more predominant in the intestinal tissue in patients with NEC.
Many groups have attempted to ameliorate the inflammatory response by blocking IL-1β with its natural antagonist, IL-1 receptor antagonist (IL-1ra). Interleukin 1ra is produced by the same cells that secrete IL-1β, and elevations of IL-1ra have been shown to be associated with improved outcome in certain human disease conditions (43, 44). Improved outcome with elevated IL-1ra has yet to be formally shown in patients with NEC. However, IL-1ra was both sensitive and specific in differentiating suspect from definitive NEC at both onset and 8 h (42), and therefore may be beneficial in diagnosing NEC at an earlier point in time.
Interleukin 1β has also been shown to play a role in intraluminal gut integrity. Previous studies showed a significant reduction of enteric glial cells in the neural plexuses of NEC affected intestine (45). Glial cells are crucial to gut integrity as mice who are lacking glial fibrillary acidic protein-positive (GFAP+) glia develop hemorrhagic jejunoileitis (46). The addition of IL-1β to culture medium containing enteric glia increased the ratio of GFAP+ cells, whereas treating the medium with anti-IL-1β or IL-ra completely abolished the stimulatory response. This led the group to conclude that IL-1β has a stimulatory effect on the production of GFAP+ cells, which may serve as a protective role for enteric mucosa (47).
On the other hand, Cominelli et al. (48) have shown that IL-1 is an early mediator in the course of immune complex rabbit colitis and that pretreatment with IL-1ra can reduce the inflammatory response. His study analyzed both IL-1α and IL-1β and showed that IL-1α levels were highly correlated to intestinal inflammation, edema, and necrosis. This may suggest that IL-1 plays a dual role in NEC, with IL-1α contributing to intestinal necrosis and IL-1β providing partial stimulation for mucosal protection via other inflammatory mediators.
Platelet-activating factor
In addition to the above cytokines, a large body of evidence suggests that PAF plays a predominant role in the development of NEC. This evidence stems from experiments in rats that show that endotoxin, hypoxia, and TNF-α-induced intestinal injury can be prevented by PAF receptor (PAFr) antagonists (49-51), thereby suggesting not only that inflammation leads to intestinal ischemia, but that by inhibiting a portion of the inflammatory cascade, intestinal ischemia can be ameliorated.
Platelet-activating factor is a phospholipid molecule produced by inflammatory cells, endothelial cells, platelets, and intestinal bacteria, which interacts with the PAFr located on platelets and neutrophils. Activation of the PAFr causes rapid platelet aggregation, release of preformed mediators, and synthesis of eicosanoids (52). In addition, systemic administration of PAF can cause severe hypotension and, in increased doses, systemic shock (4).
Newer studies have shown that cytokines such as IL-1β are released in microvesicles from platelets upon stimulation by PAF. These cytokines are released into fibrin clots and suggest that thrombi may be reservoirs for cytokine activity. The IL-1β released from these platelets causes the vascular endothelium to become adhesive to neutrophils via the aid of selectins, thereby promoting rolling of neutrophils, emigration to the site of injury, and promotion of the inflammatory cascade (53).
Caplan and Hsueh s group, with the aid of polymerase chain reaction, demonstrated that the ileum has the highest concentration of PAFr. They noted that the PAFr concentration in jejunum was 56% of that in the ileum and that other organs, such as the heart, lung, and kidney, expressed less than 1% of the PAFr concentration found in the ileum (54). The high concentration of PAFr in the ileum strongly supports the involvement of PAF in NEC, as most NEC patients show evidence of small intestinal necrosis.
Regardless of elevated concentrations of PAFr in the small intestine, PAF is normally degraded by PAH-acetylhydrolase (AH), the natural enzyme for PAF. This enzyme catalyzes the hydrolysis of PAF to lyso-PAF, a biologically inert molecule (55). Considerable evidence suggests that altered regulation of PAF-AH may play a role in NEC. Various studies show that PAF-AH is decreased in newborns (56) and that PAF-AH activity is deficient in sick neonates with NEC (57). In addition, breast milk has measurable PAF-AH activity as compared with formula and reduces the incidence of NEC (58, 59). Therefore, altered regulation of PAF-AH and elevated concentrations of PAFr inthe small intestine can be shown to be contributing factors to the development of inflammation and eventual ischemic necrosis.
Interleukin 6
Elevated levels of IL-6 in fetal blood have been associated with a significantly increased risk of neonatal morbidity (60). Interleukin 6, whose release is stimulated by a variety of other proinflammatory cytokines, including TNF-α and IL-1, serves to activate lymphocytes, thereby inducing antibody secretion by B cells and differentiation of cytotoxic T cells (61). Interleukin 6 and its associated receptors are expressed by intestinal endothelium, macrophages, and helper T cells (36). During sepsis or a systemic inflammatory response, there is an increase in enterocyte-secreted IL-6, which is augmented by bacteria, endotoxins, and other cytokines (61). Interleukin 6 is also a major activator of the acute phase reactants, including C-reactive protein (62).
Goepfert et al. (60) analyzed the relationship between neonatal outcomes and concentration of umbilical cord IL-6. They showed that high levels of IL-6 (>75th percentile for detectable IL-6) were significantly associated with neonatal disease processes, including NEC and the SIRS. Furthermore, a progressive relationship was seen between increasing IL-6 levels and increased risk of SIRS.
Harris et al. (26) performed a similar study, which looked at plasma concentrations of IL-6 in neonates. They found that IL-6 levels were elevated 5- to 10-fold in infants with bacterial sepsis plus NEC as compared with infants with sepsis alone, controls, or infants with NEC and negative cultures. They also showed that IL-6 was significantly higher in nonsurvivors as compared with survivors, thereby suggesting that elevated IL-6 is linked to increased mortality.
Other studies, however, suggest that IL-6 may promote an anti-inflammatory process via its influence on other cytokines. In mice studies examining Peyer patches after infection with Yersinia, IL-6 neutralization caused a dramatic decrease in local and circulating IL-1ra, suggesting that IL-6 may indirectly regulate IL-1 via IL-1ra (63). Similarly, in a mouse arthritis model, IL-6 enhanced the production of TIMPs, thereby causing less degradation of the cartilaginous matrix (64). Other studies showed that IL-6 inhibited superoxide production in chondrocytes, thereby decreasing local tissue damage (65). These reports suggest that IL-6 likely plays a dual role in inflammation and, despite being correlated with increased morbidity and mortality in NEC patients, may actually serve as an anti-inflammatory mediator.
Interleukin 8
Interleukin 8 (IL-8) serves as a neutrophilic chemoattractant in the inflammatory cascade, thereby serving to increase cellular activity at the site of inflammation (66). Interleukin 8 is secreted by fibroblasts, monocytes, and endothelium and has primary effect on neutrophils and monocytes (36). Several groups have focused on the role of IL-8 primarily in IBDs. Previous studies have determined that IL-8 is produced by intestinal lamina propria cells and correlates well with mucosal inflammation (67). Nadler et al.(68) from Ford s group, detected IL-8 protein in the serosa, muscularis, and epithelium of patients with NEC, but noted that IL-8 was confined mostly to the epithelium in patients with inflammatory conditions other than NEC. Likewise, Viscardi et al. (40) noticed that increased transmural and mucosal mRNA transcripts of IL-8 were associated with intestinal inflammation, but that transmural mRNA transcripts of IL-8 correlated more with the presence of necrosis. This indicates that the inflammatory and necrotic processes of NEC involve the entire thickness of bowel rather than just the mucosa.
Furthermore, Mazzucchelli et al. (69) noted that production of IL-8 mRNA is limited to areas with histological inflammation. Unaffected bowel segments in patients with IBD did not express IL-8, whereas those sections that were affected did produce IL-8. In addition, other studies on patients with Crohn disease showed that early lesions were characterized by low neutrophil counts and IL-8 production, whereas chronic lesions had higher amounts of each (70).
When the NEC literature is reviewed concerning IL-8, there is also a correlation between the amount of IL-8 and the degree of pathological/clinical severity. Previous studies suggested that levels of intestinal IL-8 mRNA transcripts were similar in acute NEC and other acute intestinal inflammatory diseases and that IL-8 did not play a role in necrosis (40). However, further studies showed that the increase in IL-8 has a delayed temporal onset and is consistently elevated in severe cases of NEC as compared with minor cases of NEC or controls (42).
Interleukin 12, Interleukin 18, and Interferon γ
Interleukins 12 and 18 have been examined in a number of studies to determine their role in NEC. Both have been implicated in diseases of the small intestine (71-75). Individually, these cytokines work to release small amounts of interferon γ (IFN-γ), but together can work synergistically to increase the amount exponentially, thereby inducing intestinal damage via production of nitric oxide and oxygen radicals (76, 77). Interleukin 12 is primarily secreted by B cells and macrophages, whereas IL-18 is secreted from macrophages and intestinal epithelial cells. Both have a direct effect on T helper cells and natural killer (NK) cells (36, 77).
Halpern et al. (78) studied IL-12 and were able to localize it via immunohistochemistry to monocytes in the intestinal submucosa and lamina propria. There was also an increase in IL-12 staining cells in those animals fed with milk substitute as opposed to the dam milk-fed controls. In addition, Halpern et al. showed a statistical correlation between the number of IL-12-positive cells and tissue damage. These results suggest that IL-12 is involved with the onset of NEC and plays a role in the development of intestinal necrosis.
Immunohistochemistry also revealed that IL-18 was increased with progression of disease. In control animals and those with low-category NEC, IL-18 was found in intestinal epithelial and lamina propria cells. As NEC progressed, IL-18 began to stain in the cytoplasm of villi and crypt enterocytes (78), thereby suggesting a progression from mucosal to transmural inflammation and necrosis.
Previous studies showed that, in the presence of IL-12, IL-18 induces IFN-γ production from T and NK cells (79-81). The increase in IFN-γ leads to the production of toxic metabolites, including nitric oxide and reactive oxygen radicals, which are destructive to tissues (77). Interestingly though, it has recently been found that IL-18 also activate TH2 cell lines, which produce the counterregulatory cytokines such as IL-4, IL-10, and IL-13 (77). This information may indicate that IL-18 is involved in both destructive and protective roles, depending on its surrounding coactivators. As these data are fairly new, further studies are required to corroborate this evidence.
The study of Halpern et al. (78), however, showed that, despite increased IL-12 and IL-18 RNA transcripts, IFN-γ was detected infrequently in all experimental neonatal rat groups. Their group attributed the low quantification of IFN-γ to the immaturity of the neonatal intestine. Although others have noted that the microenvironment of the neonatal intestine differs from more mature intestine (82-84). The studies of Nadler et al. (85) and Ford et al. (86) have shown that IFN-γ mRNA was increased in both neonatal rats and infants with NEC. Despite these results, some studies even suggest that IFN-γ plays no role in the development of colitis, as Simpson et al. (87) showed that IFN-γ knockout mice still developed colitis when stressed. These studies may suggest that although IFN-γ is elevated in most NEC patients, it may not play a direct role in the development of the ischemic colitis.
Anti-inflammatory/counterregulatory cytokines
Interleukin 4
Interleukin 4 (IL-4) is counterregulatory cytokine that has been studied in NEC and other IBDs. Interleukin 4 is often defined as an immune modulator, as it has been found to inhibit human macrophage colony formation, (88) monocyte-derived hydrogen peroxide production (89), and the release of certain inflammatory mediators such as TNF-α and IL-1β (89, 90). Interleukin 4 is produced by TH2 cells and bone marrow stroma and works to promote immunoglobulin class switching (36). In short, IL-4 helps to ameliorate the inflammatory cascade, as well as the tissue destruction caused by oxygen radicals associated with ischemia and reperfusion injury.
According to previous data, genetic polymorphisms influence cytokine production (91-95). In a study using dried blood spot samples from very low-birth-weight infants, Treszl et al. (96) showed that infants with NEC carried a mutant variant of IL-4 receptor α chain (IL-4rα) less frequently than controls. These results may indicate that an IL-4rα carrier state may be a protective factor for the development of NEC in neonates. Interleukin 4 has been known to play a role in the shift between TH1 and TH2 cells, and it was a hypothesis of Treszl et al. that the IL-4rα mutant may skew the immune system toward a TH2-dominant system, thereby defending against the onset of NEC (90).
Schreiber et al. (97) note that IL-4 normally increases the ratio of IL-1ra to IL-1β in normal monocyte supernatant. These ratios, however, are not affected in IBD supernatants. In fact, the ability of lamina propria mononuclear cells to produce IL-4 was decreased in IBD (98). In addition, they noted a diminished response by IBD monocytes with regard to the induction of macrophage mannose receptor, a molecule pivotal to macrophage-mediated host defense. The macrophage mannose receptor, normally upregulated by IL-4, serves as a mannose glycoprotein receptor that, when activated, auto-deactivates the macrophage, thereby ameliorating an immune response. This led the group to conclude that the IL-4-mediated downregulation of IL-1β, TNF-α, and superoxide anion secretion is impaired in IBD, thereby leading to uncontrolled proinflammatory cytokine release and oxygen radical tissue destruction (97).
Interleukin 10
Interleukin 10, a counterregulatory cytokine produced by TH2 cells, (36) has also been investigated with regard to NEC. Interleukin 10 has been implicated as an inhibitor of proinflammatory cytokine production and of several accessory cell functions of the macrophage, T cell, and NK cell lines (99). Kuhn et al. (100) demonstrated that IL-10-deficient knockout mice were predisposed to developing inflammatory colitis, thereby suggesting that IL-10 works to counterbalance the response to enteric inflammatory stimuli. In fact, intraperitoneal IL-10 injections in a mouse model of intestinal ischemia/reperfusion reduced local and systemic inflammatory reactions (101). Despite this observation, Edelson et al. (42) noticed significantly increased concentrations of IL-10 with severe NEC, and Riordan et al. (102) noticed higher IL-10 concentrations in nonsurviving infants with meningococcal disease. These results therefore create a question as to the utility of treatment with IL-10 in NEC, but may simply suggest that the body is trying to dampen the inflammatory response.
Because IL-10 normally serves to downregulate the inflammatory response, several studies have examined its exact role in this mechanism. Inducible nitric oxide synthase, a known contributor to tissue damage and enterocyte dysfunction (103, 104), is significantly elevated in NEC tissues and serum. Kling et al. (105) showed that the addition of IL-10 via intraperitoneal injection suppressed inducible nitric oxide synthase mRNA and nitric oxide expression in the small bowel, liver, and serum by 60%, 89%, and 11%, respectively. Furthermore, a recent study examining the effect of recombinant human IL-10 on rats undergoing ischemia and reperfusion showed that rats treated with recombinant human IL-10 fared better than those not treated. They observed less intestinal destruction, with confinement of destruction to the very tips of the villi (106).
Interleukin 10 has also been shown to decrease the productionof metalloproteinases. Pender et al. (107) noticed a decrease in both collagenase and stromelysin 1 after the addition of IL-10 to explant culture supernatants. As stromelysin 1 was previously shown to cause massive tissue destruction, the addition of IL-10 was shown here to drastically attenuate that destruction. These data indicate that IL-10 is a strong counterregulatory cytokine and that the potential of IL-10 to provide therapy in the setting of NEC is very high.
CONCLUSION
The pathophysiology of NEC is quite complex. The final injury of the intestine is caused by ischemia, but the events leading to ischemia are still being studied. Current evidence would suggest that a hypoxic injury combined with increased bacterial population in the intestine allows for bacterial invasion. This causes a release of PAF and the activation of polymorphonuclear leukocytes and monocytes. Various cytokines are released from these leukocytes, and vasoconstriction results from a surge in norepinephrine. Intestinal ischemia ensues, and tissue is damaged via oxygen radicals, nitric oxide, MMPs, and other factors. Intestinal necrosis then leads to acidosis, disseminated intravascular coagulation, severe shock, multisystem organ failure, and, eventually, death.
Understanding the cytokine pathway in the development of NEC plays key importance in developing therapy for the disease. Necrotizing enterocolitis can be categorized as an ischemia/reperfusion injury after onset of the inflammatory cascade. Further research needs to focus on the mechanisms and interrelations of the cytokine pathways. Furthermore, focus is needed on the main inflammatory cytokines, particularly PAF, TNF-α, IL-1β, and IL-10. If one could determine an adequate mechanism to inhibit the proinflammatory cytokines or to enhance the ability of counterregulatory cytokines to suppress the inflammatory response, definitive progress could be made toward a treatment modality. Once the basic science of these cytokine pathways is better understood, lifesaving therapies can be rapidly produced.
REFERENCES
1. Kafetzis DA, Skevaki C, Costalos C: Neonatal necrotizing enterocolitis: an overview. Curr Opin Infect Dis 16:349-355, 2003.
2. Santulli TV, Schullinger JN, Heird WC, Gongaware RD, Wigger J, Barlow B, Blanc WA, Berdon WE: Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 55:376-387, 1975.
3. Ballace WA, Dahms BB, Schenker N, Kliegman RM: Pathology of neonatal necrotizing enterocolitis: a ten year experience. J Pediatr 117:S6-S13, 1990.
4. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F: Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 6:6-23, 2002.
5. Barlow B, Santulli TV, Heird WC, Pitt J, Blanc WA, Schullinger JN: An experimental study of acute neonatal enterocolitis and the importance of breast milk. J Pediatr Surg 9:587-594, 1974.
6. Akisu M, Kullahcioglu GF, Baka M, Husseyinov A, Kultursay N: The role of recombinant human erythropoietin in lipid peroxidation and platelet-activating factor generation in a rat model of necrotizing enterocolitis. Eur J Pediatr Surg 11:167-172, 2001.
7. Caplan MS, Russel T, Xiao Y, Amer M, Kaup S, Jilling T: Effect of polyunsaturated fatty acid (PUFA) supplementation on intestinal inflammation and necrotizing enterocolitis (NEC) in a neonatal rat model. Pediatr Res 49:647-652, 2001.
8. Caplan MS, Hedlund E, Adler L, Hsueh W: Role of asphyxia and feeding in a neonatal rat model of necrotizing enterocolitis. Pediatr Pathol 14:1017-1028, 1994.
9. Caplan MS, Lickerman M, Adler L, Dietsch GN, Yu A: The role of recombinant platelet-activating factor acetylhydrase in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 42:779-783, 1997.
10. Touloukian RY, Posch JN, Spencer R: The pathogenesis of ischemic gastroenterocolitis of the neonate: selective gut mucosal ischemia in asphyxiated neonatal piglets. J Pediatr Surg 7:194-205, 1972.
11. Musemeche CA, Kosloske AM, Bartow SA, Umland ET: Comparative effects of ischemia, bacteria, and substrate on the pathogenesis of intestinal necrosis. J Pediatr Surg 21:536-538, 1986.
12. Chung DH, Ethridge RT, Kim S, Owens-Stovall S, Hernandez A, Kelly DR, Evers BM: Molecular mechanisms contributing to necrotizing enterocolitis. Ann Surg 233:835-842, 2001.
13. Torimoto K, Sato N, Okubo M, Yagihashi A, Wada Y, Hara I, Hayasaka H, Kikuchi K: Development of multiple necrotizing enteritis induced by tumor necrosis factor-like cytokine from lipopolysaccharide-stimulated peritoneal macrophages in rats. Am J Pathol 137:1103-1111, 1990.
14. Chan KL, Ng SP, Chan KW, Wo YH, Tam PK: Pathogenesis of neonatal necrotizing enterocolitis: a study of the role of intraluminal pressure, age and bacterial concentration. Pediatr Surg Int 19:573-577, 2003.
15. Claud EC, Savidge T, Walker WA: Modulation of human intestinal epithelial cell IL-8 secretion by human milk factors. Pediatr Res 53:419-425, 2003.
16. Cetin S, Ford HR, Sysko LR, Agarwal C, Wang J, Neal MD, Baty C, Apodaca G, Hackam DJ: Endotoxin inhibits intestinal epithelial restitution through activation of rho-GTPase and increased focal adhesions. J Biol Chem 279:24592-24600, 2004.
17. Panigrahi P, Gupta S, Gewolb IH, Morris JG Jr: Occurrence of necrotizing enterocolitis may be dependent on patterns of bacterial adherence and intestinal colonization: studies in Caco-2 tissue culture and weanling rabbit models. Pediatr Res 36:115-121, 1994.
18. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, Oh W: Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 115:1-4, 2005.
19. Hoyos AB: Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Dis 3:197-202, 1999.
20. Perdigon G, Alvarez S, Rachid M, Aguero G, Gobbato N: Immune system stimulation by probiotics. J Dairy Sci 78:1597-1606, 1995.
21. Marin ML, Tejada-Simon MV, Lee JH, Murtha J, Ustunol Z, Pestka JJ: Stimulation of cytokine production in clonal macrophage and T-cell models by Streptococcus thermophilus: comparison with Bifidobacteria sp and Lactobacillus bulgaricus. J Food Prot 61:859-864, 1998.
22. Baud V, Karin M: Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11:372-377, 2001.
23. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A: Anti-cachectin/THF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 330:662-664, 1987.
24. Ebach DR, Riehl TE, Stenson WF: Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cell ligation and puncture. Shock 23:311-318, 2005.
25. Caplan MS, Hsueh W: Necrotizing enterocolitis: role of platelet activating factor, endotoxin, and tumor necrosis factor. J Pediatr 117:S47-S51, 1990.
26. Harris MC, Costarino AT Jr, Sullivan JS, Dulkerian S, McCawley L, Corcoran L, Butler S, Kilpatrick L: Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr 124:105-111, 1994.
27. Morecroft JA, Spitz L, Hamilton PA, Holmes SJ: Plasma cytokine levels in necrotizing enterocolitis. Acta Paediatr Suppl 396:18-20, 1994.
28. Pender SL, Braegger C, Gunther U, Monteleone G, Meuli M, Schuppan D, MacDonald TT: Matrix metalloproteinases in necrotizing enterocolitis. Pediatr Res 54:160-164, 2003.
29. Pender SL, Fell JM, Chamow SM, Chamow SM, Ashkenazi A, MacDonald TT: A p55 TNF receptor immunoadhesion prevents T-cell mediated intestinal injury by inhibiting matrix metalloproteinase production. J Immunol 160:4098-4103, 1998.
30. Churg A, Wang RD, Tai H, Wang X, Xie C, Dai J, Shapiro SD, Wright JL: Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release. Am J Respir Crit Care Med 167:1083-1089, 2003.
31. Saren P, Welgus HG, Kovanen PT: TNF-α and IL-1β selectively induce expression of 92 kDa gelatinase by human macrophages. J Immunol 157:4159-4165, 1996.
32. Impola U, Toriseva M, Suomela S, Jeskanen L, Hieta N, Jahkola T, Grenman R, Kähäri V, Saarialho-Kere U: Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation. Int J Cancer 103:709-716, 2003.
33. Pender SL, Tickle SP, Docherty AJ, Howie D, Wathen NC, MacDonald TT: A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 158:1582-1590, 1997.
34. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A, Engler JA: Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4:197-250, 1993.
35. Halpern MD, Holubec H, Dominguez JA, Meza YG, Williams CS, Ruth MC, McCuskey RS, Dvorak B: Hepatic inflammatory mediators contribute to intestinal damage in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 284:G695-G702, 2003.
36. David Male: Immunology: An Illustrated Outline, 3rd ed. London: Mosby, p61,1998.
37. Minekawa R, Takeda T, Sakata M, Hayashi M, Isobe A, Yamamoto T, Tasaka K, Murata Y: Human breast milk suppresses the transcriptional regulation of IL-1β induced NF-κB signaling in human intestinal cells. Am JPhysiol Cell Physiol 287:C1404-C1411, 2004.
38. Dinarello CA, Gelfand JA, Wolff SM: Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. JAMA 269:1829-1835, 1993.
39. McCabe RP, Secrist H, Botney M, Egan M, Peters MG: Cytokine mRNA expression in intestine from normal and inflammatory bowel disease patients. Clin Immunol Immunopathol 66:52-58, 1993.
40. Viscardi RM, Lyon NH, Sun CC, Hebel JR, Hasday JD: Inflammatory cytokine mRNAs in surgical specimens of necrotizing enterocolitis and normal newborn intestine. Pediatr Pathol Lab Med 17:547-559, 1997.
41. Nakamura M, Saito H, Kasanuki J, Tamura Y, Yoshida S: Cytokine production in patients with inflammatory bowel disease. Gut 33:55-58, 1992.
42. Edelson MB, Bagwell CE, Rozycki HJ: Circulating pro- and counterinflammatory cytokine levels and severity in necrotizing enterocolitis. Pediatrics 103:766-771, 1999.
43. Wakabayashi G, Gelfand JA, Burke JF, Thompson RC, Dinarello CA: A specific receptor antagonist for interleukin 1 prevents _Escherichia coli_-induced shock in rabbits. FASEB J 5:338-343, 1991.
44. Miller LC, Lynch EA, Isa S, Logan JW, Dinarello CA, Steere AC: Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet 341:146-148, 1993.
45. Wedel T, Krammer HJ, Kuhnel W, Sigge W: Alterations of the enteric nervous system in neonatal necrotizing enterocolitis revealed by whole-mount immunohistochemistry. Pediatr Pathol Lab Med 18:57-70, 1998.
46. Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L, Johnson MH, Sofroniew MV: Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93:189-201, 1998.
47. Von Boyen GB, Steinkamp M, Reinshagen M, Schafer KH, Adler G, Kirsch J: Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia. Gut 53:222-228, 2004.
48. Cominelli F, Nast CC, Clark BD, Schindler R, Lierena R, Eysselein VE, Tjompson RC, Dinarello CA: Interleukin-1 (IL-1) gene expression, synthesis and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest 86:972-980, 1990.
49. Hsueh W, Gonzalez-Crussi F, Arroyave JL: Platelet activating factor is an endogenous mediator for bowel necrosis in endotoxemia. FASEB J 1:403-405, 1987.
50. Caplan MS, Sun XM, Hsueh W: Hypoxia causes ischemic bowel necrosis in rats: the role of platelet activating factor (PAF-acether). Gastroenterol 99:979-986, 1990.
51. Sun XM, Hsueh W: Bowel necrosis induced by tumor necrosis factor in rats is mediated by platelet-activating factor. J Clin Invest 81:1328-1331, 1988.
52. Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM: The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 30:S294-S301, 2002.
53. Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmerman GA, Weyrich AS: Activated platelets mediate inflammatory signaling by regulated interleukin 1 beta synthesis. J Cell Biol 154:485-490, 2001.
54. Wang H, Tan X, Chaug H, Gonzalez-Crussi F, Remick DG, Hsueh W: Regulation of platelet activating factor receptor gene expression in vivo by endotoxin, platelet activating factor, and endogenous tumor necrosis factor. Biochem J 322:603-608, 1997.
55. Farr RS, Wardlow ML, Cox CP, Meng KE, Greene DE: Human serum acid-labile factor is an acetylhydrolase that inactivates platelet-activating factor. Fed Proc 42:3120-3122, 1983.
56. Caplan M, Hsueh W, Kelly A, Donovan M: Serum PAF acetylhydrolase increases during neonatal maturation. Prostaglandins 39:705-714, 1990.
57. Caplan MS, Sun XM, Hsueh W, Hageman JR: Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 116:960-964, 1990.
58. Moya FR, Eguchi H, Zhao B, Furukawa M, Sfeir J, Osorio M, Ogawa Y, Johnston JM: Platelet-activating factor acetylhydrolase in term and preterm human milk: a preliminary report. J Pediatr Gastroenterol Nutr 19:236-239,1994.
59. Lucas A, Cole TJ: Breast milk and neonatal necrotizing enterocolitis. Lancet 336:1519-1523, 1990.
60. Goepfert AR, Andrews WW, Waldemar C, Ramsey PS, Cliver SP, Goldenberg RL, Hauth JC: Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity. Am J Obstet Gynecol 191:1375-1381, 2004.
61. Romagnoli C, Frezza S, Cingolani A, De Luca A, Puopolo M, De Carolis MP, Vento G, Antinori A, Tortorolo G: Plasma levels of interleukin-6 and interleukin-10 in preterm neonates evaluated for sepsis. Eur J Pediatr 160:345-350, 2001.
62. Kishimoto T: The biology of interleukin-6. Blood 74:1-10, 1989.
63. Jordan M, Otterness IG, Ng R, Gessner A, Rollinghoff M, Beuscher HU: Neutralization of endogenous IL-6 suppresses induction of IL-1 receptor antagonist. J Immunol 154:4081-4090, 1995.
64. Shingu M, Miyauchi S, Nagai Y, Yasutake C, Horie K: The role of IL-4 and IL-6 in IL-1-dependent cartilage matrix degradation. Rheumatology 34:101-106, 1995.
65. Tilg H, Dinarello CA, Mier JW: IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today 18:428-432, 1997.
66. Luster AD: Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 338:436-445, 1998.
67. Daig R, Andus T, Aschenbrenner E, Falk W, Scholmerich J, Gross V: Increased interleukin 8 expression in the colon mucosa in patients with inflammatory bowel disease. Gut 38:216-222, 1996.
68. Nadler EP, Stanford A, Zhang XR, Schall LC, Alber SM, Watkins SC, Ford HR: Intestinal cytokine gene expression in infants with acute necrotizing enterocolitis: interleukin-11 mRNA expression inversely correlates with extent of disease. J Pediatr Surg 36:1122-1129, 2001.
69. Mazzucchelli L, Hauser C, Zgraggen K, Wagner H, Hess H, Laissue JA, Mueller C: Expression of interleukin-gene in inflammatory bowel disease is related to the histologic grade of active inflammation. Am J Pathol 144:997-1007, 1994.
70. Brandt E, Colombel JF, Ectors N, Gambiez L, Emilie D, Geboes K, Capron M, Desreumaux P: Enhanced production of IL-8 in chronic but not in early ileal lesions of Crohn s disease. Clin Exp Immunol 122:180-185, 2000.
71. Kanai T, Watanabe M, Okazawa A, Nakamaru K, Okamoto M, Naganuma M, Ishii H, Ikeda M, Kurimoto M, Hibi T: Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn s disease. Gastroenterol 119:1514-1523, 2000.
72. Monteleone G, Trapasso F, Parello T, Biancone L, Stella A, Iuliano R, Luzza F, Fusco A, Pallone F: Bioactive IL-18 expression is up-regulated in Crohn s disease. J Immunol 163:143-147, 1999.
73. Monteleone G, Biancone L, Morasco R, Morrone G, Marasco O, Luzza F, Pallone F: Interleukin 12 is expressed and actively released by Crohn s disease intestinal lamina propria mononuclear cells. Gastroenterology 112:1169-1178, 1997.
74. Monteleone G, MacDonald TT, Wathen NC, Pallone F, Pender SLF: Enhancing lamina propria TH1 cell responses with interleukin 12 produces severe tissue injury. Gastroenterol 117:1069-1077, 1999.
75. Weijer S, Florquin S, van der Poll T: Endogenous interleukin-12 improves the early antimicrobial host response to murine Escherichia coli peritonitis. Shock 23:54-58, 2005.
76. Chikano S, Sawada K, Shimoyama T, Kashiwamura SI, Sugihara A, Sekikawa K, Terada N, Nakanishi K, Okamura: IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner. Gut 47:779-786, 2000.
77. Kashiwamura S, Ueda H, Okamura H: Roles of interleukin-18 in tissue destruction and compensatory reactions. J Immunol 2:S4-S11, 2002.
78. Halpern MD, Holubec H, Dominguez JA, Williams CS, Meza YG, McWilliam DL, Payne CM, McCuskey RS, Besselsen DG, Dvorak B: Up-regulation of IL-18 and IL-12 in the ileum of neonatal rats with necrotizing enterocolitis. Pediatr Res 51:733-739, 2002.
79. Ahn HJ, Maruo S, Tomura M, Mu J, Hamaoka T, Nakanishi K, Clark S, Kurimoto M, Okamura H, Fujiwara H: A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma. J Immunol 159:2125-2131, 1997.
80. Micallef MJ, Ohtsuki T, Kohno K, Tanabe F, Ushio S, Namba M, Tanimoto T, Torigoe K, Fujii M, Ikeda M: Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production. Eur J Immunol 26: 1647-1651, 1996.
81. Okamura H, Kashiwamura S, Tsutsui H, Yoshimoto T, Nakanishi K: Regulation of interferon-gamma production by IL-12 and IL-18. Curr Opin Immunol 10:259-264, 1998.
82. Insoft RM, Sanderson IR, Walker WA: Development of immune function in the intestine and its role in neonatal diseases. Pediatr Clin North Am 43:551-571, 1996.
83. Mannick E, Udall JN Jr: Neonatal gastrointestinal mucosal immunity. Clin Perinatol 23:287-304, 1996.
84. Sanderson IR: The physiochemical environment of the neonatal intestine. Am J Clin Nutr 69:1028S-1034S, 1999.
85. Nadler EP, Dickinson E, Knisely A, Zhang XR, Boyle P, Beer-Stolz D, Watkins SC, Ford HR: Expression of inducible nitric oxide synthase and interleukin 12 in experimental necrotizing enterocolitis. J Surg Res 92: 71-77, 2000.
86. Ford HR, Sorrells DL, Knisely AS: Inflammatory cytokines, nitric oxide, and necrotizing enterocolitis. Semin Pediatr Surg 5:155-159, 1996.
87. Simpson SJ, Shah S, Comisky M, de Jong YP, Wang B, Mizoguchi E, BhanAK, Terhorst C: T-cell mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon-gamma expression by T-cells. J Exp Med 187: 1225-1234, 1998.
88. Jansen JH, Wientjens GJ, Fibbe WE, Willemze R, Kluin-Nelemans HC: Inhibition of human macrophage colony formation by interleukin 4. J Exp Med 170:577-582, 1989.
89. Crawford RM, Finbloom DS, Ohara J, Paul WE, Meltzer MS: B-cell stimulatory factor 1 (interleukin-4) activates macrophages for increased tumoricidal activity and expression of Ia antigens. J Immunol 139:135-141, 1987.
90. Schreiber S, Heinig T, Panzer U, Reinking R, Bouchard A, Stahl PD, Raedler A: Impaired response of activated mononuclear phagocytes to interleukin 4 in inflammatory bowel disease. Gastroenterology 108:21-33, 1995.
91. Fan LY, Tu XQ, Zhu Y: Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. World J Gastroenterol 11:2768-2772, 2005.
92. Basturk B, Yavascaoglu I, Vuruskan H, Goral G, Oktay B, Oral HB: Cytokine gene polymorphisms as potential risk and protective factors in renal cell carcinoma. Cytokine 30:41-45, 2005.
93. Karasu Z, Ulukaya S, Ayanoglu HO, Basturk B, Ulukaya E, Akyildiz M, Tokat Y: Cytokine gene polymorphism and early graft rejection in liver transplant recipients. Transplant Proc 36:2791-2795, 2004.
94. Schwacha MG, Holland LT, Chaudry IH, Messina JL: Genetic variability in the immune-inflammatory response after major burn injury. Shock 23:123-128, 2005.
95. De Maio A, Mooney ML, Matesic LE, Paidas CN, Reeves RH: Genetic component in the inflammatory response induced by bacterial lipopolysaccharide. Shock 10:319-323, 1998.
96. Treszl A, Heninger E, Kalman A, Schuler A, Tullassay T, Vasarhelyi B: Lower prevalence of IL-4 receptor alpha-chain gene G variant in very-low-birth-weight infants with necrotizing enterocolitis. J Pediatr Surg 38:1374-1378, 2003.
97. Schreiber S, Heinig T, Panzer U, Reinking R, Bouchard A, Stahl PD, Raedler A: Impaired response of activated mononuclear phagocytes to interleukin 4 in inflammatory bowel disease. Gastroenterology 108:21-33, 1995.
98. West GA, Matsuura T, Levine AD, Klein JS, Fiocchi C: Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity. Gastroenterology 110:1683-1695, 1996.
99. Moore KW, O Garra A, de Waal Malefyt R, Vieira P, Mosmann TR: Interleukin-10. Annu Rev Immunol 11:165-190, 1993.
100. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W: Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263-274, 1993.
101. Lane JS, Todd KE, Lewis MP: Interleukin-10 reduces the systemic inflammatory response in a murine model of intestinal ischemia/reperfusion. Surgery 122:288-294, 1997.
102. Riordan FAI, Marzouk O, Thomas APJ, Sills JA, Hart CA: Pro-inflammatory and anti-inflammatory cytokines in meningococcal disease. Arch Dis Child 75:453-454, 1996.
103. Xu DZ, Lu Q, Deitch EA: Nitric oxide directly impairs intestinal barrier function. Shock 17:139-145, 2002.
104. Cuzzocrea S, Chatterjee PK, Mazzon E, Dugo L, De Sarro A, Van de Loo FA, Caputi AP, Thiemermann C: Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury. Shock 18:169-176, 2002.
105. Kling KM, Kirby L, Kwan KY, Kim F, McFadden DW: Interleukin-10 inhibits inducible nitric oxide synthase in an animal model of necrotizing pancreatitis. Int J Surg Investig 1:337-342, 1999.
106. Ozturk H, Dokucu AI, Ogun C, Buyukbayram H: Protective effects of recombinant human interleukin-10 on intestines of hypoxia-induced necrotizing enterocolitis in immature rats. J Pediatr Surg 37:1330-1333, 2002.
107. Pender SLF, Breese EJ, Gunther U, Howie D, Wathen NC, Schuppan D, MacDonald TT: Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases. Gastroenterol 115:573-583, 1998.
Keywords:
Inflammation; interleukin; neonate; shock; cascade; necrosis
©2006The Shock Society