Nitric Oxide and Intestinal Barrier Failure

Nadler, Evan P.; Upperman, Jeffrey S.; Dickinson, Eva C.; Ford, Henri R.

doi:10.1016/s1055-8586(99)70016-8

Cited by 30 publications

(16 citation statements)

References 65 publications

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“…Activation of the immune system is associated with an increase in NO production from activated macrophages. NO exerts a variety of homeostatic influences such as an activator of soluble guanylyl cyclase, a neuronal potentiator, a peripheral nervous system neurotransmitter, and a contraction regulator of both smooth muscle and vascular tissue [13,15]. Generally, the very short half-life of NO in the circulation makes it unsuitable for most convenient detection methods.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum nitric oxide metabolites in biliary atresia

et al. 2005

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Biliary atresia (BA) remains one of the most intractable liver diseases in children. The aim of this study was to investigate the possible roles of nitric oxide (NO) in BA. Serum levels of nitrite and nitrate (NO production) were determined using a colorimetric method from 65 post-operative BA patients and 12 healthy children. The patients were categorized into two groups according to their jaundice status, and serum alanine aminotransferase (ALT, a marker for liver injury). Unpaired t tests were used. Data are expressed as mean and SD in terms of mumol/l. Age and gender between BA patients and controls were comparable. Serum NO metabolites of BA patients was higher than the controls (79.77+/-21.22 vs. 65.75+/-9.44, P=0.001). Subgroup analysis revealed that there was no difference in serum nitrate/nitrite levels of BA patients without jaundice compared to those with jaundice (78.85+/-23.23 vs. 80.90+/-18.76, P=0.70). However, patients with serum ALT> or =100 IU/l had higher levels of serum NO metabolites compared to those with serum ALT<100 IU/l. In conclusion, NO production was elevated in BA patients compared to normal controls. Serum NO was associated with serum ALT levels, but not with jaundice status, in BA patients. These suggest that NO plays a role in the pathophysiology of liver injury in post-operative BA.

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Section: Discussionmentioning

confidence: 99%

Elevated serum nitric oxide metabolites in biliary atresia

et al. 2005

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“…The differences in nitrotyrosine staining between controls and infected embryos were most notable at 5 dpi. This observation was significant, since fluid accumulation in infected embryos was not detected until 5 dpi, suggesting NO may be involved in fluid accumulation by affecting enterocyte barrier function and ion transport (6,28,31). The source of the NO in vivo is unknown.…”

Section: Cd4mentioning

confidence: 98%

Astrovirus-Induced Synthesis of Nitric Oxide Contributes to Virus Control during Infection

Koci

Kelley

Larsen³

et al. 2004

J Virol

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Astrovirus is one of the major causes of infant and childhood diarrhea worldwide. Our understanding of astrovirus pathogenesis trails behind our knowledge of its molecular and epidemiologic properties. Using a recently developed small-animal model, we investigated the mechanisms by which astrovirus induces diarrhea and the role of both the adaptive and innate immune responses to turkey astrovirus type-2 (TAstV-2) infection. Astrovirus-infected animals were analyzed for changes in total lymphocyte populations, alterations in CD4 ؉ / CD8؉ ratios, production of virus-specific antibodies (Abs), and macrophage activation. There were no changes in the numbers of circulating or splenic lymphocytes or in CD4؉ /CD8 ؉ ratios compared to controls. Additionally, there was only a modest production of virus-specific Abs. However, adherent spleen cells from infected animals produced more nitric oxide (NO) in response to ex vivo stimulation with lipopolysaccharide. In vitro analysis demonstrated that TAstV-2 induced macrophage production of inducible nitric oxide synthase. Studies using NO donors and inhibitors in vivo demonstrated, for the first time, that NO inhibited astrovirus replication. These studies suggest that NO is important in limiting astrovirus replication and are the first, to our knowledge, to describe the potential role of innate immunity in astrovirus infection.Astroviruses were first identified in infants with diarrhea in 1975 by Madeley and Cosgrove (C. R. Madeley and B. P. Cosgrove, Letter, Lancet ii: [451][452] 1975) and are now recognized as one of the leading causes of childhood diarrhea worldwide. By the age of five, 90% of children have antibodies against astroviruses (17,25). In addition to their endemic nature, astroviruses also cause outbreaks of enteritis in schools, geriatric care facilities, children's hospitals, and in immunocompromised individuals (25). In fact, the elderly and the immunocompromised, such as AIDS patients, represent an expanding demographic of astrovirus disease (30).Astroviruses are transmitted mainly through a fecal-oral route (24). The virus typically has an incubation period of 1 to 4 days and causes an acute gastroenteritis which lasts approximately 4 days (9). Diarrhea is the most common symptom; however, vomiting, abdominal distention, and dehydration can occur (25). Much of what is known about astrovirus-mediated disease comes from epidemiological studies involving routine surveillance for enteric disease agents, following outbreaks, and serologic studies. Observational data from human samples and serological surveys suggest that antibodies are the key mediators of protection (18). However, there is nothing known about the role of the innate or cellular immune responses in astrovirus resistance. This is due to the lack of a small-animal model for astrovirus infection.We developed a small-animal model using turkey astrovirus type-2 (North Carolina/034/1999) (TAstV-2) to study the mechanisms of viral pathogenesis and immune protection (3,14,16). Using young turkeys, we d...

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“…Intestinal I/R injury contributes to the pathophysiological alterations in various clinical conditions such as shock, sepsis, midgut volvulus, and NEC, and leads to increase intestinal permeability and breakdown of intestinal barrier function [6]. Various mechanisms have been implicated in the initiation and progression of intestinal I/R injury including overproduction of reactive oxygen/ nitrogen species, increased expression of adhesion molecules and infiltration of leukocytes, and increased lipid oxidation and production of inflammatory mediators including cytokines [7].…”

Section: Discussionmentioning

confidence: 99%

“…Although several investigators have offered in vitro and in vivo data showing an association between proinflammatory states (i.e., NEC) and elevated levels of nitric oxide (NO), interleukin-6, tumor necrosis factor-· and platelet-activating factor [8], the mechanisms involved in local tissue destruction have remained relatively unclear. Recently, however, Nadler et al [6] proposed a paradigm whereby the upregulation of inducible NO synthase during states of inflammation results in an overproduction of NO at the intestinal mucosal surface. The production of NO may result in a cascade of events leading to DNA fragmentation and enterocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Reduced Apoptosis in Newborn Compared to Adult Rat Intestine after Ischemia-Reperfusion Injury

Luo¹,

Shih

Chiu

et al. 2004

Neonatology

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The pathogenesis of necrotizing enterocolitis (NEC) is unknown. Ischemia and reperfusion (I/R) injury has been considered to be a major contributing factor. More recent reports have noted that apoptosis is a significant and perhaps the principal contributor to cell death after I/R. Some reports revealed that infants with NEC and perforated bowel can completely recover with drainage alone. This study aims to assess the ability of newborn rat intestine to resist apoptosis after I/R injury compared with adult rat intestine. Intestines from 10 groups of rats (n = 6 for each study group) were studied: (1) normal control group; (2) ischemia group, receiving vascular occlusion for 60 min; (3) I/R groups receiving vascular occlusion for 60 min and reperfusion for 15, 30, and 60 min, respectively. Apoptosis was quantified by TUNEL methods. Statistical analysis was performed using ANOVA with Dunn’s test. TUNEL-positive cells per 10 crypts were significantly increased in the ischemia and I/R groups compared to the control group. The peak number of positive cells by TUNEL was recognized 30 min after reperfusion in adult and newborn rats and then reduced gradually. The newborn rats had significantly less TUNEL-positive cells per 10 crypts than adult rats subjected to I/R injury (p < 0.05). We demonstrated that the activation of apoptosis occurred after intestinal I/R injury, especially during the reperfusion phase. The newborn intestine was more resistant to I/R injury and thus may have significant clinical application.

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Nitric Oxide and Intestinal Barrier Failure

Cited by 30 publications

References 65 publications

Elevated serum nitric oxide metabolites in biliary atresia

Elevated serum nitric oxide metabolites in biliary atresia

Astrovirus-Induced Synthesis of Nitric Oxide Contributes to Virus Control during Infection

Reduced Apoptosis in Newborn Compared to Adult Rat Intestine after Ischemia-Reperfusion Injury

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