To evaluate the hypothesis that the proinflammatory cytokines IL-1, IL-6, and tumor necrosis factor-alpha might be the link between prenatal intrauterine infection (IUI) and neonatal brain damage, the authors review the relevant epidemiologic and cytokine literature. Maternal IUI appears to increase the risk of preterm delivery, which in turn is associated with an increased risk of intraventricular hemorrhage, neonatal white matter damage, and subsequent cerebral palsy. IL-1, IL-6, and TNF-alpha have been found associated with IUI, preterm birth, neonatal infections. and neonatal brain damage. Unifying models not only postulate the presence of cytokines in the three relevant maternal/fetal compartments (uterus, fetal circulation, and fetal brain) and the ability of the cytokines to cross boundaries (placenta and blood-brain barrier) between these compartments, but also postulate how proinflammatory cytokines might lead to IVH and neonatal white matter damage during prenatal maternal infection. Interrupting the proinflammatory cytokine cascade might prevent later disability in those born near the end of the second trimester.

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Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn

Nitrate is generally considered a water pollutant and an undesirable fertilizer residue in the food chain Research in the 1970s indicated that, by reducing nitrate to nitrite, commensal bacteria might be involved in the pathogenesis of gastric cancers and other malignancies, as nitrite can enhance the generation of carcinogenic N-nitrosamines More recent studies indicate that the bacterial metabolism of nitrate to nitrite and the subsequent formation of biologically active nitrogen oxides could be beneficial Here, we will consider the evidence that nitrate-reducing commensals have a true symbiotic role in mammals and facilitate a previously unrecognized but potentially important aspect of the nitrogen cycle

Nitrate, bacteria and human health.

The role of inflammatory cytokines and nitric oxide in the pathogenesis of necrotizing enterocolitis

Nitric oxide (NO) is normally produced in the endothelium by the constitutive isoform of the NO synthase. This physiological production of NO is important for blood pressure regulation and blood flow distribution. Several lines of evidence suggest that a hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Lipopolysaccarides and cytokines, such as tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells. Treatment with inhibitors of NO synthesis has been shown to improve hemodynamic variables and survival in several animal models of septic shock. In human septic shock, inhibition of NO synthesis has been shown to alter hemodynamic variables in short-term studies, but it is uncertain whether this treatment has beneficial long-term effects. The aim of this review is to give an overview of the physiological role of NO and to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock. A main new aspect of this review is a critical discussion of previous reports measuring plasma nitrite/nitrate during septic shock and an evaluation of the validity of interpreting these data as evidence for a hyperproduction of NO. This review also emphasizes that many septic patients have preexisting endothelial dysfunction and lung diseases, which may contribute to adverse effects by systemic inhibition of NO synthesis. Another new aspect of the present review is a focus on the lack of direct evidence of iNOS expression in human septic shock.

The Role of Nitric Oxide in Sepsis--An Overview

As a by-product of heme catabolism by the heme oxygenase system, carbon monoxide (CO) has been neglected for many years, and only recently has its role as an essential signaling molecule been appreciated. In the past decade, the use of CO gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. However, the inherent toxic nature of CO cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. From a clinical perspective, a key question is whether a safe and therapeutically effective threshold of CO can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. The advent of CO-releasing molecules (CO-RMs), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, appears a plausible alternative in the attempt to overcome the limitations of CO gas. Although in its infancy and far from being used for clinical applications, the CO-RMs technology is supported by very encouraging biological results and reflected by the chemical versatility of these compounds and their endless potential to be transformed into CO-based pharmaceuticals.

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Use of carbon monoxide as a therapeutic agent: promises and challenges.

Plasma nitric oxide levels in newborn infants with sepsis

Objective. To investigate the role of carbon monoxide (CO) and nitric oxide (NO) in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). Methods. Plasma CO and NO levels were studied in 33 asphyxiated term neonates, and 30 healthy neonates served as controls. Results. Among the 33 asphyxiated term neonates, plasma CO and NO levels in 28 neonates with HIE were significantly higher than those in the 5 infants without HIE and in the normal controls. The plasma CO and NO levels in the newborn infants with HIE stage 3 were found to be significantly higher than those in the neonates with HIE stage 1 and 2. Moreover, plasma CO and NO levels were significantly increased in neonates with brain damage and adverse outcome as compared with those in patients with normal neuroimaging and normal outcome. Conclusion. Plasma CO and NO levels after perinatal asphyxia are related to the severity of neonatal HIE, brain damage, and neurologic outcome. The present study suggests that CO and NO might play important roles in the pathogenesis of neonatal HIE.

Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy.

In a rat model of fatal infection caused by Pseudomonas aeruginosa, the circulating level of nitrite/nitrate (NO2−/NO3−), a good indicator for nitric oxide production, was remarkably increased after elevation of circulatory tumor necrosis factor (TNF). Anti-TNF MAb cotreatment was shown to blunt hypoglycemia and hyper-lacticemia and was associated with decreased mortality of septic animals. Moreover, anti-TNF MAb significantly reduced not only plasma TNF but also plasma NO2−/NO3− levels. Dcxamcthasone had a similar effects, and when anti-TNF MAb was used in combination with dexamethasone, the suppression of nitric oxide production and the protective efficacy were more remarkable compared with therapy with either anti-TNF MAb or dexamethasone alone. Our present data suggested that the protective efficacy of anti-TNF MAb may correlate with the suppression of nitric oxide production and also with a modulation in metabolic abnormalities in the septic newborn rats.

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Association between protective efficacy of antibodies to tumor necrosis factor and suppression of nitric oxide production in neonatal rats with fatal infection.

Carbon monoxide (CO) has been implicated as a new endogenously produced mediator similar to nitric oxide (NO). CO was measured in plasma samples from 7 term newborn infants with sepsis and from 30 healthy neonates. Plasma CO levels were significantly higher in the group with sepsis at the time of admission to the neonatal intensive care unit than in the healthy controls (p < 0.05). Moreover, the elevated plasma CO levels were significantly related to increased NO production, as indicated by plasma nitrite/nitrate levels (p < 0.05). The present study suggests that, in addition to NO, CO might be another important mediator taking part in the pathogenesis of neonatal sepsis.

Chikao Shen

Papers

Plasma nitric oxide levels in newborn infants with sepsis

Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy.

Association between protective efficacy of antibodies to tumor necrosis factor and suppression of nitric oxide production in neonatal rats with fatal infection.

Plasma carbon monoxide levels in term newborn infants with sepsis.

Role of carbon monoxide and nitric oxide in newborn infants with postasphyxial hypoxic-ischemic encephalopathy. Authors' reply