On the dynamics of nitrite, nitrate and other biomarkers of nitric oxide production in inflammatory bowel disease

Nitrite and nitrate are frequently used surrogate markers of nitric oxide (NO) production. Using rat models of acute and chronic DSS-induced colitis we examined the applicability of these and other NO-related metabolites, in tissues and blood, for the characterization of inflammatory bowel disease. Global NO dynamics were assessed by simultaneous quantification of nitrite, nitrate, nitroso and nitrosyl species over time in multiple compartments. NO metabolite levels were compared to a composite disease activity index (DAI) and contrasted with measurements of platelet aggregability, ascorbate redox status and the effects of 5-aminosalicylic acid (5-ASA). Nitroso products in the colon and in other organs responded in a manner consistent with the DAI. In contrast, nitrite and nitrate, in both intra- and extravascular compartments, exhibited variations that were not always in step with the DAI. Extravascular nitrite, in particular, demonstrated significant temporal instabilities, ranging from systemic drops to marked increases. The latter was particularly evident after cessation of the inflammatory stimulus and accompanied by profound ascorbate oxidation. Treatment with 5-ASA effectively reversed these fluctuations and the associated oxidative and nitrosative stress. Platelet activation was enhanced in both the acute and chronic model. Our results offer a first glimpse into the systemic nature of DSS-induced inflammation and reveal a greater complexity of NO metabolism than previously envisioned, with a clear dissociation of nitrite from other markers of NO production. The remarkable effectiveness of 5-ASA to abrogate the observed pattern of nitrite instability suggests a hitherto unrecognized role of this molecule in either development or resolution of inflammation. Its possible link to tissue oxygen consumption and the hypoxia that tends to accompany the inflammatory process warrants further investigation

Penetration and Perforation of Terminal Ileum Diverticulitis

Background. Terminal ileum diverticulitis is a rare clinical disease. It can frequently mimic other processes, such as acute appendicitis. Diagnosis and therapeutic decision making (surgical or conservative treatment) can be complex. We report four interesting cases of terminal ileum diverticulitis. Case Presentation. Case 1: a 55-year-old male presented to us with a 3-day history of severe right lower quadrant pain. Computed tomography (CT) showed penetration of terminal ileum diverticulitis. Following a 7-day conservative treatment, he underwent ileocecal resection. Pathology results revealed a false diverticulum and two in five points of perforated terminal ileum diverticulum. Case 2: a 77-year-old male presented to us with severe right lower quadrant pain and unconsciousness. CT showed penetration of terminal ileum diverticulitis and air in the mesentery. Ileocecal resection was performed 2 days postadmission. Pathology results revealed a false diverticulum and penetrated terminal ileum diverticulum. Case 3: a 61-year-old male presented to us with a right lower quadrant pain for 10 days and fever for 6 days. CT showed penetration of terminal ileum diverticulitis and abscess of the psoas muscle. Puncture and drainage of abscess were performed. Laparoscopic ileocecal resection was performed 30 days postadmission. Pathology results revealed a false diverticulum and penetrated terminal ileum diverticulum. Case 4: a 39-year-old female presented to us with right lower quadrant pain for 9 days, suspicious of appendicitis. CT showed abscess of pericecal area. Puncture and drainage were performed. A drainage tube was located into the cecum through the terminal ileum. Conservative therapy was effective, and she was discharged 23 days postadmission. Conclusions. All four cases had right lower quadrant pain. Three cases were diagnosed by CT, whereas one was diagnosed by abscess drainage. Two cases required surgical treatment within 3 days, one within about 1 month, and one case did not require surgery. The decision of whether to manage a patient surgically or conservatively is difficult. It is critical not to delay the decision of performing a surgical treatment until each patient reaches a stable general condition

An integrated approach to assessing nitroso-redox balance in systemic inflammation

Most studies examining the metabolic fate of NO during systemic inflammation have focused on measuring the quantitatively predominating, stable anions nitrite and nitrate within the circulation. However, these are not necessarily the NO-related products that govern NO metabolism and signaling in tissues. We assessed all major NO derivatives temporally in blood and vital organs during inflammation and explored their relationship to insult severity and redox status. Male rats receiving intraperitoneal endotoxin or vehicle were sacrificed for organ and blood sampling between 0 and 24 h. Endotoxin induced transient and organ-specific changes in a variety of NO metabolites. Nitrite and nitrate increased, peaking at 8 and 12 h, respectively. Sand N-nitrosation and heme-nitrosylation products also peaked at 8 h; these posttranslational protein modifications were associated with decreased myocardial function (echocardiography). Evidence of oxidative stress and systemic inflammation was also obtained. The rise in most NO derivatives was proportional to insult severity. All metabolite levels normalized within 24 h, despite evidence of persisting myocardial dysfunction and clinical unwellness. Our findings point to a complex interplay between NO production, antioxidant defense, and redox status. Although the precise (patho)physiologic roles of specific NO derivatives and their diagnostic/prognostic utility await further investigation, nitroso species in erythrocytes are the most sensitive markers of NO in systemic inflammation, detectable before clinical symptoms manifest

Nitroso-redox status and vascular function in marginal and severe ascorbate deficiency

Marginal vitamin C (ascorbic acid) deficiency is a prevalent yet underappreciated risk factor for cardiovascular disease. Along with glutathione, ascorbate plays important roles in antioxidant defense and redox signaling. Production of nitric oxide (NO) and reactive oxygen species and their interaction, giving rise to nitroso and nitrosyl product formation, are key components of the redox regulation/signaling network. Numerous in vitro studies have demonstrated that these systems are interconnected via multiple chemical transformation reactions, but little is known about their dynamics and significance in vivo. Aims: We sought to investigate the time-course of changes in NO/redox status and vascular function during ascorbate depletion in rats unable to synthesize vitamin C. Results: We here show that both redox and protein nitros(yl)ation status in blood and vital organs vary dynamically during development of ascorbate deficiency. Prolonged marginal ascorbate deficiency is associated with cell/tissue-specific perturbations in ascorbate and glutathione redox and NO status. Scurvy develops earlier in marginally deficient compared to adequately supplemented animals, with blunted compensatory NO production and a dissociation of biochemistry from clinical symptomology in the former. Paradoxically, aortic endothelial reactivity is enhanced rather than impaired, irrespective of ascorbate status. Innovation/Conclusion: Enhanced NO production and protein nitros(yl)ation are integral responses to the redox stress of acute ascorbate deprivation. The elevated cardiovascular risk in marginal ascorbate deficiency is likely to be associated with perturbations of NO/redox-sensitive signaling nodes unrelated to the regulation of vascular tone. This new model may have merit for the future study of redox-sensitive events in marginal ascorbate deficiency