Expression, activity and cellular localization of inducible nitric oxide synthase in rat ileum and colon post-irradiation

MacNaughton, Wallace K.; Aurora, Alexander R.; Bhamra, Jamie; Sharkey, Keith A.; Miller, Mark J.S.

doi:10.1080/095530098141645

Cited by 58 publications

(23 citation statements)

References 25 publications

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“…This strongly argues against an extensive contribution of nNOS or eNOS. Observations of Clark et al (1996), MacNaughton et al (1998), Haddad et al (1995), and Salvemini et al (1995) of an early iNOS expression also support our results. Reconstitution of the fast development of hyperalgesia by the NO donor RE-2047 (Rehse and Ciborski, 1995) demonstrates the importance of early NO production.…”

Section: Discussionsupporting

confidence: 91%

Suppressed Injury-Induced Rise in Spinal Prostaglandin E₂ Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

et al. 2000

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It is widely accepted that peripheral injury increases spinal inducible cyclooxygenase (COX-2) expression and prostaglandin E 2 (PGE 2 ) formation as key mediators of nociceptive sensitization. Here, we used inducible nitric oxide synthase (iNOS) genedeficient (iNOSϪ/Ϫ) mice to determine the contribution of iNOSderived nitric oxide (NO) to this process. iNOSϪ/Ϫ mice exhibited reduced thermal hyperalgesia after zymosan injection. Spinal NO and PGE 2 formation both remained at baseline levels, in contrast to wild-type (wt) mice. In wt mice reduced hyperalgesia similar to that seen in iNOSϪ/Ϫ mice was induced by local spinal, but not by systemic treatment with the iNOS inhibitor L-NIL, suggesting that the reduced heat sensitization in iNOSϪ/Ϫ mice was attributable to the lack of spinal rather than peripheral iNOS. Two additional observations indicate that the antinociceptive effects of iNOS inhibition are dependent on a loss of stimulation of PG synthesis. First, intrathecal injection of the COX inhibitor indomethacin, which exerted pronounced antinociceptive effects in wt mice, was completely ineffective in iNOSϪ/Ϫ mice. Second, treatment with the NO donor RE-2047 not only completely restored spinal PG production and thermal sensitization in iNOSϪ/Ϫ mice but also its sensitivity to indomethacin. In both types of mice induction of thermal hyperalgesia was accompanied by similar increases in COX-1 and COX-2 mRNA expression. The stimulation of PG production by NO therefore involves an increase in enzymatic activity, rather than an alteration of COX gene expression. These results indicate that NO derived from spinal iNOS acts as a fast inductor of spinal thermal hyperalgesia. Key words: nitric oxide; inducible nitric oxide synthase; zymosan; thermal hyperalgesia; paw edema; spinal microdialysis; L-NIL; RE-2047; prostaglandins; cyclooxygenaseAcute tissue damage is often accompanied by the fast development of hyperalgesia and allodynia (Andrew and Greenspan, 1999). Both peripheral mechanisms at the site of injury and central processes particularly in the spinal cord contribute to this phenomenon. Prostaglandins (PGs) Brune, 1994) as well as nitric oxide (NO) (Lawand et al., 1997) are produced in response to tissue damage peripherally and centrally. Whereas PGs are generally accepted to play a dominant role in nociceptive sensitization (Bley et al., 1998), the role of NO is less clear. Also some authors claim of an anti-nociceptive action of NO (Goettl and Larson, 1996;Hamalainen and Lovick, 1997), most favor a pronociceptive activity Kawabata et al., 1994;Chen and Levine, 1999). Part of this controversy may arise from the existence of three different isoenzymes of NO synthase (NOS) (Gonzalez-Hernandez and Rustioni, 1999), which may have distinct effects on nociception, and from the lack of specific inhibitors for these different isoforms. In the CNS including the spinal cord, NO is thought to be primarily produced by the neuronal isoform of NOS (nNOS) (Downen et al., 1999). However, endothelial NOS is also found in neur...

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Section: Discussionsupporting

confidence: 91%

Suppressed Injury-Induced Rise in Spinal Prostaglandin E₂ Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

et al. 2000

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“…With an increasing cumulative dose this anti-inflammatory effect is reversed and assigned to the situation of bowel irradiation, the probability of direct radiogenic inflammatory mucosal changes rises thus leading to the known effect, that concomitant 5-FU can increase side effects [1,15,21]. The fact that steroids have an anti-inflammatory activity in noninfectious enteritis by inhibiting the expression of iNOS in the ileum and colon may support our hypothesis [11,14]. Given these observations, we speculate that in our patient the 1.8 Gy per fraction may have diminished 5-FU-induced inflammation of the colorectal mucosa during the early phase of RCT.…”

Section: Discussionsupporting

confidence: 66%

Does Radiation Prevent 5-Fluorouracil-Induced Colitis in the Early Phase of Radiochemotherapy?

et al. 2007

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This observation led to the hypothesis that the anti-inflammatory effect of low-dose irradiation may attenuate 5-FU-induced colitis in the very early phase of RCT. It appears worthwhile to separate side effects of RCT into radiation- and chemotherapy-induced effects, which requires a detailed diagnostic work-up. This differentiation has an impact on planning individual therapy: the authors did not saw conclusive evidence of an increased radiosensitivity but chemosensitivity in their patient and therefore continued radiotherapy. This assumption was confirmed when the patient received palliative 5-FU-based chemotherapy due to pulmonary relapse, and again, severe diarrhea occurred.

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“…Ionizing radiation induces iNOS-mediated epithelial dysfunction of the colon (26). MacNaughton et al (27) noted that irradiation resulted in the dexamethasone-sensitive expression of iNOS mRNA in the ileum within 2 h and that iNOS activity was significantly elevated. Our data also revealed an increase in NOx levels in both the portal vein and systemic blood 4 h after 12-Gy irradiation.…”

Section: Discussionmentioning

confidence: 99%

Aminoguanidine Alleviates Radiation-Induced Small-Bowel Damage Through Its Antioxidant Effect

Huang

Wang

Lin

et al. 2009

International Journal of Radiation Oncology*Biology*Physics

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Expression, activity and cellular localization of inducible nitric oxide synthase in rat ileum and colon post-irradiation

Cited by 58 publications

References 25 publications

Suppressed Injury-Induced Rise in Spinal Prostaglandin E₂ Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

Suppressed Injury-Induced Rise in Spinal Prostaglandin E₂ Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

Does Radiation Prevent 5-Fluorouracil-Induced Colitis in the Early Phase of Radiochemotherapy?

Aminoguanidine Alleviates Radiation-Induced Small-Bowel Damage Through Its Antioxidant Effect

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Expression, activity and cellular localization of inducible nitric oxide synthase in rat ileum and colon post-irradiation

Cited by 58 publications

References 25 publications

Suppressed Injury-Induced Rise in Spinal Prostaglandin E2 Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

Suppressed Injury-Induced Rise in Spinal Prostaglandin E2 Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

Does Radiation Prevent 5-Fluorouracil-Induced Colitis in the Early Phase of Radiochemotherapy?

Aminoguanidine Alleviates Radiation-Induced Small-Bowel Damage Through Its Antioxidant Effect

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Suppressed Injury-Induced Rise in Spinal Prostaglandin E₂ Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice

Suppressed Injury-Induced Rise in Spinal Prostaglandin E₂ Production and Reduced Early Thermal Hyperalgesia in iNOS-Deficient Mice