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Nitrosative stress in an animal model of necrotizing enterocolitis

Nitrosative stress in an animal model of necrotizing enterocolitis
Nitrosative stress in an animal model of necrotizing enterocolitis
Necrotizing enterocolitis (NEC) is a disease of newborns characterized by gut barrier failure. We reasoned that upregulation of inducible nitric oxide synthase (iNOS) may result in nitrosative stress and accumulation of nitroso species in the intestine. Newborn rats were either breast-fed (BF), or formula-fed and additionally subjected to hypoxia (FFH). At Day 4 after birth, the distal ilea were harvested and processed for Western blot analysis and measurement of NO-related metabolites. While BF neonates showed normal morphology, FFH neonates developed signs of NEC by Day 4. These pathological changes correlated with upregulation of iNOS and increases in tissue nitrite, nitrosothiol, and nitrosamine concentrations. Enhanced nitroso levels were most prominent in the mucosal layers of the ileum and iNOS inhibition resulted in a significant decrease in both nitroso species and incidence of NEC. In contrast, increased nitrite levels were distributed evenly throughout the ileum and remained unchanged following iNOS inhibition. Similarly, specimens from NEC patients had higher intestinal levels of NO-related metabolites compared to non-NEC controls. This is the first report of tissue levels of nitroso species in the gut of an animal model of NEC and of human specimens. The results suggest that local nitrosative stress contributes to the pathology associated with NEC. Unexpectedly, the NO breakdown product nitrite, previously considered biologically inert, was found to be present throughout the ileal wall, suggesting that cellular NO metabolism is altered significantly in NEC. Whether nitrite plays a protective or deleterious role remains to be investigated.
nitric oxide, nitrite, nitrosation, hypoxia, inflammation, necrotizing enterocolitis, free radical
0891-5849
1428-37
Zamora, Ruben
adf15b45-2018-4a6a-b16b-d645751a4cca
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Boyle, Patricia
dac82223-f44a-47de-bbf3-55092a9e895e
Wong, Catarina
f99afd54-1b75-41f9-aaa8-f15b9d49eb19
Milsom, Alexandra B.
7a3c8b7d-d65a-46b4-9686-1208c539253b
Jaffe, Ronald
a9f054e9-daa4-4109-ba25-3793d14142a5
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Ford, Henri R.
3939c8fd-2144-4af3-a728-dae7c6f6833b
Zamora, Ruben
adf15b45-2018-4a6a-b16b-d645751a4cca
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Boyle, Patricia
dac82223-f44a-47de-bbf3-55092a9e895e
Wong, Catarina
f99afd54-1b75-41f9-aaa8-f15b9d49eb19
Milsom, Alexandra B.
7a3c8b7d-d65a-46b4-9686-1208c539253b
Jaffe, Ronald
a9f054e9-daa4-4109-ba25-3793d14142a5
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Ford, Henri R.
3939c8fd-2144-4af3-a728-dae7c6f6833b

Zamora, Ruben, Bryan, Nathan S., Boyle, Patricia, Wong, Catarina, Milsom, Alexandra B., Jaffe, Ronald, Feelisch, Martin and Ford, Henri R. (2005) Nitrosative stress in an animal model of necrotizing enterocolitis. Free Radical Biology and Medicine, 39 (11), 1428-37. (doi:10.1016/j.freeradbiomed.2005.07.004). (PMID:16274878)

Record type: Article

Abstract

Necrotizing enterocolitis (NEC) is a disease of newborns characterized by gut barrier failure. We reasoned that upregulation of inducible nitric oxide synthase (iNOS) may result in nitrosative stress and accumulation of nitroso species in the intestine. Newborn rats were either breast-fed (BF), or formula-fed and additionally subjected to hypoxia (FFH). At Day 4 after birth, the distal ilea were harvested and processed for Western blot analysis and measurement of NO-related metabolites. While BF neonates showed normal morphology, FFH neonates developed signs of NEC by Day 4. These pathological changes correlated with upregulation of iNOS and increases in tissue nitrite, nitrosothiol, and nitrosamine concentrations. Enhanced nitroso levels were most prominent in the mucosal layers of the ileum and iNOS inhibition resulted in a significant decrease in both nitroso species and incidence of NEC. In contrast, increased nitrite levels were distributed evenly throughout the ileum and remained unchanged following iNOS inhibition. Similarly, specimens from NEC patients had higher intestinal levels of NO-related metabolites compared to non-NEC controls. This is the first report of tissue levels of nitroso species in the gut of an animal model of NEC and of human specimens. The results suggest that local nitrosative stress contributes to the pathology associated with NEC. Unexpectedly, the NO breakdown product nitrite, previously considered biologically inert, was found to be present throughout the ileal wall, suggesting that cellular NO metabolism is altered significantly in NEC. Whether nitrite plays a protective or deleterious role remains to be investigated.

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More information

e-pub ahead of print date: 19 August 2005
Published date: 1 December 2005
Keywords: nitric oxide, nitrite, nitrosation, hypoxia, inflammation, necrotizing enterocolitis, free radical
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337840
URI: http://eprints.soton.ac.uk/id/eprint/337840
ISSN: 0891-5849
PURE UUID: b3b299cf-23d5-47e2-8a6e-9b8002053a64
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 06 Jun 2012 10:49
Last modified: 15 Mar 2024 03:41

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Contributors

Author: Ruben Zamora
Author: Nathan S. Bryan
Author: Patricia Boyle
Author: Catarina Wong
Author: Alexandra B. Milsom
Author: Ronald Jaffe
Author: Martin Feelisch ORCID iD
Author: Henri R. Ford

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