A hydrogen-sulfide derivative of mesalamine reduces the severity of intestinal and lung injury in necrotizing enterocolitis through endothelial nitric oxide synthase

Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H S-Mesalamine (ATB-429) would improve outcomes in exp...

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Bibliographic Details
Published in:American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2022-10, Vol.323 (4), p.R422-R431
Main Authors: Hosfield, Brian D, Hunter, Chelsea E, Li, Hongge, Drucker, Natalie A, Pecoraro, Anthony R, Manohar, Krishna, Shelley, W Christopher, Markel, Troy A
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Breastfeeding & lactation
Disease Models, Animal
Disulfides
Doppler effect
Enterocolitis
Enterocolitis, Necrotizing - drug therapy
Enterocolitis, Necrotizing - metabolism
Eosine Yellowish-(YS) - metabolism
Eosine Yellowish-(YS) - pharmacology
Eosine Yellowish-(YS) - therapeutic use
Euthanasia
Gastrointestinal diseases
Hematoxylin - metabolism
Hematoxylin - pharmacology
Hematoxylin - therapeutic use
Humans
Hydrogen - metabolism
Hydrogen - pharmacology
Hydrogen - therapeutic use
Hydrogen sulfide
Hydrogen Sulfide - metabolism
Illnesses
Infant, Newborn
Infant, Newborn, Diseases - metabolism
Infant, Premature
Inflammation
Injury prevention
Interleukin 6
Interleukin-6 - metabolism
Intestinal Mucosa - metabolism
Intestine
Juveniles
Lung Injury
Lungs
Mesalamine - metabolism
Mesalamine - pharmacology
Mesalamine - therapeutic use
Mice
Necrosis
Necrotizing enterocolitis
Nitric oxide
Nitric Oxide - metabolism
Nitric Oxide Synthase Type III - metabolism
Nitric-oxide synthase
Perfusion
Sulfides - metabolism
TLR4 protein
Toll-Like Receptor 4 - metabolism
Toll-like receptors
Weight Gain
Weight reduction
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Summary:Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: ) breastfed controls, ) NEC, ) NEC + 50 mg/kg mesalamine, and ) NEC + 130 mg/kg ATB-429. Mesalamine and ATB-429 doses were equimolar. Pups were monitored for sickness scores and perfusion to the gut was measured by Laser Doppler Imaging (LDI). After euthanasia of the pups, intestine and lung were hematoxylin and eosin-stained and scored for injury in a blind fashion. TLR4 expression was quantified by Western blot and IL-6 expression by ELISA. < 0.05 was significant. Both WT and eNOSKO breastfed controls underwent normal development and demonstrated milder intestinal and pulmonary injury compared with NEC groups. For the WT groups, ATB-429 significantly improved weight gain, reduced clinical sickness score, and improved perfusion compared with the NEC group. In addition, WT ATB-429 pups had a significantly milder intestinal and pulmonary histologic injury when compared with NEC. ATB-429 attenuated the increase in TLR4 and IL-6 expression in the intestine. When the experiment was repeated in eNOSKO pups, ATB-429 offered no benefit in weight gain, sickness scores, perfusion, intestinal injury, pulmonary injury, or decreasing intestinal inflammatory markers. An H S derivative of mesalamine improves outcomes in experimental NEC. Protective effects appear to be mediated through eNOS. Further research is warranted to explore whether ATB-429 may be an effective oral therapy to combat NEC.
ISSN:0363-6119
1522-1490
DOI:10.1152/ajpregu.00229.2021