Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation

Yuhki Koike; Bo Li; Niloofar Ganji; Haitao Zhu; Hiromu Miyake; Yong Chen; Carol Lee; Maarten Janssen Lok; Carlos Zozaya; Ethan Lau; Dorothy Lee; Sinobol Chusilp; Zhen Zhang; Masaya Yamoto; Richard Y Wu; Mikihiro Inoue; Keiichi Uchida; Masato Kusunoki; Paul Delgado-Olguin; Luc Mertens; Alan Daneman; Simon Eaton; Philip M Sherman; Agostino Pierro

doi:10.1038/s41467-020-18750-9

Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation

Nat Commun. 2020 Oct 2;11(1):4950. doi: 10.1038/s41467-020-18750-9.

Authors

Yuhki Koike^#^{1

2

3}, Bo Li^#^{1

2}, Niloofar Ganji^#^{1

2}, Haitao Zhu^#^{1

2}, Hiromu Miyake^{1

2}, Yong Chen^{1

2}, Carol Lee^{1

2}, Maarten Janssen Lok^{1

2}, Carlos Zozaya⁴, Ethan Lau^{1

2}, Dorothy Lee^{1

2}, Sinobol Chusilp^{1

2}, Zhen Zhang^{1

2}, Masaya Yamoto^{1

2}, Richard Y Wu^{5

6}, Mikihiro Inoue³, Keiichi Uchida³, Masato Kusunoki³, Paul Delgado-Olguin^{1

7

8}, Luc Mertens⁹, Alan Daneman¹⁰, Simon Eaton¹¹, Philip M Sherman^{5

12}, Agostino Pierro^{13

14

15}

Affiliations

¹ Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada.
² Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
³ Departments of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan.
⁴ Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁸ Heart & Stroke Richard Lewar Centre of Excellence, Toronto, ON, Canada.
⁹ The Labatt Family Heart Center, Cardiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Diagnostic Imaging, Division of Nuclear Medicine, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹¹ UCL Great Ormond Street Institute of Child Health, London, UK.
¹² Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
¹³ Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada. agostino.pierro@sickkids.ca.
¹⁴ Division of General and Thoracic Surgery, Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada. agostino.pierro@sickkids.ca.
¹⁵ Department of Surgery, University of Toronto, Toronto, ON, Canada. agostino.pierro@sickkids.ca.

^# Contributed equally.

Abstract

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Enterocolitis, Necrotizing / pathology*
Enterocytes / pathology
Humans
Hypoxia
Intestinal Mucosa / pathology
Intestines / blood supply*
Intestines / pathology*
Ischemia / pathology*
Mice, Inbred C57BL
Microcirculation*
Microvilli / pathology
Microvilli / ultrastructure

Abstract

Publication types

MeSH terms

Grants and funding