Lysosomal overloading and necrotizing enterocolitis
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ORIGINAL ARTICLE
Lysosomal overloading and necrotizing enterocolitis Masaya Yamoto1,2 · Mashriq Alganabi1 · Sinobol Chusilp1,3 · Dorothy Lee1 · Yuta Yazaki1 · Carol Lee1 · Bo Li1 · Agostino Pierro1,4 Accepted: 27 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Intestinal absorption in premature infants occurs via direct epithelial cellular endocytosis and degradation by intracellular lysosomes. Autophagy is a mechanism by which cytoplasmic organelles contribute to lysosomal degradation. However, excessive autophagy can lead to cell death. The purpose of this study was to investigate whether autophagy and endocytosis are present in the small intestinal mucosa during experimental necrotizing enterocolitis (NEC). Methods NEC was induced by gavage feeding of hyperosmolar formula, lipopolysaccharide and hypoxia between P5 and P9 (ethical approval 44032). Breastfed mice were used as control. Distal ileum was harvested on P5, P7 and P9 and analyzed for intestinal epithelial cellular morphology as well as autophagy/lysosomal activity, and cell death. Groups were compared using Student’s t test. Results During NEC, giant lysosomes were present in the intestinal villi, with some exceeding their degradation ability leading to their rupture. The NEC group had significantly increased inflammation and autophagy activity, decreased lysosome activity, and increased apoptosis compared to control. Conclusions NEC induction causes excessive autophagy and endocytosis leading to lysosomal overloading, lysosomal membrane permeabilization and rupture which results in cell death. These novel findings may help to clarify the pathogenesis of NEC. Reduction of lysosome overload and assisting in their degradation capability may reduce the burden of NEC. Keywords Necrotizing enterocolitis · Autophagy · Endocytosis · Lysosomal membrane permeabilization
Introduction Necrotizing enterocolitis (NEC) is one of the most severe gastrointestinal diseases in premature infants. Despite numerous efforts, the incidence of NEC in premature infants remains high and once the infant develops NEC, mortality is ~ 30%, despite advances in neonatal care [1, 2]. Necrotizing
* Agostino Pierro [email protected] 1
Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, University of Toronto, 1526‑555 University Ave, Toronto, ON M5G 1X8, Canada
2
Department of Pediatric Surgery, Shizuoka Children’s Hospital, Shizuoka, Japan
3
Division of Pediatric Surgery, Department of Surgery, Khon Kaen University, Khon Kaen, Thailand
4
Department of Surgery, University of Toronto, Toronto, Canada
enterocolitis is a multifactorial illness with a poorly understood pathogenesis [1–5]. The most important risk factor for NEC is prematurity. Also, multiple factors, including hypoxia, formula feeding, sepsis, abnormal colonization of the bowel, and the release of inflammatory mediators that are stimulated in the immature gut, are thought to lead to cell death and
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