Bo Li1, Augusto Zani1, Carol Lee1, Elke Zani-Ruttenstock1, Ziyi Zhang1, Xinpei Li1, Wan Ip1, Tanja Gonska2, Agostino Pierro3. 1. Division of General and Thoracic Surgery, Physiology and Experimental Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada. 2. Department of Pediatrics and Gastroenterology, The Hospital for Sick Children, Toronto, ON, Canada. 3. Division of General and Thoracic Surgery, Physiology and Experimental Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: agostino.pierro@sickkids.ca.
Abstract
BACKGROUND: Maternal separation (MS) leads to intestinal barrier dysfunction in neonatal mice. Endoplasmic reticulum (ER) stress is associated with apoptosis and pro-inflammatory response induction. We hypothesized that MS induced gut damage is associated with ER stress and that administration of an ER stress inhibitor protects gut damage. METHODS: C57BL/6 mice received intraperitoneal PBS (n=10) or Salubrinal (1mg/kg/day, n=10). MS was performed soon after treatment for 3h daily between P5 and P9. Ten untreated neonatal mice served as control. The colon was harvested on P9 and analyzed for ER stress markers (BiP, CHOP), apoptosis (CC3), goblet cell number per crypt and crypt length (Alcian blue, hematoxylin/eosin), and transcellular permeability (Ussing chamber). Groups were compared using one-way ANOVA with Bonferroni post-test. RESULTS: Compared to controls, MS mice had higher relative protein expression of ER stress and apoptosis markers (p<0.05) and reduced goblet cell number per crypt and crypt length (p<0.001). In comparison to PBS mice, Salubrinal treated mice had higher goblet cell number (p<0.05), crypt length (p<0.001), and lower transcellular permeability (p<0.05). CONCLUSIONS: Maternal separation induces ER stress and causes colon damage, but ER stress inhibitor protects morphology and permeability. This provides insights on bowel pathogenesis and potential novel treatments for diseases such as necrotizing enterocolitis.
BACKGROUND: Maternal separation (MS) leads to intestinal barrier dysfunction in neonatal mice. Endoplasmic reticulum (ER) stress is associated with apoptosis and pro-inflammatory response induction. We hypothesized that MS induced gut damage is associated with ER stress and that administration of an ER stress inhibitor protects gut damage. METHODS: C57BL/6 mice received intraperitoneal PBS (n=10) or Salubrinal (1mg/kg/day, n=10). MS was performed soon after treatment for 3h daily between P5 and P9. Ten untreated neonatal mice served as control. The colon was harvested on P9 and analyzed for ER stress markers (BiP, CHOP), apoptosis (CC3), goblet cell number per crypt and crypt length (Alcian blue, hematoxylin/eosin), and transcellular permeability (Ussing chamber). Groups were compared using one-way ANOVA with Bonferroni post-test. RESULTS: Compared to controls, MS mice had higher relative protein expression of ER stress and apoptosis markers (p<0.05) and reduced goblet cell number per crypt and crypt length (p<0.001). In comparison to PBSmice, Salubrinal treated mice had higher goblet cell number (p<0.05), crypt length (p<0.001), and lower transcellular permeability (p<0.05). CONCLUSIONS: Maternal separation induces ER stress and causes colon damage, but ER stress inhibitor protects morphology and permeability. This provides insights on bowel pathogenesis and potential novel treatments for diseases such as necrotizing enterocolitis.
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