Ceramides as Therapeutic Targets in Bronchopulmonary Dysplasia
type: CreativeWork
description: Bronchopulmonary dysplasia (BPD) is a chronic lung disorder associated with extremely premature birth, resulting from arrested development of the microvasculature and consequently disrupted alveologenesis. Premature infants are dependent on respiratory support, including oxygen supplementation and mechanical ventilation (MV), that are considered the main modifiable contributors to BPD. The mechanistic link between the injurious stimulus (e.g., hyperoxia) and disrupted lung development has been less clear. Recent works suggest the up regulation of ceramides in the injured lung as a potentially key factor. Ceramides regulate tissue growth pathways, by increasing autophagy and apoptosis. Ceramides are increased in tracheal aspirates of preterm infants receiving MV. Moreover, attenuation of ceramide synthesis by Sphingomyelin Phosphodiesterase 1 (SMPD1) inhibition prevented MV induced cell death in experimental animals. Whether ceramides may play a role in hyperoxia-induced lung injury remains less studied. To examine this issue, I employed an experimental rat model of BPD caused by exposure to hyperoxia for 14 days (85% O₂ postnatal days [PND] 1-7 and 60% O₂ PND 7-14) followed by intermittent hypoxia from PND 14-21 (termed the HIH BPD-like lung injury model). Lung injury in this model was characterized by hypoplastic pulmonary vasculature, pulmonary hypertension, and "emphysematous" lung structure due to inhibited alveologenesis. My findings demonstrated that exposure to severe hyperoxia (PND 1-7) lead to a rapid increase in the lung of pro-apoptotic ceramides, commencing on PND 1 and persisting to PND 7. Lung autophagy markers were up-regulated concurrent with increased ceramides, which was followed by increased apoptosis on PND 7, predominantly in distal lung epithelial cells. Treatment of HIH-exposed rat pups with daily S.C Desipramine 10 mg/kg/d (an SMPD1 inhibitor) prevented up-regulated lung ceramide content, autophagy, and apoptosis. Desipramine also prevented H…
abstract: Bronchopulmonary dysplasia (BPD) is a chronic lung disorder associated with extremely premature birth, resulting from arrested development of the microvasculature and consequently disrupted alveologenesis. Premature infants are dependent on respiratory support, including oxygen supplementation and mechanical ventilation (MV), that are considered the main modifiable contributors to BPD. The mechanistic link between the injurious stimulus (e.g., hyperoxia) and disrupted lung development has been less clear. Recent works suggest the up regulation of ceramides in the injured lung as a potentially key factor. Ceramides regulate tissue growth pathways, by increasing autophagy and apoptosis. Ceramides are increased in tracheal aspirates of preterm infants receiving MV. Moreover, attenuation of ceramide synthesis by Sphingomyelin Phosphodiesterase 1 (SMPD1) inhibition prevented MV induced cell death in experimental animals. Whether ceramides may play a role in hyperoxia-induced lung injury remains less studied. To examine this issue, I employed an experimental rat model of BPD caused by exposure to hyperoxia for 14 days (85% O₂ postnatal days [PND] 1-7 and 60% O₂ PND 7-14) followed by intermittent hypoxia from PND 14-21 (termed the HIH BPD-like lung injury model). Lung injury in this model was characterized by hypoplastic pulmonary vasculature, pulmonary hypertension, and "emphysematous" lung structure due to inhibited alveologenesis. My findings demonstrated that exposure to severe hyperoxia (PND 1-7) lead to a rapid increase in the lung of pro-apoptotic ceramides, commencing on PND 1 and persisting to PND 7. Lung autophagy markers were up-regulated concurrent with increased ceramides, which was followed by increased apoptosis on PND 7, predominantly in distal lung epithelial cells. Treatment of HIH-exposed rat pups with daily S.C Desipramine 10 mg/kg/d (an SMPD1 inhibitor) prevented up-regulated lung ceramide content, autophagy, and apoptosis. Desipramine also prevented H…
author: Hamraghani, Ali
language: en
keywords: Broncopulmonary dysplasia, Ceramides, Desipramine, Hyperoxia, Autophagy, Apoptosis
date published: 2024-03-13T18:36:52Z
date modified: 2026-07-24T03:39:32Z
provider: University of Ottawa
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Université d'Ottawa / University of Ottawa

PropertyValue
property ID: Handle
value: http://hdl.handle.net/10393/46034

PropertyValue
property ID: DOI
value: 10.20381/ruor-30215