title: Intestinal epithelium is more susceptible to cytopathic injury and altered permeability than the lung epithelium in the context of acute sepsis.
abstract: Mitochondrial morphology and function are altered in intestinal epithelia during endotoxemia. However, it is unclear whether mitochondrial abnormalities occur in lung epithelial cells during acute sepsis or whether mitochondrial dysfunction corresponds with altered epithelial barrier function. Thus, we hypothesized that the intestinal epithelium is more susceptible to mitochondrial injury than the lung epithelium during acute sepsis and that mitochondrial dysfunction precedes impaired barrier function. Using a resuscitated feline model of Escherichia coli-induced sepsis, lung and ileal tissues were harvested after 6 h for histological and mitochondrial ultrastructural analyses in septic (n = 6) and time-matched controls (n = 6). Human lung epithelial cells (HLEC) and Caco-2 monolayers (n = 5) were exposed to 'cytomix' (TNFα: 40 ng/ml, IL-1β: 20 ng/ml, IFNγ: 10 ng/ml) for 24-72 h, and measurements of transepithelial electrical resistance (TER), epithelial permeability and mitochondrial membrane potential (ΔΨ) were taken. Lung epithelial morphology, mitochondrial ultrastructure and pulmonary gas exchange were unaltered in septic animals compared to matching controls. While histologically intact, ileal epithelia demonstrated marked mitochondrial ultrastructural damage during sepsis. Caco-2 monolayers treated with cytomix showed a significant decrease in mitochondrial ΔΨ within 24 h, which was associated with a progressive reduction in TER and increased epithelial permeability over the subsequent 48 h. In contrast, mitochondrial ΔΨ and epithelial barrier functions were preserved in HLEC following cytomix. These findings indicate that intestinal epithelium is more susceptible to mitochondrial damage and dysfunction than the lung epithelium in the context of sepsis. Early alterations in mitochondrial function portend subsequent epithelial barrier dysfunction.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Medical Center, Columbus, OH 43210-1252, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Julian
authors.forename: Shengying
authors.initials: S
authors.lastname: Bao
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
authors.forename: Ruairi J
authors.initials: RJ
authors.lastname: Fahy
authors.forename: Guohong
authors.initials: G
authors.lastname: Shao
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Crouser
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018938:Caco-2 Cells; D002415:Cats; D002463:Cell Membrane Permeability / Q000502:physiology*; D002478:Cells, Cultured; D003106:Colon / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000302:isolation & purification*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007082:Ileum / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D020545:Respiratory Mucosa / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D018805:Sepsis / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D014409:Tumor Necrosis Factor-alpha