title: Alveolar type II epithelial cell dysfunction in rat experimental hepatopulmonary syndrome (HPS).
abstract: The hepatopulmonary syndrome (HPS) develops when pulmonary vasodilatation leads to abnormal gas exchange. However, in human HPS, restrictive ventilatory defects are also observed supporting that the alveolar epithelial compartment may also be affected. Alveolar type II epithelial cells (AT2) play a critical role in maintaining the alveolar compartment by producing four surfactant proteins (SPs, SP-A, SP-B, SP-C and SP-D) which also facilitate alveolar repair following injury. However, no studies have evaluated the alveolar epithelial compartment in experimental HPS. In this study, we evaluated the alveolar epithelial compartment and particularly AT2 cells in experimental HPS induced by common bile duct ligation (CBDL). We found a significant reduction in pulmonary SP production associated with increased apoptosis in AT2 cells after CBDL relative to controls. Lung morphology showed decreased mean alveolar chord length and lung volumes in CBDL animals that were not seen in control models supporting a selective reduction of alveolar airspace. Furthermore, we found that administration of TNF-α, the bile acid, chenodeoxycholic acid, and FXR nuclear receptor activation (GW4064) induced apoptosis and impaired SP-B and SP-C production in alveolar epithelial cells in vitro. These results imply that AT2 cell dysfunction occurs in experimental HPS and is associated with alterations in the alveolar epithelial compartment. Our findings support a novel contributing mechanism in experimental HPS that may be relevant to humans and a potential therapeutic target.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Wenli
authors.initials: W
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Bingqian
authors.initials: B
authors.lastname: Hu
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Sachin
authors.initials: S
authors.lastname: Batra
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: Division of Neonatology, Department of Pediatrics, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Alcorn
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fallon
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States of America.
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D003135:Common Bile Duct / Q000601:surgery; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression; D020065:Hepatopulmonary Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008856:Microscopy, Fluorescence; D011650:Pulmonary Alveoli / Q000166:cytology*; D037661:Pulmonary Surfactant-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D007555:Isoxazoles; D037661:Pulmonary Surfactant-Associated Proteins; D014409:Tumor Necrosis Factor-alpha; D002635:Chenodeoxycholic Acid; C412815:GW 4064