title: Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure.
abstract: BACKGROUND
  Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake.
  
  
  RESULTS
  As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups.
  
  
  CONCLUSIONS
  Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.
authors.affiliation: Department of Digestive Surgery, University Hospital Northern Norway.
authors.forename: Geir I
authors.initials: GI
authors.lastname: Nedredal
authors.affiliation: Vascular Biology Research Group, Department of Medical Biology, University of Tromsø.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Elvevold
authors.affiliation: Liver and Pancreas Transplant and Hepatobiliary Surgery Unit, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
authors.forename: Marcio F
authors.initials: MF
authors.lastname: Chedid
authors.affiliation: Department of Anesthesia and Intensive Care, University Hospital Northern Norway.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ytrebø
authors.affiliation: Hepato-Neuro Laboratory, CRCHUM, Universite de Montreal, Canada.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rose
authors.affiliation: Department of Gastroenterology, Luton & Dunstable University Hospital, Luton, UK.
authors.forename: Sambit
authors.initials: S
authors.lastname: Sen
authors.affiliation: Vascular Biology Research Group, Department of Medical Biology, University of Tromsø
authors.forename: Bård
authors.initials: B
authors.lastname: Smedsrød
authors.affiliation: Institute of Liver and Digestive Health, Royal Free Hospital, London, UK.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
authors.affiliation: Department of Digestive Surgery, University Hospital Northern Norway.
authors.forename: Arthur
authors.initials: A
authors.lastname: Revhaug
mesh_terms: D000818:Animals; D001692:Biological Transport; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D017114:Liver Failure, Acute / Q000097:blood / Q000150:complications / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D055370:Lung Injury / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D034421:Sus scrofa; D013997:Time Factors
chemical_list: C518288:FITC-albumin; D018836:Inflammation Mediators; D012709:Serum Albumin; D006820:Hyaluronic Acid; D016650:Fluorescein-5-isothiocyanate