title: Prevention of acute lung injury in swine: depletion of pulmonary intravascular macrophages using liposomal clodronate.
abstract: BACKGROUND
  Swine contain large numbers of pulmonary intravascular macrophages (PIMs) that mediate the physiological response observed in acute lung injury (ALI). As the hyperacute dysfunction observed in pulmonary xenotransplantation is similar to endotoxin-induced ALI, PIMs may play a critical role in pulmonary xenograft dysfunction. We used liposomal clodronate to eliminate the PIM population in a model of acute swine lung injury.
  
  
  METHODS
  Experimental swine (n = 6) received liposomal clodronate (1.25 g/10 kg) and control swine (n = 5) received saline containing liposomes before infusion of lipopolysaccharide (450 ng/kg).
  
  
  RESULTS
  Control swine demonstrated higher peak pulmonary artery pressures (41.8 +/- 2.2 versus 16.8 +/- 1.2 mm Hg; P < 0.0001) and higher peak pulmonary vascular resistances (1405 +/- 209 versus 353 +/- 81 dynes. s. cm(-5); P = 0.0016) in response to lipopolysaccharide infusion. Clodronate treated swine also had significantly lower serum levels of tumor necrosis factor-alpha, interleukin-6, and thrombin.
  
  
  CONCLUSIONS
  Liposomal clodronate effectively attenuates acute swine lung injury induced by endotoxin. This method of depletion of the PIM population presents a promising new treatment of swine lungs before xenotransplantation.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. gaca0001@mc.duke.edu
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Gaca
authors.forename: Daniel
authors.initials: D
authors.lastname: Palestrant
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lukes
authors.forename: Michael
authors.initials: M
authors.lastname: Olausson
authors.forename: William
authors.initials: W
authors.lastname: Parker
authors.forename: R Duane
authors.initials: RD
authors.lastname: Davis
mesh_terms: D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000235:genetics; D000963:Antimetabolites / Q000494:pharmacology*; D004002:Clodronic Acid / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D008171:Lung Diseases / Q000276:immunology* / Q000517:prevention & control / Q000601:surgery*; D016040:Lung Transplantation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics; D011669:Pulmonary Wedge Pressure; D013552:Swine; D013917:Thrombin / Q000378:metabolism; D014183:Transplantation, Heterologous; D014655:Vascular Resistance
chemical_list: D015703:Antigens, CD; D000963:Antimetabolites; C497857:CD46 protein, human; D016207:Cytokines; D008070:Lipopolysaccharides; D008081:Liposomes; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D004002:Clodronic Acid; D013917:Thrombin