Prevention of acute lung injury in swine: depletion of pulmonary intravascular macrophages using liposomal clodronate.
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.
Gaca
Jeffrey G
JG
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. gaca0001@mc.duke.edu
Palestrant
Daniel
D
Lukes
Daniel J
DJ
Olausson
Michael
M
Parker
William
W
Davis
R Duane
RD
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
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