Depletion of alveolar macrophages by clodronate-liposomes aggravates ischemia-reperfusion injury of the lung.
BACKGROUND
Macrophages play an important role in ischemia-reperfusion injury of various organs. Liposome-encapsulated dichloromethylene diphosphonate (clodronate-liposome) depletes local macrophages in vivo. However, the effect of this approach on alveolar macrophages in pulmonary ischemia-reperfusion injury has not yet been evaluated.


METHODS
Clodronate-liposomes in Hanks' balanced salt solution (HBSS) or HBSS alone were given intratracheally to anesthetized male Lewis rats in the clodronate or the control group (n = 6/each group). After 3 days, we subjected the lungs to ischemia (37 degrees C, 60 minutes) and reperfusion (60 minutes) in an isolated blood-perfused rat lung model. Analysis during reperfusion included gas exchange, hemodynamics, and airway mechanics. At the end of reperfusion, we determined leukocyte recruitment and macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage fluid.


RESULTS
In the clodronate group, 4 experiments had to be terminated within 10 minutes of reperfusion because of severe lung injury, whereas all lungs of the controls could be studied during the 60-minute reperfusion period (p < 0.05). Clodronate significantly decreased dynamic airway compliance (p < 0.05) and increased airway resistance. Besides a tendency toward greater pulmonary vascular resistance, this was associated with recruitment of polymorphonuclear neutrophils (p < 0.05) and increased MIP-2 concentrations in the bronchoalveolar lavage fluid (p < 0.05).


CONCLUSIONS
Intratracheal administration of liposome-encapsulated clodronate does not benefit, but aggravates, warm ischemia-reperfusion injury of the lung, increasing MIP-2-associated alveolar neutrophil recruitment and airway mechanical dysfunction.
Nakamura
Takayuki
T
Department of Thoracic and Cardiovascular Surgery, University of Saarland, 66421 Homburg and Saarbrücken, Germany.
Abu-Dahab
Rana
R
Menger
Michael D
MD
Schäfer
Ulrich
U
Vollmar
Brigitte
B
Wada
Hiromi
H
Lehr
Claus-Michael
CM
Schäfers
Hans-Joachim
HJ
D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D054426:Chemokine CXCL2; D004002:Clodronic Acid / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008081:Liposomes; D008168:Lung / Q000166:cytology* / Q000473:pathology* / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008955:Models, Cardiovascular; D015846:Monokines / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects
D050071:Bone Density Conservation Agents; D054426:Chemokine CXCL2; D008081:Liposomes; D015846:Monokines; D004002:Clodronic Acid