Pulmonary macrophage inhibition and inhaled nitric oxide attenuate lung ischemia-reperfusion injury.
BACKGROUND
Lung ischemia-reperfusion injury (LIRI) is postulated to occur biphasically. Donor pulmonary macrophages mediate early injury, and neutrophil-dependent injury predominates in the later phase of LIRI. We hypothesized that the biphasic response to LIRI would be attenuated by the administration of gadolinium, a known pulmonary macrophage inhibitor, and inhaled nitric oxide (NO), a pulmonary vasodilator that also interferes with neutrophil chemotaxis.


METHODS
Using our isolated, ventilated, blood-perfused rabbit lung model, study groups (n = 10 per group) underwent two hours of reperfusion after 18 hours of cold ischemia (4 degrees C). Lungs received gadolinium alone, or inhaled NO in the presence or absence of macrophage inhibition with gadolinium.


RESULTS
Compared with control animals, pulmonary macrophage inhibition with the concurrent administration of inhaled NO increased lung compliance (p < 0.01) and oxygenation (p = 0.03), while also decreasing pulmonary artery pressure (p < 0.01), myeloperoxidase content by 63% (p < 0.01), wet to dry ratios by 23% (p < 0.01), and lung tissue (p < 0.01) and bronchoalveolar lavage tumor necrosis factor-alpha (TNF-alpha) protein levels (p < 0.01).


CONCLUSIONS
The severity of LIRI was most significantly reduced by the inhibition of pulmonary macrophages and the concomitant use of inhaled NO. Pulmonary macrophages, likely through the elaboration of proinflammatory cytokines such as TNF-alpha, not only cause early injury themselves but also prime cells such as neutrophils to injure lungs in the later stages of LIRI. The LIRI was effectively blunted by the reduction of macrophage-dependent injury by gadolinium while inhaled NO also attenuated injury by reducing pulmonary hypertension and minimizing neutrophil sequestration.
Gazoni
Leo M
LM
Department of Surgery, University of Virginia, Charlottesville, Virginia 22908, USA. lmg2x@virginia.edu
Tribble
Curtis G
CG
Zhao
Min Q
MQ
Unger
Eric B
EB
Farrar
Robert A
RA
Ellman
Peter I
PI
Fernandez
Lucas G
LG
Laubach
Victor E
VE
Kron
Irving L
IL
D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005682:Gadolinium / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000008:administration & dosage*; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005682:Gadolinium; D009195:Peroxidase; C038958:gadolinium chloride