Intercellular adhesion molecule-1 contributes to pulmonary oxygen toxicity in mice: role of leukocytes revised.
In immature or injured lungs, impaired alveolar gas exchange forces the use of elevated levels of inhaled oxygen to maintain life. But, at high concentrations oxygen induces lung injury, edema, and bronchopulmonary dysplasia, probably by stimulating the generation of reactive oxygen radicals and subsequent neutrophil infiltration. In addition to regulating neutrophil diapedesis, intercellular adhesion molecule-1 (ICAM-1) expression is marked on inflamed alveolar epithelium, suggesting a role for ICAM-1 in oxygen-induced, neutrophil-mediated parenchymal damage. To test this, we evaluated the rat anti-mouse ICAM-1 monoclonal antibody YN1/1.7 in 2 protocols of oxygen-induced toxicity in adult, male Balb-c mice: greater than or equal to 95% O2 for 84 hr and greater than or equal to 95% O2 for 60 hr followed by 48 hr at 21% (ambient) O2. YN1/1.7 treatment partially attenuated the neutrophil infiltration, lung damage (lavage lactate dehydrogenase [LDH] activity) and dysfunction (reductions in respiratory system compliance [Crs] and diffusion capacity of the lungs for carbon monoxide [DLCO] in the 84 hr exposure protocol. In the milder 60 hr exposure protocol, YN1/1.7 completely blocked the oxygen-induced lung dysfunction (reductions in Crs and DLco). These results confirm the contribution of leukocytes in the pathogenesis of pulmonary oxygen toxicity and indicate that antagonism of ICAM-1 may provide a therapeutic approach to reducing hyperoxic lung injury and dysfunction.
Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
C D
CD
Wegner
W W
WW
Wolyniec
A M
AM
LaPlante
K
K
Marschman
K
K
Lubbe
N
N
Haynes
R
R
Rothlein
L G
LG
Letts
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D018799:Intercellular Adhesion Molecule-1; D008171:Lung Diseases / Q000139:chemically induced / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects; D010100:Oxygen / Q000009:adverse effects*; D010102:Oxygen Inhalation Therapy / Q000009:adverse effects*
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D018799:Intercellular Adhesion Molecule-1; D010100:Oxygen