Inhibition of CD18 or CD11b attenuates acute lung injury after acid instillation in rabbits.
Acid-induced lung injury is mediated primarily by activated neutrophils. Although a prior study demonstrated that acid-induced neutrophil influx into the air spaces was not CD18 dependent, we hypothesized that either a neutralizing anti-CD18 monoclonal antibody (MHM23) or a neutrophil inhibitory factor (NIF), NIF (CD11b,18), might attenuate acid-induced lung injury in rabbits by interfering with neutrophil activation. This hypothesis derived from in vitro stu ies that reported that anti-CD18 therapy prevented tumor necrosis factor-alpha-induced neutrophil activation. Hydrochloric acid (pH = 1.5 in one-third normal saline) or one-third normal saline (4 ml/kg) was instilled into the lungs of ventilated, anesthetized rabbits. The rabbits were studied for 6 h. In acid-instilled rabbits without the anti-CD18 monoclonal antibody or NIF (CD11b,18), severe lung injury developed. In acid-instilled rabbits, pretreatment (5 min before acid) with the anti-CD18 monoclonal antibody (2 mg/kg i.v.) or pretreatment with the NIF (anti-CD11b,18, 10 mg/kg i.v.) prevented 50-70% of acid-induced abnormalities in oxygenation, the increase in extravascular lung water, and extravascular protein accumulation. The anti-CD18 monoclonal antibody was associated with a significant increase in air space neutrophils by bronchoalveolar lavage, suggesting that the neutrophils respond normally to chemotactic stimuli but that the neutrophils did not injure the lung even though they accumulated in the air spaces. In summary, neutralization of CD18 attenuates the acute lung injury after acid instillation without reducing the number of neutrophils in the air spaces, suggesting that anti-CD18 therapy may be beneficial because of its capacity to reduce neutrophil activation.
Folkesson
H G
HG
Cardiovascular Research Institute, University of California, San Francisco 94143-0130, USA.
Matthay
M A
MA
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001773:Blood Cells / Q000166:cytology; D001794:Blood Pressure; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018821:CD18 Antigens / Q000276:immunology*; D002199:Capillary Permeability; D015633:Extravascular Lung Water / Q000378:metabolism; D006339:Heart Rate; D006851:Hydrochloric Acid; D006863:Hydrogen-Ion Concentration; D008171:Lung Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D016177:Macrophage-1 Antigen / Q000276:immunology*; D008297:Male; D010101:Oxygen Consumption; D011652:Pulmonary Circulation; D011817:Rabbits; D012119:Respiration
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D006851:Hydrochloric Acid