JM Miotla, TJ Williams, PG Hellewell and PK Jeffery
Department of Lung Pathology, Royal Brompton: National Heart and Lung Institute, London, United Kingdom.

We have investigated the requirement of neutrophil emigration and the role for CD11b/CD18-mediated events in the experimental induction of acute lung injury. BALB/c mice received lipopolysaccharide (LPS) (3 mg/kg) intravenously (i.v.) 2 h prior to i.v. zymosan (10 mg/kg) and extravascular albumin accumulation was assessed after 30 min. Compared with saline-treated controls, zymosan alone caused a 6-fold increase in the accumulation of 125I-human serum albumin in whole lung tissue (P<0.05). Combined treatment with LPS and zymosan further increased extravascular albumin accumulation (P<0.05 compared with zymosan alone). The monoclonal antibody 5C6, directed against murine CD11b, was injected, 1 mg i.v. 15 min prior to LPS or 15 min before the zymosan, and compared with immunoglobulin G-injected controls. Albumin accumulation was significantly reduced by 5C6 when given prior to the LPS (P<0.01), but not when given before zymosan in the combined LPS and zymosan treatment. Interestingly, albumin accumulation induced by zymosan alone was not reduced by 5C6. The lungs of the mice treated with LPS and zymosan showed a marked, diffuse accumulation of inflammatory cells which, by light microscopy, appeared to be interstitial. Foci of neutrophil aggregates were seen in noncapillary microvessels, and pretreatment with 5C6 appeared to reduce their frequency. In the animals treated with zymosan alone, LPS alone, or LPS and zymosan in combination, electron microscopy established that approximately 25% of all nucleated cells were neutrophils: 99% of the neutrophils were restricted to the intravascular compartment. Pretreatment with 5C6 prior to LPS and zymosan treatment reduced the increase in percentage of neutrophils by half. These results indicate a disassociation between induction of permeability and neutrophil emigration in our murine model and suggest that the release of neutrophil-derived factors such as platelet-activating factor, proteases, or oxidants may be involved.

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