Expression of leukocyte-endothelial adhesion molecules during acute inflammation in the lung

Neutrophil (PMN)-endothelial cell adhesion is a critical step in the response of PMNsto inflammation. In the systemic circulation, the leukocyte adhesion molecule, L-selectin, facilitates PMN adhesion to inflamed endothelium while CD11/CD18 is required for PMN emigration into extravascular tissues. An inducible endothelial ligand for CD18 is intercellular adhesion molecule-1 (ICAM-1). In the pulmonary circulation, PMNs emigrate by either a CD 18-independent or CD 18-dependent mechanism. The objective of this thesis was to quantitate and compare the surface expression of L-selectin, CD 18, and ICAM-1 during CD18-independent and CD 18-dependent emigration. Rabbits and mice received airway instillates of Streptococcus pneumoniae or Escherichia coil endotoxin to induce CD 18-independent or CD18-dependent emigration, respectively. Ultra thin cryosections of frozen lung were immunogold labeled for L-selectin, CD 18, and ICAM-1. Gold particles on the plasma membranes were quantitated by transmission electron microscopy. In rabbits, CD 18-independent emigration was associated with L-selectin down modulation and CD18 up modulation on intravascular PMNs.A similar alteration of L-selectin and CD18 expression was observed during CD 18-dependent emigration but only after PMNs emigrated into the interstitium. Alterations in L-selectin and CD18 expression were only observed on PMNs within the inflammatory focus. In mice, capillary endothelial ICAM-1 expression was unchanged during CD 18-independent emigration. During CD 18-dependent emigration, ICAM-1 expression increased 4.2-fold and this increase bordered on statistical significance, suggesting that the mechanism of adhesion may be regulated by the expression of endothelial rather than PMN adhesion molecules. ICAM-1 was also constitutively expressed on alveolar Type I but not Type II pneumocytes, the precursors of Type I cells. During pneumonia, Type II but not Type I pneumocytes showed increasedICAM-1 expression, suggesting that ICAM-1 expression represents an early event in differentiation preceding proliferation. In vitro studies of unstimulated human PMNs showed that L-selectin was preferentially expressed on the PMN surface microvilli that mediate initial contact with endothelium. During transendothelial migration, L-selectin down modulation is temporally correlated with PMN-endothelial contact. These studies describe the ultrastructural localization of adhesion molecules in normal and inflamed lungs and increase our understanding of the correlation between expression and function of adhesion molecules.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat