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UBC Theses and Dissertations

Expression of leukocyte-endothelial adhesion molecules during acute inflammation in the lung Burns, Alan R.


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.

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