Rat pulmonary cyclooxygenase-2 expression in response to endotoxin challenge - Differential regulation in the various types of cells in the lung

Cyclooxygenase (Cox), the key enzyme of prostanoid synthesis, consists of t he two isoforms Cox-1 and Cox-2, both recently noted to be constitutively e xpressed in rat lungs with a distinct profile of cellular distribution. The responsiveness of pulmonary Cox-1 and Cox-2 expression to intravascular en dotoxin lipopolysaccharide (LPS) administration was investigated in isolate d, ventilated rat lungs, buffer-perfused with or without admixture of rat p lasma. Immunohistochemical staining intensity was measured by a previously described method of silver enhancement and epipolarization image analysis, Both the Cox-1 mRNA, quantified in the whole lung homogenate, and the cellu lar localization of Cox-1 were unchanged in response to LPS, In contrast, t ime- and dose-dependent up-regulation of Cox-2 mRNA (lung homogenate) occur red, and differential LPS reactivity at the cellular level was observed. Up -regulation of Cox-2 in cell types expressing this enzyme already under bas eline conditions was noted in bronchial epithelial cells, bronchial and vas cular smooth muscle cells, cells within the BALT and myocytes of the large hilar veins. De novo induction of Cox-2 occurred in endothelial cells and t he majority of alveolar macrophages. Down-regulation of Cox-2 was observed in perivascular and peribronchial macrophage-like cells. Moreover, differen tial impact of plasma components was noted: for the large majority of cells , CD14 surface expression correlated with Cox-2 responsiveness to LPS indep endent of plasma, whereas the presence of plasma components was a prerequis ite for the LPS response in CD14-negative cells. LPS did not provoke physio logical changes in the perfused lungs, but markedly enhanced baseline prost anoid generation. We conclude that LPS-induced Cox-2 regulation occurs in a complex, cell-specific manner, which may be relevant for pathogenetic sequ elae in septic lung injury and acute respiratory failure.