The bacterial endotoxin [lipopolysaccharide (LPS)]-binding protein CD14 modulates the host response to LPS, but membrane-associated and soluble forms of the molecule exert different biological effects. CD14 anchored to the mononuclear phagocyte membrane (mCD14) enhances response to LPS. Soluble CD14 (sCD14) may block LPS stimulation of CD14-bearing cells while supporting LPS presentation to non-CD14-bearing cells. We analyzed cell mCD14 and sCD14 expression in simultaneously collected human bronchoalveolar macrophages (BAM) and peripheral blood monocytes (PBM). Expression of mCD14 in freshly isolated BAM was only 9% as high as in PBM. Levels of sCD14 in 48 h in BAM culture supernatants were 19% as high as in PBM cultures. Interleukin (IL)-6 increased CD14 expression in both BAM and PBM but exerted different effects on CD14 distribution in these cell types. IL-6 increased only sCD14 release (2.5-fold) in BAM while increasing only mCD14 expression (2.5-fold) in PBM. IL-4 reduced both mCD14 (> 40%) and sCD14 (> 60%) expression in both cell types. We speculate that the balance between sCD14 and mCD14 expression influences the response to aspirated or inhaled LPS in the bronchoalveolar compartment. Cytokine expression and monocyte recruitment may influence this process by modulating CD14 expression.
Dipyridamole, an inhibitor of platelet aggregation, has been shown to have beneficial effects in disorders characterized by extravascular fibrin deposition. Mononuclear phagocytes are present in extravascular sites and are capable of expressing both plasminogen activator and procoagulant activities, which suggests these cells play a central role in extravascular fibrin turnover. We therefore sought to determine whether dipyridamole affects the expression of plasminogen activator and procoagulant activities by rabbit alveolar macrophages cultured in vitro. We found that dipyridamole (10 to 100 mumol/L) caused increases in both cell-associated and released plasminogen activator activity, which reached levels of 240% (P less than .05) and 543% (P less than .01) of controls, respectively. In contrast, dipyridamole decreased the cell-associated procoagulant activity of alveolar macrophages to as little as 21.3% of controls (P less than .01). Similar effects were seen in cells cotreated with lymphokines. The procoagulant activity expressed by these cells functioned as a tissue thromboplastin. The plasminogen activator of control and treated cells was a urokinase as determined by molecular weight characteristics (50 kilodaltons) and by antibody neutralization profiles using polyclonal antibodies against human urokinase and tissue plasminogen activator. These effects of dipyridamole could not be duplicated by structurally dissimilar agents sharing some of the pharmacological actions of dipyridamole; however, two pyrimidopyrimidine compounds structurally similar to dipyridamole effectively mimicked the effects on both procoagulant and plasminogen activator activities. We conclude that dipyridamole may have antithrombotic effects by directly modulating the role of mononuclear phagocytes in fibrin turnover. Thus, dipyridamole may be useful in situations where extravascular fibrin deposition is important to the pathogenesis of tissue injury and repair.
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