LIPOLYSACCHARIDE-INDUCED MONOCYTE RETENTION IN THE LUNG ROLE OF MONOCYTE STIFFNESS, ACTIN ASSEMBLY, AND CD18-DEPENDENT ADHERENCE

Blood monocytes and monocyte-derived macrophages accumulate in the lun gs and can modulate pulmonary inflammatory and reparative processes th rough their elaboration of cytokines and growth factors. Endotoxemia, often a prelude to acute lung injury, induces a monocytopenia, likely resulting from monocyte accumulation in the lung. We hypothesized that LPS would induce monocyte lung retention by increasing monocyte stiff ness and thereby diminishing the cell's ability to deform and transit the narrow pulmonary capillary network, and that LPS would induce CD18 -dependent adhesion of monocytes to endothelium, prolonging their rete ntion. LPS induced a rapid and concentration-dependent increase in hum an monocyte stiffness, net filamentous actin assembly, and retention i n a filtration model of pulmonary capillaries. These LPS-induced respo nses were dependent on the integrity of actin filaments in that cytoch alasin D, an agent that disrupts filamentous actin assembly, attenuate d each of these processes. LPS induced CD18-dependent and -independent human monocyte adhesion to unstimulated human endothelial cell monola yers. In vivo, rabbit monocytes were retained in the lungs of animals rendered endotoxemic. Pretreatment of monocytes ex vivo with LPS enhan ced their lung retention suggesting that LPS was acting directly on mo nocytes. Initial rung retention during endotoxemia was attenuated by i nhibiting monocyte F-actin assembly with cytochalasin D. Anti-CD18 Abs caused a slight decrease in initial retention of monocytes, but led t o a 90% inhibition of retention by 2 h. Control IgG had no effect. The se data suggest that the initial retention of monocytes in the lung du ring endotoxemia is dependent on alterations in their stiffness and as sembly/organization of F-actin, and that CD18-dependent adhesive mecha nisms prolong monocyte retention in the lung during this process.