Monocyte Lung Retention During Normal Conditions (Health) and During Disease States (Endotoxemia): A Medical Application of Scale Modeling

Abstract

Under normal conditions blood monocytes flow through the capillary network of the lungs, but during certain conditions (infection, injury) they accumulate in the lungs and modulate pulmonary inflammatory and reparative processes via their elaboration of cytokines and growth factors. The mechanisms that regulate monocyte retention, accumulation, and migration in the lung microvasculature during these conditions are largely unknown. Endotoxemia is a condition that often precedes acute lung injury. We have previously shown in an in vivo rabbit model of LPS-induced endotoxemia, that monocyte lung retention is markedly increased (verses saline controls). It was hypothesized that initially lipopolysaccharide (LPS) would induce monocyte (7–10 μm diameter) lung retention by increasing monocyte stiffness and thus diminishing the cell’s ability to deform and transit the narrow pulmonary capillary network (6–8 μm diameter), and that later, LPS would induce CD18-dependent monocyte adhesion to lung vascular endothelium, prolonging their retention. These mechanisms were confirmed in vitro, in that LPS induced a rapid concentration-dependent increase in human monocyte stiffness, net filamentous actin (F-actin) assembly/organization, and retention in a filtration model simulating the pulmonary capillary network. These LPS-induced responses were dependent on the integrity of F-actin in that cytochalasin D, an agent that disrupts F-actin assembly, attenuated each of these processes. LPS, in a concentration- and time-dependent fashion, induced CD18-dependent and -independent human monocyte adhesion to unstimulated human endothelial cell monolayers in vitro. These in vitro mechanisms were active in vivo. Pretreatment of rabbit monocytes ex vivo with LPS enhanced their lung retention in vivo, suggesting that LPS was acting, in part, directly on monocytes. Initial monocyte lung retention in vivo during endotoxemia was attenuated by inhibiting monocyte F-actin assembly with cytochalasin D. Anti-CD18 antibodies caused only a slight decrease in initial monocyte lung retention in vivo, but led to a 90% inhibition of retention by 2 hrs. Control IgG had no effect. These data together suggest that initial lung retention of monocytes during endotoxemia is dependent on alterations in their stiffness and assembly/organization of F-actin, and that CD18-dependent adhesive mechanisms prolong monocyte lung retention during endotoxemia. Additional FDA-approved human studies have confirmed that monocytes marginate in the lungs of normal humans, and that altered monocyte accumulation occurs in patients with interstitial lung disease (including idiopathic pulmonary fibrosis-IPF).