Exploring the pathophysiological mechanism of pulmonary edema focusing on the role of macrophages and their interaction with the glycocalyx: Using an immunological model of pulmonary edema induced by cognate anti-MHC antibody

Abstract

Abstract Background: Pulmonary tissue is protected from fluid leakage by an endothelial structural barrier, the glycocalyx (GCX). Once this barrier is disrupted, pulmonary edema rapidly develops. The depletion of the GCX is associated with leukocyte accumulation in the pulmonary vasculature, possibly causing the endothelial cells to become hyperpermeable. Whether neutrophils or macrophages are responsible for the development of pulmonary edema remains controversial. We used a mouse model of pulmonary edema induced by cognate anti-MHC antibody to explore the pathophysiological mechanism of pulmonary edema by examining the role of responsive neutrophils and macrophages and their interactions with the GCX.Methods: Anti-MHC class I antibody was administered intravenously to male BALB/c mice to induce pulmonary edema. Pulmonary edema was evaluated by measuring the wet-to-dry weight ratio of the lungs. Changes in the GCX were evaluated by electron microscopy and measurements of the serum level of soluble syndecan-1, a major GCX component. Heparin sulphate was administered to examine its protective effect on the GCX. Macrophages were depleted using clodronate to examine their role in the development of pulmonary edema. Results: The GCX of the pulmonary vascular endothelium degraded after the administration of an anti-MHC class I antibody, accompanied by an increase in the serum syndecan-1 and heparan sulfate levels. Macrophage depletion inhibited the development of pulmonary edema, and the administration of supplemental heparin, an inhibitor of heparan sulfate-degrading enzymes, suppressed the pulmonary edema. Conclusions: We demonstrated that the GCX is degraded in a mouse model of pulmonary edema induced by anti-MHC class I antibody. Macrophage depletion suppressed the development of the pulmonary edema. These results suggest that macrophages (and/or monocytes) may play a key role in pulmonary edema. Heparin inhibited both the degradation of the GCX in the pulmonary vascular endothelium and pulmonary edema. Our study may suggest an interventional mechanism for inhibiting pulmonary edema.