Early Endothelial Signaling Transduction in Developing Lung Edema

Abstract

The lung promptly responds to edemagenic conditions through functional adaptations that contrast the increase in microvascular filtration. This review presents evidence for early signaling transduction by endothelial lung cells in two experimental animal models of edema, hypoxia exposure, and fluid overload (hydraulic edema). The potential role of specialized sites of the plasma membranes considered mobile signaling platforms, referred to as membrane rafts, that include caveolae and lipid rafts, is presented. The hypothesis is put forward that early changes in the lipid composition of the bilayer of the plasma membrane might trigger the signal transduction process when facing changes in the pericellular microenvironment caused by edema. Evidence is provided that for an increase in the extravascular lung water volume not exceeding 10%, changes in the composition of the plasma membrane of endothelial cells are evoked in response to mechanical stimuli from the interstitial compartment as well as chemical stimuli relating with changes in the concentration of the disassembled portions of structural macromolecules. In hypoxia, thinning of endothelial cells, a decrease in caveolae and AQP-1, and an increase in lipid rafts are observed. The interpretation of this response is that it favors oxygen diffusion and hinder trans-cellular water fluxes. In hydraulic edema, which generates greater capillary water leakages, an increase in cell volume and opposite changes in membrane rafts were observed; further, the remarkable increase in caveolae suggests a potential abluminal–luminal vesicular-dependent fluid reabsorption.

A Methodological Approach to Identify Natural Compounds with Antifibrotic Activity and the Potential to Treat Pulmonary Fibrosis Using Single-Cell Sequencing and Primary Human Lung Macrophages

“…When tissue injury is transient, the fibrotic stage allows for the reorganization of the tissue architecture, after which the fibrotic lesions can be resolved. However, in the case of ongoing tissue injury in the lung due to either chronic infection, environmental insult, aberrant immune responses, genetic abnormalities such as telomeropathies [6], or microvasculature hyperpermeability (reviewed in [7,8]), fibrosis can continue to progress without resolution. Until now, it has been unclear if any of these different pathways converged at a point where common factors then continue to drive progressive and aberrant fibrosis in the lung.…”