New insights into the mechanisms of pulmonary edema in acute lung injury

Abstract

Appearance of alveolar protein-rich edema is an early event in the development of acute respiratory distress syndrome (ARDS). Alveolar edema in ARDS results from a significant increase in the permeability of the alveolar epithelial barrier, and represents one of the main factors that contribute to the hypoxemia in these patients. Damage of the alveolar epithelium is considered a major mechanism responsible for the increased pulmonary permeability, which results in edema fluid containing high concentrations of extravasated macromolecules in the alveoli. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of pro-coagulant processes, cell death and mechanical stretch. The disruption of tight junction (TJ) complexes at the lateral contact of epithelial cells, the loss of contact between epithelial cells and extracellular matrix (ECM), and relevant changes in the communication between epithelial and immune cells, are deleterious alterations that mediate the disruption of the alveolar epithelial barrier and thereby the formation of lung edema in ARDS.

Keywords: Lung injury; alveolar epithelial barrier; mechanisms; pulmonary edema; tight junctions (TJs).

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1

Characteristic radiological and histopathological findings in patients with acute respiratory distress syndrome (ARDS). (A) Chest X-ray shows diffuse and bilateral infiltrates in a patient that fulfills criteria of ARDS; (B) representative lung tissue sections obtained in autopsies from critically-ill patients without ARDS (control group) or in patients with a clinical diagnosis of ARDS showing the anatomopathological diagnosis of diffuse alveolar damage (DAD). Hematoxylin-eosin staining shows DAD characterized by leukocyte infiltrates, increased thickness of the alveolar wall, endothelial cell damage, loss of alveolar epithelial cells with deposition of hyaline membranes on the denudated basement membrane (arrow), flooding of airspaces by protein-rich edema fluid (arrow head), alveolar hemorrhage and vascular congestion and microthrombi. (Original magnification, 40×).

Figure 2

Increased alveolar permeability to high molecular-weight plasma proteins in acute respiratory distress syndrome (ARDS). Representative lung tissue sections obtained in autopsies from critically-ill patients without ARDS (control group) or in patients with a clinical diagnosis of ARDS showing the anatomopathological diagnosis of diffuse alveolar damage (DAD). The images correspond to merged signals of immunofluorescence labeled IgM (pink signal, originally 488 nm wavelength), DAPI staining of nuclei (light blue signal, originally 358 nm wavelength) and light microscopy of the alveolar structure obtained by differential interference contrast (DIC). Left images show IgM (pink signal) restrained within the alveolar walls in a control lung. Right images show plasma IgM extravasation (pink signal) in alveolar airspaces of a patient with ARDS-DAD. (Original magnification, 20× and 40×).

Figure 3

Schematic of alveolar epithelium and intercellular tight junction (TJ) structure. Squamous alveolar type I (AT-I) and cuboidal alveolar type II (AT-II) cells conform the alveolar epithelium. The tight junctions between adjacent AT-I cells are narrower than those between AT-I and AT-II cells. Occludin, claudins (cldn-3, -4 and -18) and ZOs proteins are expressed in both cells, but with different claudin expression patterns. AT-I: Cldn-18>cldn-3>cldn-4. Type II: cldn-3>cldn-4>cldn-18 (27). ECM, extracellular matrix; JAMs, junctional adhesion molecules.