Bench-to-bedside review: acute respiratory distress syndrome - how neutrophils migrate into the lung

Abstract

Acute lung injury and its more severe form, acute respiratory distress syndrome, are major challenges in critically ill patients. Activation of circulating neutrophils and transmigration into the alveolar airspace are associated with development of acute lung injury, and inhibitors of neutrophil recruitment attenuate lung damage in many experimental models. The molecular mechanisms of neutrophil recruitment in the lung differ fundamentally from those in other tissues. Distinct signals appear to regulate neutrophil passage from the intravascular into the interstitial and alveolar compartments. Entry into the alveolar compartment is under the control of CXC chemokine receptor (CXCR)2 and its ligands (CXC chemokine ligand [CXCL]1-8). The mechanisms that govern neutrophil sequestration into the vascular compartment of the lung involve changes in the actin cytoskeleton and adhesion molecules, including selectins, beta2 integrins and intercellular adhesion molecule-1. The mechanisms of neutrophil entry into the lung interstitial space are currently unknown. This review summarizes mechanisms of neutrophil trafficking in the inflamed lung and their relevance to lung injury.

Figure 1

Neutrophil trafficking in the lung. Neutrophils (polymorphonuclear leukocytes [PMNs], colored blue) enter a pulmonary capillary (left). Because of the small diameter of the capillary, neutrophils must deform, which increases transit time ('margination') even under resting conditions (inset A: margination). In venules, adhesion molecule (AM)-dependent rolling can occur. In response to an inflammatory stimulus (red arrow), neutrophils adhere to the capillary endothelium (inset B: sequestration). AMs and chemokines (not shown) might be involved in this process. Alveolar macrophages and type II pneumocytes produce CXC chemokines, which attract neutrophils to migrate through the endothelium (inset C1: transendothelial migration), interstitial space, and epithelium (inset C2: transepithelial migration) to reach the alveolar space. The requirement of AMs for the different steps is dependent on the stimulus and the used model (see text for details). Arrows indicate directions of flow, and dashed lines indicate endothelial and epithelial basement membrane.