Mechanisms of Leukocyte Sequestration in Inflamed Lungs

Abstract

The lungs are an important site of host defense. The capillary blood contains an increased concentration of neutrophils and other leukocytes compared with large vessels, due to the structure of the pulmonary capillary bed, the diameter of spherical leukocytes, and their poor deformability compared with erythrocytes. During inflammation within the distal airways, neutrophils sequester within the pulmonary capillaries and emigrate into the parenchyma. This sequential process involves complex events regulating interactions between mechanical and adhesive properties of both neutrophils and endothelial cells. Initial changes in the cytoskeleton may stiffen the neutrophils and prevent them from deforming, while subsequent dynamic cytoskeletal remodeling of neutrophils and endothelial cells results in crawling and transendothelial migration. Emigration of neutrophils can occur through at least two adhesion pathways: one that requires the CD11/CD18 adhesion complex and one that does not. Which pathway is selected is determined by the stimulus and the signaling pathways that are initiated. Migration through the alveolo-capillary wall is also highly regulated. Neutrophils released from the bone marrow traffic first through the pulmonary microvasculature, and the phenotype of these newly released neutrophils impacts pulmonary host defense. The many recent studies underline the complexity of neutrophil responses and host defense and the uncertainties of our knowledge.

High-dose oral N -acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis

“…Oral NAC treatment likely decreases airway neutrophil count via multiple pathways. First, NAC can increase actin-dependent deformability (35), leading to reduced stasis in narrow lung capillaries (36). Second, NAC can inhibit the NF-B pathway (37), leading to decreased IL-8 production (as seen in a subset of patients), which can in turn limit neutrophil recruitment.…”

In situ Microrheological Determination of Neutrophil Stiffening Following Adhesion in a Model Capillary

“…This sequestration is a necessary and critical step for neutrophil migration through the capillaries to the site of inflammation. 5,9,13 Unlike the well-understood multistep adhesion cascade seen in post-capillary venules, in which adhesion molecules play an important role in leukocyte trafficking, most of the studies analyzing the effects of known biochemical mediators, have found no influence of adhesion molecules on the initial steps of sequestration. 1,17 It has, however, been found that once neutrophils became arrested in the lung capillaries during inflammation, adhesion molecules were required to keep them sequestered.…”

“…1,17 It has, however, been found that once neutrophils became arrested in the lung capillaries during inflammation, adhesion molecules were required to keep them sequestered. 5 The exact roles played by biochemical events and mechanical deformations, however, are not fully understood. 4 Decoupling the contributions of adhesion molecules and mechanical deformation is difficult.…”

“…Transit times for relatively undeformable neutrophils are 10-20 times longer than those for more deformable red blood cells. 5 Increased transit time is primarily responsible for the presence of a marginated pool of leukocytes in the lungs that is 20-60 times the concentration in systemic circulation. 5 Since the marginated pool is critical for the immediate inflammatory response to sepsis, it is also critical to understand the sequestration mechanism.…”

“…10 A blood cell must pass through about 40-100 segments while making its journey from an arteriole to venule. 5 Since the diameter of capillary segments (2-8 lm) is usually smaller than that of transiting blood cells, these cells undergo repeated deformation while passing through capillary beds. Transit times for relatively undeformable neutrophils are 10-20 times longer than those for more deformable red blood cells.…”