Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled?

Abstract

In response to infections or tissue injury, circulating leucocytes adhere to and migrate from the vessel lumen to interstitial inflammatory sites to combat invading pathogens. However, these defensive actions may also cause host tissue injury and microvascular dysfunction through oxidative bursts or enzyme release. For decades, the interaction between leucocytes and microvessel walls has been considered as a critical event leading to organ dysfunction. Extensive investigations have therefore focused on blocking specific adhesive ligands to prevent tissue injury. However, anti-adhesion therapies have shown limited success in preventing vascular dysfunction in clinical trials. Numerous studies have demonstrated temporal and spatial dissociations of leucocyte adhesion and/or emigration from permeability increases. The mechanisms that initiate the adhesion cascade have been found to be distinct from those that trigger the leucocyte oxidative burst responsible for increasing microvessel permeability. Recent studies demonstrated that endothelial activation by inflammatory mediators is critical for initiating platelet adhesion and platelet-dependent leucocyte recruitment resulting in augmented increases in microvessel permeability. These new developments suggest that targeting endothelial activation via directly enhancing endothelial barrier function might be a more efficient strategy than focusing on anti-adhesion or platelet/leucocyte depletion to prevent vascular damage during inflammation. Owing to space limitations and the wide range of studies in the field, this article will not serve as a comprehensive review. Instead, it will highlight the emerging evidence of adhesion-uncoupled permeability changes and establish a basis for re-evaluating the coupled relationship between leucocyte/platelet activation and microvessel permeability to achieve a better understanding of permeability regulation during inflammation.

Figure 1

Video images of a rat mesenteric venule before and after leucocyte adhesion induced by systemic application of TNF-α. TNF-α induced significant leucocyte adhesion (19 leucocytes/100 μm of vessel length, right image) without increasing microvessel permeability. The hydraulic conductivity (L_p) measured before (control, left image) and after leucocyte adhesion (right image) was 3.5 ± 0.3 and 3.6 ± 0.5 (SD) × 10⁻⁷ cm/s/cmH₂O, respectively. With a similar number of adherent leucocytes to that shown in the right image, the measured permeability coefficient to α-lactalbumin was also not altered from that of the control (from Zeng et al. and used with permission).

Figure 2

Electron micrographs demonstrating ultrastructural evidence of intimate contact between neutrophils (N) and endothelial cells (E) during entire emigration process in hamster cheek pouch venules exposed to LTB4 (L, vessel lumen; I, interstitium; P, pericyte process). (A) The emigrating neutrophil (N) is enveloped by endothelial cells during migration. (B) The centre neutrophil is partially emigrating through endothelial cells and the right neutrophil has completed emigration through the endothelial layer but is retained by pericyte process. (C) The extended endothelial cells at the luminal side are in the process of enveloping the trailing end of an emigrating neutrophil. (D) Endothelial cells reestablish the contact by forming a bridge on the luminal surface of an emigrated neutrophil, which exhibits an intact inter-endothelial junction (arrowhead). After crossing the endothelial layer of the vessel wall, the abluminal side of the emigrating neutrophil remains bordered by a pericyte process without directly reaching to the interstitium (modified from Lewis and Granger and used with permission).

Figure 3

Electron micrographs demonstrating PAF-induced endothelial gap formation and the exposed endothelial basal lamina in rat mesenteric venules. The top graph illustrates an intact endothelial junction from a microvessel perfused with albumin-Ringer's solution. The vessel shown in the bottom graph was perfused with PAF plus fluorescence microspheres (FM, 100 nm) for 10 min before fixation and demonstrates PAF-induced endothelial gap formation. The accumulated FMs at inter-endothelial junctions (arrows with a solid line) were retained by intact basal membrane underneath the gaps (arrows with a dotted line) that may be the initiation sites for platelet interaction (from Jiang et al. and used with permission).

Figure 4

Video images showing rat venules under control conditions (left panels) and after TNF-α and PAF application (right panels) with (A) and without (B) PAF-induced initial increases in microvessel permeability. (A) The addition of PAF that induces endothelial gap formation and a transient increase in permeability results in platelet/leucocyte aggregate adhesion to the vessel walls (the right image is one example), which was accompanied by a prolonged increase in L_p. (B) Applying isoproterenol, an agent that inhibits PAF-induced permeability increases, prior to TNF-α and PAF application changed the adhesion pattern from aggregated blood cells (right image in A) to single attached leucocytes (right image in B). L_p measured in the presence of single attached leucocytes showed no significant increase. These results support the hypothesis that an increase in permeability with formed endothelial gaps plays a key role in platelet adhesion and platelet/leucocyte aggregation, as well as the subsequent prolonged permeability increases (modified from He et al. and used with permission).