NDLI: Leukadherin-1 ameliorates endothelial barrier damage mediated by neutrophils from critically ill patients

Content Provider	Springer Nature : BioMed Central
Author	Dickinson, Catherine M. LeBlanc, Brian W. Edhi, Muhammad M. Heffernan, Daithi S. Faridi, Mohd. Hafeez Gupta, Vineet Cioffi, William G. O’Brien, Xian Reichner, Jonathan S.
Abstract	Background Multi-organ failure occurs during critical illness and is mediated in part by destructive neutrophil-to-endothelial interactions. The β2 integrin receptor, CR3 (complement receptor 3; Mac-1; CD11b/CD18), which binds endothelial intercellular adhesion molecule-1 (ICAM-1), plays a key role in promoting the adhesion of activated neutrophils to inflamed endothelia which, when prolonged and excessive, can cause vascular damage. Leukadherin-1 (LA-1) is a small molecule allosteric activator of CR3 and has been shown to promote adhesion of blood neutrophils to inflamed endothelium and restrict tissue infiltration. Therefore, LA-1 offers a novel mechanism of anti-inflammatory action by activation, rather than inhibition, of the neutrophil CR3 integrin. However, whether promotion of neutrophil-to-endothelial interaction by this novel therapeutic is of benefit or detriment to endothelial barrier function is not known. Methods Critically ill septic and trauma patients were prospectively enrolled from the surgical and the trauma ICU. Blood was collected from these patients and healthy volunteers. Neutrophils were isolated by dextran sedimentation and adhered to TNF-α (tumor necrosis factor-α)-activated human umbilical vein endothelial (HUVEC) monolayers in the presence or absence of fMLP (formylmethionine-leucine-phenylalanine) and/or LA-1. Electric cell-substrate impedance sensing (ECIS) and exposure of underlying collagen were used to quantify endothelial barrier function and permeability. Results Neutrophils from critically ill trauma and septic patients caused similar degrees of endothelial barrier disruption which exceeded that caused by cells obtained from healthy controls both kinetically and quantitatively. LA-1 protected barrier function in the absence and presence of fMLP which served as a secondary stimulant to cause maximal loss of barrier function. LA-1 protection was also observed by quantifying collagen exposure underlying endothelial cells challenged with fMLP-stimulated neutrophils. LA-1 treatment resulted in decreased migration dynamics of neutrophils crawling on an endothelial monolayer with reduced speed (μm/s = 0.25 ± 0.01 vs. 0.06 ± 0.01, p < 0.05), path length (μm = 199.5 ± 14.3 vs. 42.1 ± 13.0, p < 0.05), and displacement (μm = 65.2 ± 4.7 vs. 10.4 ± 1.3; p < 0.05). Conclusion Neutrophils from patients with trauma or sepsis cause endothelial barrier disruption to a similar extent relative to each other. The CR3 agonist LA-1 protects endothelial barrier function from damage caused by neutrophils obtained from both populations of critically ill patients even when exposed to secondary stimulation.
Related Links	https://jintensivecare.biomedcentral.com/counter/pdf/10.1186/s40560-018-0289-5.pdf
Ending Page	10
Page Count	10
Starting Page	1
File Format	HTM / HTML
ISSN	20520492
DOI	10.1186/s40560-018-0289-5
Journal	Journal of Intensive Care
Issue Number	1
Volume Number	6
Language	English
Publisher	BioMed Central
Publisher Date	2018-03-15
Access Restriction	Open
Subject Keyword	Intensive Critical Care Medicine Neutrophil Endothelium Barrier function Sepsis Trauma Leukadherin-1
Content Type	Text
Resource Type	Article
Subject	Critical Care and Intensive Care Medicine
Journal Impact Factor	3.8/2023
5-Year Journal Impact Factor	4.6/2023

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