Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte–endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice

Abstract

Thorlacius, H. (2013). Direct in vivo observations of P-selectin glycoprotein ligand-1-mediated leukocyte-endothelial cell interactions in the pulmonary microvasculature in abdominal sepsis in mice. Inflammation Research, 62(3), 275-282. DOI: 10.1007/s00011-012-0575-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal AbstractObjective P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to play a significant role in septic lung injury. However, the detailed role of PSGL-1 in the pulmonary leukocyte recruitment remains elusive. We have developed a method based on intravital fluorescence microscopy of the lung microcirculation to examine the role of PSGL-1 in the extravasation process of leukocytes in septic lung damage.Methods Male C57BL/6 mice were treated with a control antibody or an anti-PSGL-1 antibody prior to cecal ligation and puncture (CLP). Leukocyte-endothelium interactions and microvascular hemodynamics were studied in pulmonary arterioles, capillaries and venules 4 hours after CLP.Results Immunoneutralization of PSGL-1 decreased CLP-induced leukocyte rolling in pulmonary arterioles and venules significantly. Inhibition of PSGL-1 had no effect on leukocyte adhesion in venules, whereas the number of adherent leukocytes in lung arterioles and the number of trapped leukocytes in capillaries were markedly decreased. Moreover, immunoneutralization of PSGL-1 improved microvascular perfusion in the lung of septic animals.Conclusions Taken together, these results document that PSGL-1 mediates leukocyte rolling in arterioles and venules. However, inhibition of PSGL-1 only decreases leukocyte adhesion in arterioles, suggesting that leukocyte rolling is not a prerequisite for pulmonary venular adhesion of leukocytes in sepsis. In addition, our data show that capillary trapping of leukocytes is dependent on PSGL-1 function.

Proinflammatory role of neutrophil extracellular traps in abdominal sepsis

“…Together, these findings suggest that NETs are a potent inducer of systemic inflammation in abdominal sepsis. It is well established that neutrophil infiltration is a ratelimiting step in septic lung injury (23,47,55). It was therefore of great interest to study the effect of NET depletion on neutrophil infiltration in septic lung damage in the present study.…”

“…In this context, it is important to note that DNAse treatment exerted no direct effect on neutrophil functions, such as CXCL2-induced Mac-1 upregulation and chemotaxis. Pulmonary recruitment of leukocytes is a multistep process, including initial sequestration in microvessels and firm adhesion on the endothelium, followed by transendothelial and transepithelial migration (47,55,56). Trafficking of leukocytes in inflamed tissues is coordinated by secreted chemokines (40,51).…”

Increased Soluble VCAM-1 and Normal P-Selectin in Cystic Fibrosis: a Cross-Sectional Study

“…Its major ligands include P-selectin glycoprotein ligand-1 and TIM-1—T cell immunoglobulin and mucin domain 1 [62, 63]. The role of sP-selectin in atherosclerosis development and its association with the risk of venous thromboembolism is supported by studies of SELP polymorphisms [64, 65] and research in animal models [66].…”

The Role of Tyrosine Phosphorylation of Protein Kinase C Delta in Infection and Inflammation

“…During sepsis, systemic inflammation leads to increased adhesion molecule expression on neutrophils and endothelial cells, resulting in increased neutrophil-endothelial cell interaction, vascular endothelial damage, and organ dysfunction [108,109,110]. While neutrophils are critical to host defense, neutrophil dysregulation has a critical role in the early course of organ damage through the release of proteases, neutrophil extracellular traps (NETs), and oxygen radicals.…”