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Leukocyte adhesion to endothelium in inflammation

Affinity membrane is widely employed to promote specific adsorption of toxins and reduce the blood purification therapeutic time. However, it suffers from insufficient toxin binding and low hemocompatibility. Herein, a novel anticoagulant affinity membrane (AAM) was developed to clear bilirubin from human blood in a pore-flow-through way. Firstly, a nylon net membrane with a regularly arranged pore as the matrix was coated with poly(pyrrole-3-carboxylic acid) via chemical vapor deposition (CVD) method. Then, poly(L-arginine) (PLA) as a highly specific ligand of bilirubin, was immobilized onto the surface of the composited membrane after the modification of heparin. Owing to the 3-dimensional molecular architecture of PLA, up to 86.1 % of bilirubin was efficiently cleared. Besides, the AAM exhibited effective anticoagulant activity in the measurement of clotting time, with suppressed thrombus formation, low hemolysis ratio, minimized platelet and leukocyte adhesion, and excellent biosafety. Therefore, the AAM has enormous potential in blood purification therapy for enhancing hemocompatibility and bilirubin removal.

Renal homeostasis is regulated by the interplay among different cell types in the kidneys including endothelial cells. In the present study we investigated the phenotypic regulation of endothelial cells by BRG1, a chromatin remodeling protein, in a mouse model of obstructive nephropathy (ON). We report that endothelial-specific deletion of BRG1 attenuated renal inflammation induced by unilateral ureteral tract obstruction (UUO) in mice, as evidenced by down-regulation of pro-inflammatory cytokines and diminished infiltration of immune cells. Moreover, endothelial BRG1 deficiency suppressed UUO-induced renal fibrosis in mice as measured by expression of pro-fibrogenic genes, picrosirius red staining of collagenous tissues, and quantification of hydroxylproline levels. Mechanistically, BRG1 activated the transcription of adhesion molecules and chemokines in endothelial cells by recruiting histone modifying enzymes leading to macrophage adhesion and chemotaxis. In conclusion, we propose that epigenetic regulation of endothelial function by BRG1 may play an active role in ON pathogenesis.

Human milk oligosaccharides (HMOs) possess antimicrobial activity against a number of bacterial pathogens. HMOs prevent infection by serving as decoy receptors that competitively bind pathogens thus preventing pathogen attachment to host epithelial cell receptors. In a second mechanistic pathway, we recently demonstrated that heterogenous HMO extracts exert antimicrobial action against Group B Streptococcus by increasing cellular permeability. As human milk contains ca. 200 unique glycans however, our understanding of which pharmacophores are most important to HMO antimicrobial activity remains immature. In the present study, we describe the first evaluation of the antimicrobial and antibiofilm activities of five structurally defined, ubiquitous sialylated HMOs against Group B Streptococcus.

Bumetanide is a potent loop diuretic that acts as an inhibitor of sodium-potassium-chloride cotransporter 2 (NKCC2) and its isoform NKCC1. Although the expression of NKCC2 is limited to the kidney, NKCC1 is widely expressed in various cells, where it participates in a variety of physiological functions including ion transport, alveolar fluid secretion, and cell volume regulation. We investigated the role of NKCC1 in modulation of host immunity. Lipopolysaccharide (LPS) stimulated the expression and phosphorylation of NKCC1 in RAW264.7 cells in vitro and activated these cells to produce inflammatory cytokines. Enlarging the cell volume in a low-osmotic microenvironment amplified the LPS-induced inflammatory responses and phagocytosis activity of RAW264.7 cells. Pretreatment with the NKCC1 inhibitor bumetanide attenuated LPS-induced activation of inflammatory cells and cell volume-related function. Mice treated with an intratracheal bumetanide spray showed greater resistance to LPS-induced tissue inflammation and acute lung injury in vivo. Our studies suggest that NKCC1 plays a unique role as an amplifier of LPS-induced macrophage functions and that NKCC1 might be a novel target for treating sepsis-related acute respiratory distress syndrome.