The effect of heparins on plasma concentration of heparin-binding protein: a pilot study.

Background: Neutrophil-derived heparin-binding protein (HBP) plays a role in the pathophysiology of impaired endothelial dysfunction during inflammation. HBP has been suggested as a predictor of organ dysfunction and disease progression in sepsis. We investigated the effects of heparins on plasma concentrations of HBP in patients undergoing surgery.

Heparinoid sevuparin inhibits -induced vascular leak through neutralizing neutrophil-derived proteins.

Acute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as group A (GAS). In the pathogenesis of sepsis-associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil-induced lung plasma leakage in a murine model of systemic inflammation evoked by heat-killed GAS (hkGAS).

Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak.

The Nuclear Receptor LXR Limits Bacterial Infection of Host Macrophages through a Mechanism that Impacts Cellular NAD Metabolism.

Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages.

Tandem Benzophenone Amino Pyridines, Potent and Selective Inhibitors of Human Leukotriene C4 Synthase.

Cysteinyl leukotrienes (cys-LTs) are lipid mediators of inflammation. The enzyme catalyzing synthesis of cys-LTs, leukotriene C4 synthase (LTC4S), is considered an important drug target. Here we report the synthesis and characterization of three tandem benzophenone amino pyridines as inhibitors of LTC4S in vitro and in vivo.

Assessing large-vessel endothelial permeability using near-infrared fluorescence imaging--brief report.

Objective: Loss of endothelial barrier function in arterial blood vessels is characteristic of vascular pathologies, including atherosclerosis. Here, we present a near-infrared fluorescence (NIRF) imaging methodology for quantifying endothelial permeability and macromolecular uptake in large arteries in the mouse and evaluate its applicability for studying mechanisms of vascular inflammation.

Approach And Results: To validate the NIRF methodology, macrovascular inflammation was induced in C57bl/6 mice by local tumor necrosis factor-α stimulation of the carotid artery or in apolipoprotein E-deficient mice by Western diet for 4 weeks.

Complexity of antimicrobial peptide regulation during pathogen-host interactions.

Antimicrobial peptides (AMPs) are a key component of the immune system and are expressed by a large variety of organisms. AMPs are capable of eliminating a broad range of micro-organisms, illustrated by murine models where lack of AMP expression resulted in enhanced susceptibility to infection. Despite the importance of AMPs in immune defences, it is not clear whether a change in AMP expression is pathogen-specific or reflects a general response to groups of pathogens.

Alteration of Leukocyte Count Correlates With Increased Pulmonary Vascular Permeability and Decreased PaO2:FiO2 Ratio Early After Major Burns.

Leukocytes are activated systemically and their numbers increase soon after a burn followed by a rapid decline to low normal or subnormal levels, possibly by increased extravasation. Experimental data support that an important target for such extravasation is the lungs and that leukocytes when they adhere to endothelial cells cause an increase in vascular permeability. The authors investigated a possible relation between early increased pulmonary vascular permeability or a decreased PaO2:FiO2 ratio and the dynamic change in concentration of blood leukocytes after a burn.

Cathelicidin LL-37 induces time-resolved release of LTB4 and TXA2 by human macrophages and triggers eicosanoid generation in vivo.

In humans, LL-37 and eicosanoids are important mediators of inflammation and immune responses. Here we report that LL-37 promotes leukotriene B4 (LTB4) and thromboxane A2 (TXA2) generation by human monocyte-derived macrophages (HMDMs). LL-37 evokes calcium mobilization apparently via the P2X7 receptor (P2X7R), activation of ERK1/2 and p38 MAPKs, as well as cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase in HMDMs, leading to an early (1 h) release of LTB4.

Vitamin D₃ and phenylbutyrate promote development of a human dendritic cell subset displaying enhanced antimicrobial properties.

A promising strategy in the fight against multidrug-resistant pathogens is the induction of endogenous AMPs, with compounds such as VitD₃ and PBA. These compounds display an array of immunomodulatory effects that remain to be investigated in further detail to establish their role in the clearance of infection and possible modulation of AMP expression. Here, we have investigated the effects of VitD₃ and PBA on human monocyte-DC differentiation and found that VitD₃ and PBA promote the development of a stretched CD14⁺/CD1a⁻ DC subset.

Antimicrobial peptide LL-37 promotes bacterial phagocytosis by human macrophages.

LL-37/hCAP-18 is the only human member of the cathelicidin family and plays an important role in killing various pathogens, as well as in immune modulation. In this study, we investigated the effect of LL-37 on bacterial phagocytosis by macrophages and demonstrate that LL-37 enhances phagocytosis of IgG-opsonized Gram-negative and Gram-positive bacteria in a dose- and time-dependent manner by dTHP-1 cells. In addition, LL-37 enhanced phagocytosis of nonopsonized Escherichia coli by human macrophages.

Cathelicidin LL-37 induces angiogenesis via PGE2-EP3 signaling in endothelial cells, in vivo inhibition by aspirin.

Objective: LL-37, the unique cathelicidin expressed in humans, in addition to acting as an endogenous antibiotic, is an important cell-signaling molecule upregulated in ovarian, breast, and lung tumors. However, the role of LL-37 in tumor microenvironment and its specific actions on the endothelial compartment remain elusive. Prostanoids are key regulators of inflammation, and cyclooxygenases (COXs) display proangiogenic activity in vitro and in vivo, mediated principally through prostaglandin E2 (PGE2).

Heparin binding protein in patients with acute respiratory failure treated with granulocyte colony-stimulating factor (filgrastim)--a prospective, placebo-controlled, double-blind study.

Background: Heparin Binding Protein (HBP) is released to blood circulation from activated neutrophils in bacterial infections. It is a potential inducer of vascular leakage and precludes the development of septic shock. Filgrastim induces the production of new neutrophils and modulates their bacterial-killing activity.

Neutrophil-derived cathelicidin promotes adhesion of classical monocytes.

Rationale: The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood.

Induction of the human cathelicidin LL-37 as a novel treatment against bacterial infections.

As traditional antibiotics gradually become inefficient, there is a high demand for development of anti-infectives with a mechanism of action that is different from existing antibiotics. Current antibiotics target the pathogen directly, thereby contributing to the selection of multidrug-resistant bacterial strains. AMPs, such as the human cathelicidin LL-37, are small cationic peptides that are part of host defense.

Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice.

Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear.

Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury.

Impaired release of antimicrobial peptides into nasal fluid of hyper-IgE and CVID patients.

Background: Patients with primary immunodeficiency (PID) often suffer from frequent respiratory tract infections. Despite standard treatment with IgG-substitution and antibiotics many patients do not improve significantly. Therefore, we hypothesized that additional immune deficits may be present among these patients.

Anesthesia aggravates lung damage and precipitates hypotension in endotoxemic sheep.

Beneficial anti-inflammatory properties have been ascribed to volatile anesthetics in septic conditions, but no studies have compared anesthesia to the conscious state in a large-animal model. The aim of this study was to investigate the effect of isoflurane anesthesia on cardiovascular and respiratory function, leukocyte activation, and lung damage in a model of endotoxemia in sheep. Conscious (n = 6) and anesthetized (n = 6) sheep were made endotoxemic by continuous infusion of LPS for 48 h.

Phagocyte partnership during the onset and resolution of inflammation.

Neutrophils, monocytes and macrophages are closely related phagocytic cells that cooperate during the onset, progression and resolution of inflammation. This Review highlights the mechanisms involved in the intimate partnership of phagocytes during each progressive phase of the inflammatory response. We describe how tissue-resident macrophages recognize tissue damage to promote the recruitment of neutrophils and the mechanisms by which infiltrating neutrophils can then promote monocyte recruitment.

Immune cell recruitment to inflammatory loci is impaired in mice deficient in basement membrane protein laminin alpha4.

For leukocytes to penetrate the vessel wall, they need to interact sequentially with the endothelial lining and the perivascular BM. The matrix protein laminin-411 is a major constituent of the vascular BM. The laminin alpha4 chain is a component of laminin-411 and has structural and signaling functions.

Distinct infiltration of neutrophils in lesion shoulders in ApoE-/- mice.

Inflammation and activation of immune cells are key mechanisms in the development of atherosclerosis. Previous data indicate important roles for monocytes and T-lymphocytes in lesions. However, recent data suggest that neutrophils also may be of importance in atherogenesis.

Neutrophil granule proteins tune monocytic cell function.

Polymorphonuclear leukocytes (PMNs) release the contents of granules during their migration to inflammatory sites. On liberation from the first leukocyte to enter injured tissue, the granule proteins play a central role in the early inflammatory response. In particular, mononuclear phagocytes interact intimately with PMNs and their secretion products.

Mechanisms underlying neutrophil-mediated monocyte recruitment.

Extravasation of polymorphonuclear leukocytes (PMNs) to the site of inflammation precedes a second wave of emigrating monocytes. That these events are causally connected has been established a long time ago. However, we are now just beginning to understand the molecular mechanisms underlying this cellular switch, which has become even more complex considering the emergence of monocyte subsets, which are affected differently by signals generated from PMNs.

Neutrophil-derived heparin binding protein--a mediator of increased vascular permeability after burns?

Increased vascular permeability and oedema formation constitute a major clinical challenge following burns. Several clinical studies show that leukocytes are systemically activated following burns. Neutrophils have the capability to increase vascular permeability via mechanisms thought to involve the release of heparin binding protein (HBP).

Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases.

Junctional adhesion molecule A (JAM-A) is a transmembrane adhesive glycoprotein that participates in the organization of endothelial tight junctions and contributes to leukocyte transendothelial migration. We demonstrate here that cultured endothelial cells not only express a cellular 43-kDa variant of JAM-A but also release considerable amounts of a 33-kDa soluble JAM-A variant. This release is enhanced by treatment with proinflammatory cytokines and is associated with the down-regulation of surface JAM-A.