Thrombin and vascular inflammation

Vascular endothelium is a key regulator of homeostasis. In physiological conditions it mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. However, endothelial dysfunction caused by physical injury of the vascular wall, for example during balloon angioplasty, acute or chronic inflammation, such as in atherothrombosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites. At the same time, the dysfunction promotes thrombin generation, fibrin deposition, and coagulation. The serine protease thrombin plays a pivotal role in the coagulation cascade. However, thrombin is not only the key effector of coagulation cascade; it also plays a significant role in inflammatory diseases. It shows an array of effects on endothelial cells, vascular smooth muscle cells, monocytes, and platelets, all of which participate in the vascular pathophysiology such as atherothrombosis. Therefore, thrombin can be considered as an important modulatory molecule of vascular homeostasis. This review summarizes the existing evidence on the role of thrombin in vascular inflammation.     

CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease

CD40 ligand (CD40L) and its receptor CD40 participate in numerous inflammatory pathways that contribute to multiple pathophysiological processes. A role for CD40-CD40L interactions has been identified in atherosclerosis, and such interactions are known to destabilize atherosclerotic plaques by inducing the expression of cytokines, chemokines, growth factors, matrix metalloproteinases and pro-coagulant factors. The CD40-CD40L interaction has also been implicated in immune system disorders. Recent studies have suggested that CD40-CD40L interactions regulate oxidative stress and affect various signaling pathways in both the immunological and cardiovascular systems. Here, we discuss the emerging role of CD40-CD40L-mediated processes in oxidative stress, inflammatory pathways and vascular diseases. Understanding the roles and regulation of CD40-CD40L-mediated oxidative signaling in immune and non-immune cells could facilitate the development of therapeutics targeting diverse inflammatory diseases.     

Selectin-carbohydrate interactions during inflammation and metastasis

L-, E-, and P-selectin are membrane-anchored, C-type lectins that initiate tethering and rolling of flowing leukocytes on endothelial cells, platelets, or other leukocytes during inflammation. The selectins bind to sialylated, fucosylated, or, in some cases, sulfated glycans on glycoproteins, glycolipids, or proteoglycans. However, they bind with relatively high affinity or avidity to only a few, appropriately modified glycoproteins on leukocytes or endothelial cells. One leukocyte mucin, PSGL-1, tethers flowing leukocytes to P-selectin on activated platelets or endothelial cells, and also helps tether leukocytes to L-selectin on other leukocytes. The physiologic expression of the selectins is tightly controlled to limit the inflammatory response. But dysregulated expression of the selectins may contribute to inflammatory and thrombotic disorders, and perhaps to tumor metastases. This revised version was published online in November 2006 with corrections to the Cover Date.     

The neutrophil in vascular inflammation

Here we focus on how neutrophils have a key regulatory role in vascular inflammation. Recent studies using advanced imaging techniques have yielded new insights into the mechanisms by which neutrophils contribute to defense against bacterial infections and also against sterile injury. In these settings, neutrophils are recruited by various mechanisms depending on the situation. We also describe how these processes may be disrupted in systemic infections, with a particular emphasis on mouse models of sepsis. Neutrophils are often immobilized in the lungs and liver during systemic infections, and this immobilization may be a mechanism through which bacteria can evade the innate immune response or allow neutrophils to form neutrophil extracellular traps that trap and kill bacteria in blood. The platelet is also an important player in sepsis, and we describe how it collaborates with neutrophils in the formation of neutrophil extracellular traps.     

Interleukin 17 in vascular inflammation

Interleukin (IL)-17 (also known as IL-17A) is produced by activated T cells. It is a marker cytokine of the T(H??) lineage. IL-17 production is induced in infections, autoimmune diseases and other inflammatory events. IL-17 is involved in host defense, but also inflammatory tissue destruction. Vascular disease, mostly in the chronic form of atherosclerosis, is a leading cause of death. While normal vessels harbor only few leukocytes, large numbers of both innate and adaptive immune cells accumulate during vascular inflammation, both in chronic forms such as atherosclerosis and in acute vasculitis. IL-17 has a role in chronic vascular inflammation of atherosclerosis and possibly hypertensive vascular changes. In acute inflammation, IL-17 is elevated and may be causally involved in the autoimmune vasculitides including vasculitis in systemic lupus erythematodes. Blood vessels are important targets in alloimmune graft rejection and a number of studies provide data on a role of IL-17 in this context. This brief review summarizes the currently available evidence for and putative mechanisms of action of IL-17 in mouse models of and human vascular disease.     

Bartonella-host-cell interactions and vascular tumour formation

Bartonellae are arthropod-borne bacterial pathogens that typically cause persistent infection of erythrocytes and endothelial cells in their mammalian hosts. In human infection, these host-cell interactions result in a broad range of clinical manifestations. Most remarkably, bartonellae can trigger massive proliferation of endothelial cells, leading to vascular tumour formation. The recent availability of infection models and bacterial molecular genetic techniques has fostered research on the pathogenesis of the bartonellae and has advanced our understanding of the virulence mechanisms that underlie the host-cell tropism, the subversion of host-cell functions during bacterial persistence, as well as the formation of vascular tumours by these intriguing pathogens.     

Biophysics of selectin-ligand interactions in inflammation and cancer

Selectins (L-, E- and P-selectin) are calcium-dependent transmembrane glycoproteins that are expressed on the surface of circulating leukocytes, activated platelets, and inflamed endothelial cells. Selectins bind predominantly to sialofucosylated glycoproteins and glycolipids (E-selectin only) present on the surface of apposing cells, and mediate transient adhesive interactions pertinent to inflammation and cancer metastasis. The rapid turnover of selectin-ligand bonds, due to their fast on- and off-rates along with their remarkably high tensile strengths, enables them to mediate cell tethering and rolling in shear flow. This paper presents the current body of knowledge regarding the role of selectins in inflammation and cancer metastasis, and discusses experimental methodologies and mathematical models used to resolve the biophysics of selectin-mediated cell adhesion. Understanding the biochemistry and biomechanics of selectin-ligand interactions pertinent to inflammatory disorders and cancer metastasis may provide insights for developing promising therapies and/or diagnostic tools to combat these disorders.     

Endothelial connexin-integrin crosstalk in vascular inflammation

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment – including vascular stiffness and shear stress – modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.     

Tumor-host interactions: the role of inflammation

It is well established that interactions between tumor cells and the host tissue stroma play a key role in determining whether and how any given solid malignancy will develop. In most cases, tumor cells hijack stromal cell functions for their own benefit and ultimately dictate the rules of engagement to the host tissue microenvironment. However, the contribution of the different stromal cell components to tumor growth remains to be clarified. Because most solid tumors are accompanied by a local inflammatory response, it has long been thought that inflammation and carcinogenesis are related. If formal proof that cancer can be initiated by inflammation in the absence of exogenous carcinogens is still lacking, there is abundant evidence that the inflammatory response can play a central role in modulating tumor growth and progression. This review will discuss some of the mechanisms whereby inflammation can both enhance and inhibit tumor growth.     

Leukocyte – endothelial interactions in inflammation

At sites of inflammation, infection or vascular injury local proinflammatory or pathogen-derived stimuli render the luminal vascular endothelial surface attractive for leukocytes. This innate immunity response consists of a well-defined and regulated multi-step cascade involving consecutive steps of adhesive interactions between the leukocytes and the endothelium. During the initial contact with the activated endothelium leukocytes roll along the endothelium via a loose bond which is mediated by selectins. Subsequently, leukocytes are activated by chemokines presented on the luminal endothelial surface, which results in the activation of leukocyte integrins and the firm leukocyte arrest on the endothelium. After their firm adhesion, leukocytes make use of two transmigration processes to pass the endothelial barrier, the transcellular route through the endothelial cell body or the paracellular route through the endothelial junctions. In addition, further circulating cells, such as platelets arrive early at sites of inflammation contributing to both coagulation and to the immune response in parts by facilitating leukocyte–endothelial interactions. Platelets have thereby been implicated in several inflammatory pathologies. This review summarizes the major mechanisms and molecules involved in leukocyte–endothelial and leukocyte-platelet interactions in inflammation.     

Epithelium-fibroblast interactions in response to airway inflammation

Dramatic changes to the architecture of the airway walls have been commonly described in the airways of patients with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Much research has focused on how airway inflammation drives these structural changes, particularly in terms of the mechanisms/mediators that are involved, and a number of parallels are observed between the disease phenotypes. For example, the increased deposition of extracellular matrix (ECM) at focal sites in the airway wall is seen in asthma and all interstitial lung diseases that involve fibrosis. In addition, increased expression of a number of well characterized cytokines and growth factors, such as TGF-beta and epidermal growth factor (EGF) have been demonstrated in these diseases. However, the role of the lesser-known cytokines, including the leukaemia inhibitory factor (LIF) and other members of the IL-6 family of cytokines in the pathogenesis of airway remodelling and fibrosis is largely unknown. However, the use of genetic manipulation in vivo and more specific inhibitors/antibodies in vitro has now provided increasing evidence to support the hypothesis that a complex interaction exists between these cytokines, ECM and integrins in regulating the function of both epithelial cells and fibroblasts.     

Il-13 and IFN-gamma: interactions in lung inflammation

Chronic inflammatory diseases of the lungs, such as asthma, are frequently associated with mixed (Th2 and Th1) T cell responses. We examined the impact of critical Th1 and Th2 cytokines, IFN-gamma and IL-13, on the responses in the lungs. In a mouse model of airway inflammation induced by mixed T cell responses, the number of Th1 (IFN-gamma-positive) cells was found to be negatively correlated with airway hyperreactivity. In these mice, blockade of IL-13 partially inhibited airway hyperreactivity and goblet cell hyperplasia but not inflammation. In contrast, in mice that responded with a polarized Th2 response to the same Ag, blockade of IL-13 inhibited airway hyperreactivity, goblet cell hyperplasia, and airway inflammation. These results indicated that the presence of IFN-gamma would modulate the effects of IL-13 in the lungs. To test this hypothesis, wild-type mice were given recombinant cytokines intranasally. IFN-gamma inhibited IL-13-induced goblet cell hyperplasia and airway eosinophilia. At the same time, IFN-gamma and IL-13 potentiated each other's effects. In the airways of mice given IL-13 and IFN-gamma, levels of IL-6 were increased as well as numbers of NK cells and of CD11c-positive cells expressing MHC class II and high levels of CD86. In conclusion, IFN-gamma has double-sided effects (inhibiting some, potentiating others) on IL-13-induced changes in the lungs. This may be the reason for the ambiguous role of Th1 responses on Th2 response-induced lung injury.     

An update on factor XII-driven vascular inflammation

The plasma protein factor XII (FXII) is the liver-derived zymogen of the serine protease FXIIa that initiates an array of proteolytic cascades. Zymogen activation, enzymatic FXIIa activity and functions are regulated by interactions with cell receptors, negatively charged surfaces, other serine proteases, and serpin inhibitors, which bind to distinct protein domains and regions in FXII(a). FXII exerts mitogenic activity, while FXIIa initiates the pro-inflammatory kallikrein-kinin pathway and the pro-thrombotic intrinsic coagulation pathway, respectively. Growing evidence indicates that FXIIa-mediated thrombo-inflammation plays a crucial role in various pathological states besides classical thrombosis, such as endothelial dysfunction. Consistently, increased FXIIa levels are associated with hypercholesterolemia and hypertriglyceridemia. In contrast, FXII deficiency protects from thrombosis but is otherwise not associated with prolonged bleeding or other adverse clinical manifestations. Here, we review current concepts for FXII(a)-driven vascular inflammation focusing on endothelial hyperpermeability, receptor signaling, atherosclerosis and immune cell activation.     

Relaxin inhibits early steps in vascular inflammation

Increased expression of endothelial adhesion molecules, high levels of the monocyte chemoattractant protein-1 (MCP-1) and enhanced VLA4 integrin/VCAM-1 and CCR-2/MCP-1 interactions are initial steps in vascular inflammation. We sought to determine whether relaxin, a potent vasodilatory and anti-fibrotic agent, mitigates these early events compromising endothelial integrity. The effect of relaxin coincubation on the TNF-α-stimulated expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin; the MCP-1 expression by human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HAoSMC); as well as on direct monocyte–endothelium cell adhesion was quantified by ELISA or adhesion assay. CCR-2 and PECAM expression on HUVEC and THP-1 monocytes was investigated by FACS analysis. Relaxin treatment suppressed significantly TNF-α-induced upregulation of VCAM-1 and PECAM, CCR-2, and MCP-1 levels and direct monocyte adhesion to HUVEC. Our findings identify relaxin as a promising inhibitory factor in early vascular inflammation. By attenuating the upregulation of VCAM-1, key adhesion molecule in early vascular inflammation, and of MCP-1, a chemokine pivotal to monocyte recruitment, relaxin decreased initial monocyte–endothelium contact. This may be of relevance for the prevention and treatment of atherosclerosis and of other pro-inflammatory states.     

Estrogen is a modulator of vascular inflammation

Vascular inflammation underlies the pathogenesis of atherosclerosis. Atherosclerotic changes in the vasculature lead to conditions such as coronary artery disease and stroke, which are the major causes of morbidity and mortality worldwide. Epidemiological studies in premenopausal women suggest a beneficial role for estrogen in preventing vascular inflammation and consequent atherosclerosis. However, the benefits of estrogen areabsent or even reversed in older postmenopausal subjects. The modulation of inflammation by estrogen under different conditions might explain this discrepancy. Estrogen exerts its antiinflammatory effects on the vasculature through different mechanisms such as direct antioxidant effect, generation of nitric oxide, prevention of apoptosis in vascular cells and suppression of cytokines and the renin-angiotensin system. On the other hand, estrogen also elicits proinflammatory changes under certain conditions, which are less completely understood. Some of the mechanisms underlying a possible proinflammatory role for estrogen include increased expression of the proinflammatory receptor for advanced glycation end products, increased tyrosine nitration of cellular proteins, and generation of reactive oxygen species through an uncoupled eNOS. In this review, we have presented evidence for both antiinflammatory and proinflammatory pathways modulated by estrogen and how interactions among such pathways might determine the effects of estrogen on the vascular system.     

Neurogenic inflammation, vascular permeability, and mast cells

Electrical stimulation (ES) of sensory nerves causes increased vascular permeability and vasodilatation, a process known as neurogenic inflammation. The purpose of this study was to assess the role of mast cells in neurogenic inflammation induced by ES of sensory nerves. ES of the rat saphenous nerve for 1, 3, 5, 15, or 30 min induced a 166 to 436% increase in the amount of 125I-albumin deposited in the skin. Through the initial 15 min of ES, the histamine content of the skin remained unchanged. However, 30 min of ES caused a 22.1% decrease in skin histamine (p less than 0.05). ES for 5 min followed by measurement of vascular permeability from 0 to 30 min thereafter resulted in maximal increases in 125I-albumin in the skin immediately after cessation of the pulse of ES. When skin histamine was measured at various intervals after a 5-min pulse of ES, no change in the histamine content was observed through the subsequent 30 min. When mast cell degranulation was assessed histologically, 5 min of ES failed to stimulate mast cell degranulation. However, 30 min of ES caused a significant increase in the proportion of degranulating mast cells. When draining venous plasma histamine was monitored before, during and after ES, no change in plasma histamine was observed. In contrast, the intradermal injection of 5 micrograms of compound 48/80 produced a significant increase in plasma histamine. In order to examine the possibility that histamine might be released but remain in the skin after ES, skin "blisters" were developed by intradermal injections of saline. There was a significant increase in the amount of 125I-albumin extravasated into blister fluid measured after 3, 5, and 10 min of ES and a significant increase in histamine after 5 or 10 min. Therefore, prolonged ES of sensory nerves can cause mast cell degranulation. However, ES causes increased vascular permeability at times when no mast cell activation can be observed. These data suggest that the initial phases of neurogenic inflammation are independent of mast cell activation.     

Syndecans in wound healing, inflammation and vascular biology

Syndecans are heparan sulphate proteoglycans consisting of a type I transmembrane core protein modified by heparan sulphate and sometimes chondroitin sulphate chains. They are major proteoglycans of many organs including the vasculature, along with glypicans and matrix proteoglycans. Heparan sulphate chains have potential to interact with a wide array of ligands, including many growth factors, cytokines, chemokines and extracellular matrix molecules relevant to growth regulation in vascular repair, hypoxia, angiogenesis and immune cell function. This is consistent with the phenotypes of syndecan knock-out mice, which while viable and fertile, show deficits in tissue repair. Furthermore, there are potentially important changes in syndecan distribution and function described in a variety of human vascular diseases. The purpose of this review is to describe syndecan structure and function, consider the role of syndecan core proteins in transmembrane signalling and also their roles as co-receptors with other major classes of cell surface molecules. Current debates include potential redundancy between syndecan family members, the significance of multiple heparan sulphate interactions, regulation of the cytoskeleton and cell behaviour and the switch between promoter and inhibitor of important cell functions, resulting from protease-mediated shedding of syndecan ectodomains.