Kidney diseases and chemokines

Infiltrating inflammatory cells into the kidney mediate the initiation and progression of damage by direct cytotoxicity, the secretion of soluble factors such as cytokines and proteases, or by the subsequent induction of further immune response. Before leukocytes can exert their effects on renal damage or repair, they have to reach the site of injury. It has become clear in recent years that a group of small proteins called chemokines are the chemotactic cytokines considered to be the main regulators of directional leukocyte trafficking under homeostatic and inflammatory conditions. In this review, we summarize available in vivo studies on the neutralization of chemokines and chemokine receptors in renal inflammatory disease, and especially focus on the potential therapeutic effects of chemokine blockade in glomerulonephritis and renal transplantation. Although interference with chemokine expression holds great promises for the treatment of inflammatory renal diseases, it has been shown that such an approach may actually worsen in diseases under certain circumstances. This suggests that inhibition of chemokine expression and action must be time and compartment specific to provide therapeutic benefit for renal structure and function.     

A closer look at chemokines and their role in asthmatic responses

Inflammatory cell recruitment is a hallmark phenomenon of all inflammatory diseases, including allergic asthma. In allergy and asthma, recruitment of inflammatory cells such as T cells, dendritic cells, mast cells, eosinophils and neutrophils, is mediated via a number of chemokines and their receptors. Not only are chemokines involved in recruitment of these cells, they also play a role in activation and differentiation of inflammatory cells, among others, by selectively activating Th1 or Th2 cells or by effects on epithelial or endothelial cells. Binding of chemokines with their receptors has been demonstrated to be highly promiscuous and the subsequent activation pattern on effector cells is very heterogeneous, which has lead to confusion and has complicated research in this field. Nonetheless, chemokines and their receptors are important potential therapeutical targets in allergy and asthma because of their central role in cell recruitment and activation during inflammation.     

脑缺血损伤的炎症免疫机制

脑缺血是指脑循环血流量减少为特征的中枢神经系统疾病 ,因其发病率、致残率和死亡率均较高 ,严重地影响了人类的生存质量。探讨脑缺血损伤的机制 ,对减轻脑缺血损伤和提高人类的生存质量极其重要。脑缺血损伤的炎症免疫机制研究将为临床寻找有效的治疗方法提供重要的思路。脑缺血的炎症免疫损伤是一个复杂的病理过程 ,炎症免疫细胞、免疫因子和NO等都参与了脑缺血损伤的病理过程 ,其中细胞因子首先诱导产生 ,尔后诱导粘附分子和趋化因子的表达 ,促使炎症免疫细胞浸润到损伤组织 ,炎症免疫细胞及其产生的细胞因子又相互诱导激活 ,进一步加重组织损伤。NO及其合酶在脑缺血的炎症免疫损伤中占重要地位     

Chemokines and atherosclerotic plaque progression: towards therapeutic targeting?

Atherosclerosis is currently viewed as an inflammatory disease in which the initiation and progression of the atherosclerotic plaque towards a rupture prone, unstable plaque is driven by leukocyte recruitment mediated by various inflammatory mediators. Recently, interest in chemotactic cytokines or chemokines with regard to atherosclerosis has been growing as chemokines mediate the influx of leukocytes that is typical of atherothrombosis. The activity of the majority of chemokines is overlapping and chemokines are not only produced by the various cellular constituents of the atherosclerotic plaque but also by activated platelets. Consequently, the direct influence of individual chemokines on plaque destabilisation and rupture is widespread and rather unclear. Experimental research has already established the role of a number of chemokines in advanced atherosclerosis. Nevertheless, given the complexity and size of the chemokine family, further screening of cardiovascular disease for chemokine level and genetic polymorphisms for chemokines will be warranted as the search for viable biomarkers of plaque destabilization as well as novel therapeutic targets for specific atheroregressive therapeutic compounds is ongoing. With regard to the latter, clinical trials with specific chemokine inhibitory strategies, like chemokine receptor antagonists, are already underway in other inflammatory disorders. Summarizing, chemokine inhibition likely constitutes an important therapeutic option next to already established drugs in the management of cardiovascular disease.     

Brain cytokines and chemokines: roles in ischemic injury and pain

Cytokines and chemokines were originally identified as essential mediators for inflammatory and immune responses. Enhanced production and release of cytokines/chemokines are observed also in the central nervous system (CNS) under diverse pathological conditions. There is growing evidence showing that brain cytokines/chemokines play crucial roles in the neuro-glio-vascular interaction underlying the pathology of various brain disorders and therefore are potential targets for development of novel and effective therapeutics for CNS diseases. Here the evidence of the involvement of cytokines/chemokines in ischemic brain injury and pain is reviewed.     

Cytokines and chemokines as regulators of angiogenesis in health and disease

The intricate interplay between the endothelium and immune cells has been well recognized in the context of immune responses. However, the fact that this inter-relation extends well beyond immune regulation is becoming increasingly recognized, with particular regards to the influence of the immune system on the essential endothelial process of angiogenesis, where the contribution of cytokines drives the angiogenic process. As angiogenesis is an important component of numerous pathological states, among these chronic inflammatory conditions and cancer, understanding the role of cytokines and chemokines in guiding new vessel formation provides key insight into novel therapeutic modalities. Here we review the actions of principal cytokines and chemokines on the angiogenic process and discuss how both can be considered potential pharmaceutical targets or pharmaceuticals themselves for modulation of angiogenesis in chronic inflammation associated with cancer, rheumatoid arthritis and other inflammatory diseases.     

Involvement of chemokines in pain.

It is well established that neuroinflammation plays an important role in neurodegenerative diseases like Alzheimer's disease, stroke, traumatic brain- and spinal cord injury and demyelinating diseases. Likewise, it has been suggested that neuroinflammation plays an important role in nociception and hyperalgesia. Most research concerning inflammatory aspects of pain has concerned the effects of proinflammatory cytokines, prostaglandins and growth factors. Recently, it has been suggested that chemokines play a role in inflammatory pain. Chemokines do not only attract blood leukocytes to the site of injury but also contribute directly to nociception.     

Involvement of mast cells in angiogenesis and chronic inflammation

Mast cells (MC) are granulated secretory cells that have long been recognized as a rich source of biologically highly active mediators such as biogenic amines, prostaglandins, leukotrienes, proteases, cytokines and chemokines. Most of their biological functions however has been rather elusive. There are now emerging data assigning these cells a relevant role in orchestrating angiogenesis, both in normal and pathological conditions. MC indeed synthesize and release a large array of proangiogenic factors upon different stimulation pathways. In addition, MC have been recognized as key cells in mediating host innate and adaptive immune responses. This review summarizes the most recent acquisitions concerning MC involvement in angiogenic processes and chronic inflammatory reactions.     

Chemokine blockers--therapeutics in the making?

Chemokines are a family of small chemoattractant cytokines that have an important role in controlling leukocyte migration. The finding that some chemokines and their receptors are upregulated in both acute and chronic inflammatory diseases, and that they are key players in the development of AIDS, has provided the pharmaceutical industry with new targets for therapeutic intervention in these diseases. Although the chemokine system shows apparent redundancy in vitro, target validation is possible largely through expression studies in human disease tissues and the use of transgenic and knockout mice as disease models. Several approaches are being developed to block the effects of chemokines, including small-molecule antagonists of chemokine receptors, modified chemokines and antibodies directed against chemokine receptors. Here, we describe the rationale behind these different approaches, the pitfalls that have been encountered and future perspectives.     

Chemokines in rheumatic diseases

Chemotactic cytokines, termed chemokines, mediate the ingress of leukocytes into the inflamed synovium. In this review, authors discuss the role of the most relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. Rheumatoid arthritis was chosen as a prototype to discuss these issues, as the majority of studies on the role of chemokines in inflammatory diseases were carried out in arthritis. However, other rheumatic diseases including systemic lupus erythematosus, systemic sclerosis, Sj?gren's syndrome, mixed connective tissue disease, polymyositis/dermatomyositis, antiphospholipid syndrome and systemic vasculitides are also discussed in this context. Apart from discussing the pathogenic role of chemokines and their receptors, authors also review the regulation of chemokine production by other inflammatory mediators, as well as the important relevance of chemokines for antirheumatic therapies.     

Opportunities for novel therapeutic agents acting at chemokine receptors

Chemokines are proinflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors. They also have a role in pathological conditions that require neovascularization and are implicated in the suppression of viral replication. By interaction with their respective G-protein-coupled receptor, chemokines have a profound influence over the selective recruitment of specific cell types in acute inflammatory disease and, hence, inhibition of their action should be of therapeutic benefit. Only now are small molecule inhibitors becoming available to validate this speculation. In this review, without seeking to be comprehensive, the authors provide an introduction to chemokines, their receptors and their role in certain disease processes. Also, recent disclosures claiming novel nonpeptide ligands for chemokine receptors are summarized.     

Targeting chemokines in proteinuria-induced renal disease

INTRODUCTION: Proteinuria is a common finding in glomerular diseases that contributes to the progression of chronic kidney injury. Tubular cells reabsorb the excess of albumin and other plasma proteins from the tubular lumen, triggering several pathophysiologic responses, such as overexpression of fibrogenic mediators and inflammatory chemokines. Chemokines are implicated both in the recruitment of inflammatory infiltrate and in a number of physiological and pathological processes related to protein overload. AREAS COVERED: In recent years, the specific chemokines and their receptors and the intracellular signaling pathways involved in proteinuria-induced renal damage have been identified. This review provides an overview of the role of chemokines and their receptors in proteinuria-related renal disease and summarizes novel therapeutic approaches to restrain the progression of renal damage. EXPERT OPINION: Inhibition of chemokine-induced biological activities is a promising therapeutic strategy in proteinuric disorders. Neutralizing antibodies and small organic molecules targeting chemokines and chemokine receptors have been proven to prevent inflammation and renal damage in experimental models of protein overload. Some of these compounds are currently being tested in human clinical trials.     

Therapeutic potential of anti-inflammatory drugs in focal stroke

The importance of cytokines, especially TNF-α and IL-1β, are emphasised in the propagation and maintenance of the brain inflammatory response to injury. Much data supports the case that ischaemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo upregulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon after focal ischaemia and trauma, as well as at the time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now becoming more understood. In this review, we discuss the role of TNF-α and IL-1β in traumatic and ischaemic brain injury and associated inflammation and the co-operative actions of chemokines and adhesion molecules in this process. We also address novel approaches to target cytokines and reduce the brain inflammatory response and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated and treatment with a second generation p38 MAPK inhibitor, SB-239063, provides a significant reduction in infarct size, neurological deficits and inflammatory cytokine expression produced by focal stroke. SB-239063 can also provide direct protection of cultured brain tissue to in vitro ischaemia. This robust SB-239063-induced neuroprotection emphasises a significant opportunity for targeting MAPK pathways in ischaemic stroke injury and also suggests that p38 inhibition should be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.     

Cytokines/chemokines and adhesion molecules in local inflammatory responses of the lung

It is well accepted that local inflammatory responses are regulated by dynamic reactions among a variety of inflammatory cells. Most of the cells derived from bone marrow and hematopoietic cytokines play an important role in the maturation processes. Proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha) and IL-6 are also important in the induction of inflammatory responses. Recent progress in research, furthermore, has elucidated the critical role of chemokines and adhesion molecules in the recruitment and activation of the inflammatory cells in the lung. This article will focus on their roles in the pathogenesis of airway inflammatory disorders such as asthma.     

Therapeutic potential of anti-inflammatory drugs in focal stroke

The importance of cytokines, especially TNF-alpha and IL-1beta, are emphasised in the propagation and maintenance of the brain inflammatory response to injury. Much data supports the case that ischaemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo upregulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon after focal ischaemia and trauma, as well as at the time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now becoming more understood. In this review, we discuss the role of TNF-alpha and IL-1beta in traumatic and ischaemic brain injury and associated inflammation and the co-operative actions of chemokines and adhesion molecules in this process. We also address novel approaches to target cytokines and reduce the brain inflammatory response and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated and treatment with a second generation p38 MAPK inhibitor, SB-239063, provides a significant reduction in infarct size, neurological deficits and inflammatory cytokine expression produced by focal stroke. SB-239063 can also provide direct protection of cultured brain tissue to in vitro ischaemia. This robust SB-239063-induced neuroprotection emphasises a significant opportunity for targeting MAPK pathways in ischaemic stroke injury and also suggests that p38 inhibition should be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.     

Neuro-glio-vascular interaction in ischemic brains

The brain contains glial cells (astrocytes, microglia, and oligodendrocytes) and endothelial cells in addition to neurons. Under various pathologic conditions, the invasion of leukocytes such as neutrophils, monocytes/macrophages, and lymphocytes is observed. Interactions among these cell types play crucial roles both in brain function and dysfunction. However, the molecular basis of such interactions remains unclear. Cytokines and chemokines were originally identified as essential mediators of inflammatory and immune responses. Enhanced production and release of cytokines/chemokines are observed also in the central nervous system under various pathologic conditions. There is growing evidence showing that brain cytokines/chemokines play crucial roles in the neuro-glio-vascular interaction underlying the pathology of various brain disorders and therefore are potential targets for the development of novel and effective therapeutics for central nervous system diseases. This article reviews the evidence for the involvement of cytokines/chemokines in ischemic brain injury and presents our data on introducing organotypic brain slice cultures and in vitro blood brain barrier models as useful tools to investigate neuro-glio-vascular interaction.     

Eotaxins and CCR3 receptor in inflammatory and allergic skin diseases: therapeutical implications

Cell migration is mediated by a group of chemotactic cytokines called chemokines: low molecular weight molecules that have been shown as important leukocyte chemical attractants to sites of inflammation and infection. Eotaxin-1, also called CCL11, was first described in 1994, as a highly specific eosinophils chemokine. Many cell types including lymphocytes, macrophages, bronchial smooth muscle cells, endothelial cells and eosinophils, are able to produce this chemokine, predominantly after cytokine stimulation, however little is known about its expression in human skin in vivo. Eotaxin-1 also regulates the chemiotaxis and, in some conditions, activation of basophils, mast cells and T lymphocytes. Chemokine receptors are named from their ligand families, thus the CC chemokine eotaxin-1 binds to the CCR3 receptor which is expressed on eosinophis, mast cells, Th2 type lymphocytes and even on keratinocytes. It seems that eotaxin-1 is one of the most important cytokines involved in tissue inflammation playing a central role in the pathogenesis of allergic airway diseases (asthma and rhinitis), in inflammatory bowel disease and gastrointestinal allergic hypersensitivity and recently it has been proposed as a therapeutical target for these conditions. Our group has studied the role of eotaxin-1 in the pathogenesis of two skin conditions: dermatitis herpetiformis and AIDS-associated eosinophilic folliculitis, demonstrating that this chemokine, together with Th2 type cytokines (IL-13 and IL-4) is important in cell recruitment, inflammation and tissue damage; moreover eotaxin has proven to paly an important role in other skin conditions such as, bullous pemphigoid, pemphigoid gestationis, atopic dermatitis and allergic drug reactions Recent advances in the understanding of eotaxin-1-mediated mechanisms of chemotaxis in allergic and inflammatory conditions may predict that therapeutic antagonism is achievable. This paper will focus on the role that eotaxin and its receptor play in the pathogenetical mechanism in a number of dermatologic diseases, some of which, like atopic dermatitis, may benefit from the introduction of novel and more selective therapeutic options.     

Chemokines as novel therapeutic targets in inflammatory diseases

Chemokines and their receptors are a large family of inflammatory molecules responsible for a number of biological functions, including the accumulation of leukocytes at tissue sites. Over the past 10 years, a number of studies have indicated a role for chemokines and chemokine receptors in the pathophysiology of several inflammatory diseases, examples of which are multiple sclerosis, atherosclerosis, rheumatoid arthritis, and gastrointestinal diseases including hepatic disease. For this reason, it is not surprising that modulation of their pharmacology could be a prime target for drug discovery. This commentary provides a brief synopsis of our current knowledge of the role of chemokines and their receptors in the inflammatory process, and highlights the pros and possibly cons of chemokine and chemokine receptor antagonism in the therapeutic approach to several inflammatory diseases.     

Toll样信号受体介导的脑出血后炎症反应

炎症机制对脑损伤和脑损伤后的潜在修复有重要的作用。脑出血后产生的各种刺激促进了炎症反应的进展。血肿组分通过激活小胶质细胞,从而释放促炎性细胞因子和趋化因子,以吸引病灶周围的炎性浸润。临床研究发现,炎症信号途径参与了小胶质细胞激活、白细胞浸润、Toll样受体的激活等。近年来对于Toll样受体的研究越来越多,有研究表明,Toll样受体介导的炎症通路在肿瘤、各种炎症性疾病、风湿免疫性疾病、糖尿病等疾病中发挥了重要的作用,此外,Toll样受体还参与中枢神经系统疾病的发病,如阿尔兹海默病、脑中风、多发性硬化等。了解Toll样受体与脑出血的关系,对基础研究和临床治疗方面越来越重要。     

Toll-like receptors: promising therapeutic targets for inflammatory diseases

The health of living organisms is constantly challenged by bacterial and viral threats. The recognition of pathogenic microorganisms by diverse receptors triggers a variety of host defense mechanisms, leading to their eradication. Toll-like receptors (TLRs), which are type I transmembrane proteins, recognize specific signatures of the invading microbes and activate a cascade of downstream signals inducing the secretion of inflammatory cytokines, chemokines, and type I interferons. The TLR response not only counteracts the pathogens but also initiates and shapes the adaptive immune response. Under normal conditions, inflammation is downregulated after the removal of the pathogen and cellular debris. However, a dysfunctional TLR-mediated response maintains a chronic inflammatory state and leads to local and systemic deleterious effects in host cells and tissues. Such inappropriate TLR response has been attributed to the development and progression of multiple diseases such as cancer, autoimmune, and inflammatory diseases. In this review, we discuss the emerging role of TLRs in the pathogenesis of inflammatory diseases and how targeting of TLRs offers a promising therapeutic strategy for the prevention and treatment of various inflammatory diseases. Additionally, we highlight a number of TLR-targeting agents that are in the developmental stage or in clinical trials.