Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases

The traditional view of atherosclerosis has recently been expanded from a predominantly lipid retentive disease to a coupling of inflammatory mechanisms and dyslipidemia. Studies have suggested a novel role for polymorphonuclear neutrophil (PMN)-dominant inflammation in the development of atherosclerosis. Human neutrophil peptides (HNPs), also known as alpha-defensins, are secreted and released from PMN granules upon activation and are conventionally involved in microbial killing. Current evidence suggests an important immunomodulative role for these peptides. HNP levels are markedly increased in inflammatory diseases including sepsis and acute coronary syndromes. They have been found within the intima of human atherosclerotic arteries, and their deposition in the skin correlates with the severity of coronary artery diseases. HNPs form complexes with LDL in solution and increase LDL binding to the endothelial surface. HNPs have also been shown to contribute to endothelial dysfunction, lipid metabolism disorder, and the inhibition of fibrinolysis. Given the emerging relationship between PMN-dominant inflammation and atherosclerosis, HNPs may serve as a link between them and as a biological marker and potential therapeutic target in cardiovascular diseases including coronary artery diseases and acute coronary syndromes.     

Early kinetics of calprotectin in plasma following inguinal hernia surgery

Calprotectin is one of the most abundant proteins of neutrophil granulocytes. It is released upon neutrophil activation and is considered a sensitive and clinically useful marker for neutrophil-mediated inflammation, including bacterial infections. However, early kinetics of calprotectin activation following inflammatory activation has hitherto been unknown. The aim of the present study was to determine the early phase of the kinetics of calprotectin, in comparison with the inflammatory markers CRP, IL-6, TNF-α, and procalcitonin, in plasma following a standardized temporary mild inflammatory response, using uncomplicated inguinal hernia surgery as a model. The study cohort consisted of 17 adult patients (15 male and 2 female) undergoing elective surgery for hernia. Values of calprotectin increased significantly at 2 h following surgery, and continued to increase to reach the highest level at 24–36 h after surgery, values still not exceeding upper normal reference level. This contrasts to IL-6 and CRP, for which an elevation was found first later, 4 h and 24–36 h post-surgery, respectively, for IL-6, and CRP. No significant increase was seen for TNF-α, or procalcitonin. The data demonstrate a very rapid and significant but modest increase in calprotectin following induction of mild inflammation, supporting that calprotectin can be useful for early detection of inflammatory response.     

血管生成素与炎症性疾病

血管生成素（angiogenin,ANG）是首个被发现来源于肿瘤的具有血管生成能力的蛋白质,但其在炎症中的作用机制尚未完全阐明. 研究表明, ANG在炎症性疾病的发生发展中起重要作用,并与炎症的调控密切相关,而慢性炎症正是导致肿瘤形成、生长和转移的因素之一. 本文以ANG与炎症的关联为基础,结合我们的工作阐述ANG在炎症性疾病特别是肿瘤中的作用和调控机制,明确ANG与蛋白质的相互作用、对信号通路的调控及核内作用是其发挥功能的重要机制,也可能是调控肿瘤炎症的重要机制. 因而,深入研究ANG与炎症的关系不仅可加深我们对ANG兼具抗炎、抗新生血管双重功能的认识,更可为炎症性疾病的治疗提供潜在的作用靶点和新的思路和方法.     

Netrin-1: An emerging player in inflammatory diseases

Netrin-1 is a member of the laminin-like protein family and was initially identified as a potent chemotactic molecule involved in axonal guidance and cell migration during embryonic development. Many studies have focused on the non-neural effects of netrin-1, and the results revealed that netrin-1 may be extensively involved in the regulation of angiogenesis, inflammation, tissue remodeling, and cancer. The pathogenic or protective effect of netrin-1 suggests that it may be a potential therapeutic target in multiple diseases. Netrin-1 plays different roles by interacting with its receptors, such as deleted in colorectal cancer (DCC)/neogenin and the uncoordinated-5 homolog family members (UNC5). Interestingly, contradictory actions in certain physiological pathways serve to highlight its manifold and often opposite effects on numerous physiological and pathophysiological processes. Netrin-1 regulates inflammation and leukocyte infiltration, suggesting roles for netrin-1 in the immune response. In this study, we review recent advances in the understanding of netrin-1 and its receptors in many inflammatory diseases and look forward to the bioavailability of netrin-1 for the future.     

New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding protein

a-FABP is indespensible in inflammation and may serve as a new potential drug target for inflammation related diseases. We have successfully designed and synthesized a series of aromatic substituted pyrazoles as new human a-FABP inhibitors. The compounds strongly bound to the hydrophobic binding pocket of a-FABP, while showed significantly lower binding affinities to the closely related homologue protein h-FABP. The most potent and selective compound 5g bound to a-FABP with an apparent K_i value below 1.0 nM, while did not inhibit h-FABP at 50 μM and thus represents one of the most potent and selective a-FABP inhibitors to date. The strong binding capacity of these inhibitors was further validated by their effective blockade of inflammatory responses as determined by the production of pro-inflammatory cytokines upon LPS stimulation. Compound 5g may serve as a lead compound for developing new effective therapeutic agent for prevention and treatment of atherosclerosis, type 2 diabetes and other inflammatory and metabolic related diseases.     

Calprotectin — A Novel Marker of Obesity

Background

The two inflammatory molecules, S100A8 and S100A9, form a heterodimer, calprotectin. Plasma calprotectin levels are elevated in various inflammatory disorders. We hypothesized that plasma calprotectin levels would be increased in subjects with low-grade systemic inflammation i.e. either obese subjects or subjects with type 2 diabetes.

Methodology/Principal Findings

Plasma calprotectin and skeletal muscle S100A8 mRNA levels were measured in a cohort consisting of 199 subjects divided into four groups depending on presence or absence of type 2 diabetes (T2D), and presence or absence of obesity. There was a significant interaction between obesity and T2D (p = 0.012). Plasma calprotectin was increased in obese relative to non-obese controls (p<0.0001), whereas it did not differ between obese and non-obese patients with T2D (p = 0.62). S100A8 mRNA levels in skeletal muscle were not influenced by obesity or T2D. Multivariate regression analysis (adjusting for age, sex, smoking and HOMA2-IR) showed plasma calprotectin to be strongly associated with BMI, even when further adjusted for fitness, CRP, TNF-α or neutrophil number.

Conclusions/Significance

Plasma calprotectin is a marker of obesity in individuals without type 2 diabetes.     

The CCN family: a new class of inflammation modulators?

Uncontrolled or sustained inflammation is the underlying cause of or actively contributes to the progression of many chronic pathologies such as atherosclerosis, arthritis, or neuroinflammatory diseases. Matricellular proteins of the CCN family (CYR61/CTGF/NOV) have emerged as localized multitasking signal integrators. These structurally conserved secreted proteins specifically interact with and signal through various extracellular partners, in particular integrins, which enable them to play crucial roles in various processes including development, angiogenesis, wound healing and diseases such as fibrosis, vascular disease and cancer. In this review, we discuss the possibility that the CCN family members could represent a putative new class of modulators of inflammation. In this context, we focused on their relationship with cytokines and chemokines. In vitro, CCN expression is finely regulated by diverse inflammatory mediators including cytokines (TNFα, IL1β, TGF-β), small factors such as prostaglandins, nitric oxide, histamine and serotonin, and extracellular matrix enzymes. In addition, CCN proteins acting alone or in concert with their specific partners appear to be potent regulators of the production of cytokines and chemokines in a context-dependent manner. Finally, emerging studies suggest a potential role for CCN proteins in chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis, inflammatory kidney diseases and neuroinflammatory pathologies such as Alzheimer’s disease. CCN members could therefore represent new potential therapeutic targets for drug development against such diseases.     

Calprotectin - a pleiotropic molecule in acute and chronic inflammation

Calprotectin (MRP8/14, S100A8/S100A9, 27E10 antigen) is a heterodimer of two calcium-binding proteins present in the cytoplasm of neutrophils and expressed on the membrane of monocytes. Upon neutrophil activation or endothelial adhesion of monocytes, calprotectin is released and may be detected in serum or body fluids as potentially useful clinical inflammatory marker. The soluble form of calprotectin provides both bacteriostatic and cytokine-like effects in the local environment. When calprotectin metabolism is affected on a systemic level, the zinc-binding properties of protein may induce severe dysregulation of zinc homeostasis with severe clinical symptoms. The distribution of membrane form of calprotectin is restricted to monocytes and immature macrophages and the presence of calprotectin-positive infiltrating cells reflects the influx of mononuclear phagocytes to the site of inflammation. Calprotectin expression and release seems to be of particular importance in immune and immunopathological reactions.     

Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers

Background

Vascular endothelial cells contribute to the pathogenesis of numerous human diseases by actively regulating the stromal inflammatory response; however, little is known regarding the role of endothelial inflammation in the growth of human tumors and its influence on the prognosis of human cancers.

Methods

Using an experimental model of tumor necrosis factor-alpha (TNF-α)-mediated inflammation, we characterized inflammatory gene expression in immunopurified tumor-associated endothelial cells. These genes formed the basis of a multivariate molecular predictor of overall survival that was trained and validated in four types of human cancer.

Results

We report that expression of experimentally derived tumor endothelial genes distinguished pathologic tissue specimens from normal controls in several human diseases associated with chronic inflammation. We trained these genes in human cancer datasets and defined a six-gene inflammatory signature that predicted significantly reduced overall survival in breast cancer, colon cancer, lung cancer, and glioma. This endothelial-derived signature predicted outcome independently of, but cooperatively with, standard clinical and pathological prognostic factors. Consistent with these findings, conditioned culture media from human endothelial cells stimulated by pro-inflammatory cytokines accelerated the growth of human colon and breast tumors in immunodeficient mice as compared with conditioned media from untreated endothelial cells.

Conclusions

This study provides the first prognostic cancer gene signature derived from an experimental model of tumor-associated endothelial inflammation. These findings support the notion that activation of inflammatory pathways in non-malignant tumor-infiltrating endothelial cells contributes to tumor growth and progression in multiple human cancers. Importantly, these results identify endothelial-derived factors that could serve as potential targets for therapy in diverse human cancers.     

Immunobiology of mesenchymal stem cells

Mesenchymal stem cells (MSCs) can be isolated from almost all tissues and effectively expanded in vitro. Although their true in situ properties and biological functions remain to be elucidated, these in vitro expanded cells have been shown to possess potential to differentiate into specific cell lineages. It is speculated that MSCs in situ have important roles in tissue cellular homeostasis by replacing dead or dysfunctional cells. Recent studies have demonstrated that in vitro expanded MSCs of various origins have great capacity to modulate immune responses and change the progression of different inflammatory diseases. As tissue injuries are often accompanied by inflammation, inflammatory factors may provide cues to mobilize MSCs to tissue sites with damage. Before carrying out tissue repair functions, MSCs first prepare the microenvironment by modulating inflammatory processes and releasing various growth factors in response to the inflammation status. In this review, we focus on the crosstalk between MSCs and immune responses and their potential clinical applications, especially in inflammatory diseases.     

Modulation of inflammation by autophagy: Consequences for human disease

Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.     

Role of IL-6 in Asthma and Other Inflammatory Pulmonary Diseases

The incidence and severity of chronic lung diseases is growing and affects between 100 and 150 million people worldwide and is associated with a significant rate of mortality. Unfortunately, the initial cause that triggers most chronic lung diseases remains unknown and current available therapies only ameliorate, but do not cure the disease. Thus, there is a need for identification of new targets and development of novel therapies especially for those most severely affected. IL-6, like other inflammatory cytokines, has been shown to be elevated in different lung diseases, but it was considered a byproduct of ongoing inflammation in the lung. However, recent studies support a dissociation of IL-6 from inflammation in the lung and suggest that this cytokine plays an active role in pathogenesis of asthma and, in all likelihood, COPD. IL-6 may therefore be a germane target for treatment of these and other chronic lung disease. Here, we provide an overview of the studies in mouse models and human patients that provide support for the involvement of IL-6 in lung diseases.     

Chemokines in cardiovascular remodeling: clinical and therapeutic implications

Chemokines are newly discovered molecules that mediate the migration of leukocytes into inflammed tissues and control the inflammatory reactions in various immune-mediated diseases. Both in animal models and in human specimens, chemokine expression is associated with atherosclerotic lesion development and vascular remodeling and restenosis after angioplasty. Furthermore, recent studies have demonstrated that chemokines play an important role in the pathophysiology of acute coronary syndromes, post-infarction left ventricular remodeling and chronic heart failure. The capacity to control activation and movement of inflammatory cells suggests that chemokines and their receptors might provide novel targets for therapeutic intervention in a number of conditions characterized by chronic inflammation, including cardiovascular diseases. The present review summarizes current knowledge regarding the potential pathogenic role of chemokines in major cardiovascular disorders, as well as the modulation of the chemokine network as a novel, interesting therapeutic modality in this field.     

Inflammatory markers: linking unstable plaques to coronary event, an interventional perspective

Abundant data links inflammatory mechanisms to atheromatous plaque destabilization leading to plaque rupture and coronary events. The discovery of inflammatory cells and inflammatory mediators within atherosclerotic plaques prone to rupture led to a series of studies demonstrating an association between various markers of inflammation and future coronary events. Inflammatory markers have also been used in patients undergoing coronary angioplasty in an attempt to predict restenosis and risk for post-procedural coronary events. This review article provides an overview on the potential use of inflammatory markers in the context of coronary interventions.     

Modeling immune complex-mediated autoimmune inflammation

A number of autoimmune diseases are thought to feature a particular type of self-sustaining inflammation, caused by the deposition of immune complexes (IC) in the inflamed tissue and a consequent activation of local effector cells. The persistence of this inflammation is due to a positive feedback loop, where autoantigen particles released as part of the tissue damage caused by the inflammation stimulate autoreactive B cells, leading to the formation of further immune complexes and their subsequent deposition. We present a mathematical model for the exploration of IC-mediated autoimmune inflammation and its clinical implications. We characterize the possible differences between normal individuals and those susceptible to such inflammation, and show that both random perturbations and bifurcations can lead to disease onset. Our model explains how defects in the mechanisms responsible for cellular debris clearance contribute to the development of disease, in agreement with empirical evidence. Moreover, we show that parameters governing the dynamics of immune complexes, such as their clearance rate, have an even stronger effect in determining the behavior of the system. We demonstrate the existence of hysteresis, implying that once IC-mediated autoimmune inflammation is triggered, its long-term suppression may be difficult to achieve. Our results can serve to guide the development of novel therapies to autoimmune diseases involving this type of inflammation.     

Inflammatory markers and coronary heart disease

PURPOSE OF REVIEW: Despite changes in lifestyle and the use of effective pharmacologic interventions to lower cholesterol levels, coronary heart disease remains the major cause of morbidity and mortality in the developed world. Cholesterol screening fails to identify almost 50% of those individuals who will present with acute coronary syndromes. Recent evidence from laboratory and prospective clinical studies demonstrates that atherosclerosis is not simply a disease of lipid deposition, but rather is an inflammatory process with highly specific cellular and molecular responses. The clinical utility of inflammatory markers has been examined in a variety of atherothrombotic diseases. Because C-reactive protein is highly stable in stored frozen samples, and automated and robust analytical systems for its measurement are available, it has become the most widely examined inflammatory marker. RECENT FINDINGS: C-reactive protein has consistently been shown to be a useful prognostic indicator in acute coronary syndromes and is a strong predictor of future coronary events in apparently healthy individuals. In addition, C-reactive protein can identify individuals with normal lipid levels who are at increased risk for future coronary events. Because drugs such as aspirin and statins reduce inflammatory risk, C-reactive protein has the potential to guide the use of these therapies in high-risk individuals for primary prevention. SUMMARY: C-reactive protein may have a role in global risk assessment for primary prevention and in targeting those patients who will benefit from anti-inflammatory therapies. In addition, it may also be a good prognostic indicator in patients with acute coronary syndromes.     

髓样细胞触发性受体-1基础研究与临床应用

髓样细胞触发性受体-1（triggering receptor expressed on myeloid cells-1,TREM-1）是表达于中性粒细胞、单核细胞与巨噬细胞表面的免疫球蛋白家族胞膜受体。有研究显示,TREM-1能够放大模式识别受体介导的炎性反应,在全身炎性反应综合征（SIRS）中发挥重要作用。TREM．1在慢性炎性活动期、恶性肿瘤等病理过程中也有不同程度上凋。以TREM-1为靶点的靶向药物有望对上述疾病治疗产生重大影响。同时,游离型TREM-1（soluble TREM-1,sTREM-1）可作为判断多种疾病预后的重要指标。     

Therapeutic potential of human elafin

Elafin is an endogenous human protein composed of an N-terminal transglutaminase substrate motif and a C-terminal WAP (whey acidic protein)-domain with antiproteolytic properties. Elafin is expressed predominantly in epithelial tissue and potently inhibits the neutrophil-derived serine proteases elastase and proteinase-3 by a competitive tight-binding mechanism. Furthermore, it inhibits EVE (endogenous vascular elastase). Studies on several animal models show that antiprotease augmentation with human elafin is an effective strategy in the treatment of inflammatory vascular, systemic and pulmonary diseases and of inflammation triggered by reperfusion injury. This raises the possibility that elafin might be effective in the treatment of a variety of human inflammatory diseases. In a Phase I clinical trial, elafin was well tolerated. Phase II trials are underway to investigate the therapeutic effects of elafin on post-operative inflammation and the clinical consequences of major surgery. Of particular interest is the reduction of post-operative morbidity after oesophagus cancer surgery, coronary artery bypass surgery and kidney transplantation.     

Clinical and anti-aging effect of mud-bathing therapy for patients with fibromyalgia

This study focuses on two inflammatory diseases, viz., “diabetes mellitus (DM)” that causes serious complications such as retinopathy, nephropathy, and neuropathy, and “ischemic colitis” which is evoked by DM. Ischemic colitis originates from the reduction in mesenteric blood flow to the colon with existence of the occlusive or non-occlusive reasons. Our study objective was to provide early diagnostic approach for ischemic colitis in streptozotocin (STZ)-induced diabetic rats. Sprague-Dawley rats were divided into four groups: (i) control use of 0.1 M citrate buffer, the solvent of streptozotocin (C), (ii). induced ischemia (I), (iii) rats subjected to 60 mg/kg STZ intraperitoneally to induce type 1 diabetes (D) (48 h after STZ injection, blood glucose levels >200 mg/dl were considered as diabetic), and (iv) diabetic rats subjected to intestinal ischemia (D+I). The third diabetic group (D) was not operated. At the end of the experimental period, rats were sacrificed, C-reactive protein (CRP) and calprotectin levels were measured in the serum and colon tissue specimens. Tissue specimens were also analyzed histologically. We found that serum and colon calprotectin levels were elevated in the D+I group compared to the D and/or I group alone, but relatively calprotectin levels increased in I as compared to C group in colon tissues. CRP levels were significantly increased with ischemic colitis in diabetes, while colon CRP levels were decreased. These results provide evidence for the existence of inflammation in the STZ-induced diabetic rats with ischemic colitis. In conclusion, our measurements of serum calprotectin levels of STZ-induced diabetic rats with ischemic colitis provide a practical approach for an early diagnosis of ischemic colitis. Furthermore, these biochemical analyses correlate well with the histopathologic findings of STZ-induced diabetic rats with ischemic colitis. Future studies would be desirable to further strengthen the role of calprotectin in the early diagnosis of ischemic colitis in diabetics clinical settings.     

The function and regulation of TET2 in innate immunity and inflammation

TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.