Crosstalk network among multiple inflammatory mediators in liver fibrosis

Liver fibrosis is the common pathological basis of all chronic liver diseases,and is the necessary stage for the progression of chronic liver disease to cirrhosis.As one of pathogenic factors,inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells,cytokines,and the related signaling pathways.Damaged hepatocytes induce an increase in proinflammatory factors,thereby inducing the development of inflammation.In addition,it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis.The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production,which in turn initiate the fibrotic response.Compared with the past,the research on the pathogenesis of liver fibrosis has been greatly developed.However,the liver fibrosis mechanism is complex and many pathways involved need to be further studied.This review mainly focuses on the crosstalk regulatory network among inflammatory cells,cytokines,and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases.Moreover,we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.     

Implications for the role of lipopolysaccharide in the development of atherosclerosis

Mounting scientific evidence over decades has established that atherosclerosis is a chronic inflammatory disorder. Among the potentially critical sources of vascular inflammation during atherosclerosis are the components of pathogenic bacteria, especially lipopolysaccharide (LPS). Toll-like receptor (TLR)-4, expressed on different inflammatory cells involved with the recognition of bacterial LPS, has been recognized to have mutations that are prevalent in a number of ethnic groups. Such mutations have been associated with a decreased risk of atherosclerosis. In addition, epidemiological investigations have proposed that LPS confers a risk factor for the development of atherosclerosis. Gram-negative bacteria are the major source of LPS in an individual's serum, which may be generated during subclinical infections. The major cell receptors on inflammatory cells involved in the pathogenesis of atherosclerosis, like macrophages, monocytes, and dendritic cells (DCs), are CD14, MD-2, and LPS binding protein (LBP). These receptors have been blamed for the development of atherosclerosis through dysregulated activation following LPS recognition. Lipoproteins may also play a role in modulating the LPS-induced inflammatory events during atherosclerosis development. In this review article, we attempt to clarify the role of LPS in the initiation and progression of atherosclerotic lesion development.     

Is Synovial Macrophage Activation the Inflammatory Link Between Obesity and Osteoarthritis?

Osteoarthritis (OA) is the most common musculoskeletal disease, affecting nearly 25 % of the world population (WHO reports), leading to pain and disability. There are as yet no clinically proven therapies to halt OA onset or progression; the development of such therapies is, therefore, a national as well as international research priority. Obesity-related metabolic syndrome has been identified as the most significant, but also an entirely preventable risk factor for OA; however, the mechanisms underlying this link remain unclear. We have examined the available literature linking OA and metabolic syndrome. The two conditions have a shared pathogenesis in which chronic low-grade inflammation of affected tissues is recognized as a major factor that is associated with systemic inflammation. In addition, the occurrence of metabolic syndrome appears to alter systemic and local pro-inflammatory cytokines that are also related to the development of OA-like pathologies. Recent findings highlight the importance not only of the elevated number of macrophage in inflamed synovium but also the activation and amplification of the inflammatory state and other pathological changes. The role of local inflammation on the synovium is now considered to be a pharmacological target against which to aim disease-modifying drugs. In this review, we evaluate evidence linking OA, synovitis and metabolic syndrome and discuss the merits of targeting macrophage activation as a valid treatment option for OA.     

Assessment of spinal pain

Spinal pain or back pain is a very common symptom that can have many reasons. The most studied location is low back pain, and it is considered to be nonspecific in the majority of cases. Only a small proportion of patients have axial inflammation as the major cause of their back complaints with chronic inflammatory back pain (IBP) as the most prominent clinical feature of spondyloarthritis (SpA). The recognition of IBP and patients with axial spondyloarthritis (axSpA) is challenging in primary care, and it is important to further facilitate the early diagnosis of SpA. Proposals for improving the referral of patients with a possible diagnosis of axSpA include clinical parameters, human leukocyte antigen (HLA) B27, and imaging parameters.Imaging is crucial for the visualization, objective validation, and understanding of back pain. Numerous diseases such as degenerative disk disease, degenerative changes in the intervertebral (facet) joints and the associated ligaments, spinal instability, herniation of the intervertebral disk, and spinal stenosis have to be differentiated in interpreting imaging of the spine. The sacroiliac joints and the spine are of major importance for the diagnosis and classification of axSpA. Conventional radiographs and magnetic resonance imaging (MRI) are the most important imaging technologies for visualization of structural changes such as syndesmophytes and axial inflammation such as sacroiliitis and spondylitis.The pathogenesis of axSpA is largely genetically determined. HLA B27 has the strongest contribution to the total genetic burden, but other major contributors such as endoplasmic reticulum aminopeptidase (ERAP)-1 and interleukin (IL)-23R have also been identified.     

Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease

Phosphodiesterase-4 isoenzymes have absolute specificity for cyclic adenosine-3',5'-monophosphate and are considered potential therapeutic targets for the treatment of chronic inflammatory disorders, such as chronic obstructive pulmonary disease, with small-molecule inhibitors. Several selective phosphodiesterase-4 inhibitors are in clinical trials of chronic obstructive pulmonary disease, including cilomilast and roflumilast. Despite some encouraging data from phase III clinical trials, the current generation of phosphodiesterase-4 inhibitors is hampered by a low therapeutic ratio. Indeed, a major obstacle is their propensity to evoke non-steroid-like side effects, of which nausea, diarrhea, abdominal pain, vomiting, and dyspepsia are the most common. In addition, a particularly worrying potential toxicity of phosphodiesterase-4 inhibitors, also shared by phosphodiesterase-3 inhibitors and other vasodilators, is arteritis/periarteritis. One potential means of improving the therapeutic ratio and safety of phosphodiesterase-4 inhibitors may lie in the development of compounds that have broader phosphodiesterase specificity. Of the 11 phosphodiesterase families that have been unequivocally identified, dual-specificity compounds that inhibit phosphodiesterase-4 and phosphodiesterase-1, phosphodiesterase-3, or phosphodiesterase-7 may offer the best opportunities to enhance clinical efficacy.     

Últimos avances en pancreatitis crónica

The most important advances in chronic pancreatitis concern its etiopathogenesis, nutritional aspects, and improvements in diagnostic techniques and some treatment options. In the etiopathogenesis of this disease, the importance of smoking and its association with alcohol have been confirmed. Exocrine pancreatic insufficiency (EPI) secondary to chronic pancreatitis is associated with bone metabolism alterations (osteopenia and osteoporosis), a reduction in liposoluble vitamins and alterations in essential amino acid levels. Endoscopic ultrasound has been confirmed as the most highly developed technique for the diagnosis of chronic pancreatitis, especially due to new image optimization technologies. Breath tests for the diagnosis of EPI continue to be developed (optimization of the C-13 mixed triglyceride test and the development of a new test based on C-13-labelled bicarbonate determination). Modest results in pain treatment have been achieved with the use of antioxidants, pancreatic enzymes and/or intravenous secretin. The association of chronic pancreatitis with pancreatic cancer requires strict follow-up, especially in patients with inflammatory masses in the context of chronic pancreatitis.     

Pathogenic interactions between alcohol and hepatitis C

Alcohol is the most commonly abused substance in the United States, and alcohol abuse leads to alcoholic liver disease, a long recognized major public health concern. The high prevalence of chronic hepatitis C virus (HCV) infection, along with the clinical observation that HCV infection is common in alcoholic patients presenting with liver disease, has directed attention to the interaction between alcohol and HCV infection. Clinical studies have identified alcohol use as an independent risk factor for progression of fibrosis in chronic HCV infection. Experimental evidence suggests additive inhibitory effects between HCV and alcohol on antiviral immune responses. In addition, specific pathways have been identified by which HCV core protein and alcohol interact to activate hepatocytes. Nonspecific inflammatory cell recruitment and proinflammatory cytokine activation have also been implicated in both alcohol-and HCV-induced liver diseases. Further investigation of these and other pathways by which alcohol and HCV interact should unravel the mechanisms that accelerate the progression of liver disease.     

Genetics of pancreatitis: A guide for clinicians

Chronic pancreatitis is an inflammatory disease of the pancreas leading to progressive fibrosis that presents with severe abdominal pain and may result in exocrine and/or endocrine insufficiency at later stages. Although alcohol is the strongest contributing factor for disease development, some patients feature none of the known classical risk factors and were consequently classified as having idiopathic or, in the presence of a positive family history, hereditary disease. Today, several mutations have been identified that predispose carriers to development of chronic pancreatitis. The genetic studies of the past decade have clearly contributed to a better understanding of the disease’s pathogenesis. Currently known mutations associated with chronic pancreatitis and the implications for clinicians are discussed in this review.     

A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia

Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, delta opioid receptor ligands have been useful in enhancing morphine's potency. The underlying molecular basis for these observations is not understood. We propose the modulation of receptor function by physical association between mu and delta opioid receptors as a potential mechanism. In support of this hypothesis, we show that mu-delta interacting complexes exist in live cells and native membranes and that the occupancy of delta receptors (by antagonists) is sufficient to enhance mu opioid receptor binding and signaling activity. Furthermore, delta receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric associations between mu-delta opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.     

B-cell involvement in chronic graft-versus-host disease

Chronic graft-versus-host disease is a serious complication in long-term survivors of allogeneic hematopoietic stem cell transplantation, with several organ systems affected. Chronic graft-versus-host disease is an important cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. This article reviews the pathogenesis of chronic graft-versus-host disease. In particularly, the role of B cells in chronic graft-versus-host disease is evaluated, as is evident from several studies which have investigated the presence of antibodies as well as studies which have analyzed B cells as a target for immunotherapy. Thirty autoantibodies and 5 alloantibodies have been identified in chronic graft-versus-host disease patients in 24 studies, and 8 autoantibodies and 5 alloantibodies seemed to be strongly associated with chronic graft-versus-host disease. In addition, various studies have observed significant improvements in chronic graft-versus-host disease using the anti-CD20(+) antibody rituximab. However, it appears to be highly likely that both B cells as well as T cells are of major importance in chronic graft-versus-host disease. Further research is required to clarify the pathogenesis of chronic graft-versus-host disease.     

Regional musculoskeletal pain. The neck.

Tumours, infections, aneurysms and metabolic and inflammatory diseases are rare causes of neck pain. Most cases involve neck pain of unknown origin or a whiplash-associated disorder. Neck pain is common in the general community and more common in certain occupations. The natural history is relatively benign, but some 10% of patients will suffer chronic, severe symptoms. Psychosocial factors have been refuted as risk factors; the cardinal risk factors relate to occupation. In whiplash, the severity of initial symptoms is the cardinal determinant of chronicity. History is the major factor when considering diagnosis, physical examination adding little to the diagnosis. Imaging is not indicated in the vast majority of cases. The available evidence does not support most of the physical, medical and surgical therapies currently practised. Confident reassurance is paramount and justified for acute cases. Proven options for chronic neck pain are few.     

Vascular development in inflammatory bowel disease

There are 4 major concepts in vascular development: vasculogenesis (formation of blood vessels from angioblasts), angiogenesis (formation of vascular sprouts from preexisting vessels), arteriogenesis (thickening and development of vessels) and lymphangiogenesis (formation of lymphatic vessels). In the last decade, these concepts, especially angiogenesis and lymphangiogenesis, have acquired major importance due to their role in tumoral growth and metastatic dissemination. Moreover, the activity of various diseases that involve chronic inflammation, such as asthma, psoriasis and rheumatoid arthritis, has been associated with vascular development. Several growth factors and cytokines are involved in this process and consequently investigation into these elements, both in peripheral blood and their expression in affected tissues, could elucidate the role of vascular development in diseases whose pathogenesis involves chronic inflammation, such as inflammatory bowel disease. The presence of distinct molecules involved in vascular development processes, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor and placental growth factor, among others, has been studied in both ulcerative colitis and Crohn's disease, although not extensively. It has been suggested that the phenomena of vasculogenesis, angiogenesis and lymphangiogenesis play a critical, although not exclusive, role in the inflammation that characterizes inflammatory bowel disease. In general, the results obtained to date suggest that new vascular formation is involved in the pathogenesis of these diseases.     

Hepatocellular expression of lymphocyte function-associated antigen 3 in chronic hepatitis.

T lymphocyte-mediated cytolytic immune reactions are considered a major cause of hepatocyte injury in chronic viral and autoimmune hepatitis. To further investigate local immune responses, we studied the expression of lymphocyte antigens and cell-cell interaction molecules known to be involved in effector-target cell interactions by light and electron microscopy in liver biopsy specimens from patients with chronic viral and autoimmune hepatitis. CD8+ lymphocytes were found to be the predominant population of cells in the inflammatory infiltrate in chronic hepatitis B and non-A, non-B hepatitis. In contrast, CD4+ cells constituted a comparably higher proportion of cells and were more numerous than CD8+ cells in chronic autoimmune hepatitis. In both viral and autoimmune hepatitis, a substantial portion of lymphocytes expressed activation antigens such as T11/3 (CD2R) and IL-2-R (CD25). Lymphocyte function-associated antigen-3 (CD58), which mediates lymphocyte adhesion and activation and is the natural ligand of the CD2/T11 lymphocyte surface receptor, could be demonstrated on endothelial cells and hepatocytes. Hepatocellular lymphocyte function-associated antigen-3 expression in chronic hepatitis showed membranous and cytoplasmic staining of hepatocytes and had a positive correlation with the degree of inflammatory activity. These results suggest that effector-target interactions between hepatocytes and lymphocytes mediated by the lymphocyte function-associated antigen-3/CD2 pathway play a role in chronic inflammatory liver disease. Possible functional consequences of this interaction include enhancement of antigen-specific immune reactions and antigen-independent mechanisms of T cell activation, which may contribute considerably to the degree of inflammatory activity and tissue damage in chronic hepatitis.     

Aspects on pathophysiological mechanisms in COPD

Chronic obstructive pulmonary disease (COPD) is a condition which is characterized by irreversible airway obstruction due to narrowing of small airways, bronchiolitis, and destruction of the lung parenchyma, emphysema. It is the fourth most common cause of mortality in the world and is expected to be the third most common cause of death by 2020. The main cause of COPD is smoking but other exposures may be of importance. Exposure leads to airway inflammation in which a variety of cells are involved. Besides neutrophil granulocytes, macrophages and lymphocytes, airway epithelial cells are also of particular importance in the inflammatory process and in the development of emphysema. Cell trafficking orchestrated by chemokines and other chamoattractants, the proteinase-antiproteinase system, oxidative stress and airway remodelling are central processes associated with the development of COPD. Recently systemic effects of COPD have attracted attention and the importance of systemic inflammation has been recognized. This seems to have direct therapeutic implications as treatment with inhaled glucocorticosteroids has been shown to influence mortality. The increasing body of knowledge regarding the inflammatory mechanism in COPD will most likely have implications for future therapy and new drugs, specifically aimed at interaction with the inflammatory processes, are currently being developed.     

Pathophysiology of chronic rhinosinusitis

Chronic rhinosinusitis (CRS), a disease presenting with chronic symptoms such as nasal obstruction, rhinorrhea, hyposmia and facial pain, is highly prevalent and has a considerable impact on quality of life and health care expenditures. The disease is characterized by chronic inflammation of the sinonasal mucosa and can present with nasal polyps. Current consensus classifies CRS into CRS with nasal polyps and CRS without nasal polyps. This review illustrates the diversity of pathophysiological observations in CRS and highlights selected etiological hypotheses. A wide spectrum of alterations is described regarding histopathology, pattern of T cells and inflammatory effector cells, remodeling, immunoglobulin production, chemokine and eicosanoid production, and the role of microorganisms. The pathophysiological diversity observed in CRS seems to stand in contrast to its nonspecific clinical presentation, but is of the utmost importance in the development and application of highly individualized treatments. Identification of specific disease subgroups and their etiologies is an important and challenging task for future research.     

Cell membrane binding components for constituents of the extracellular matrix: structural mediator of the epithelial matrix interaction in the gastrointestinal tract

Growth, migration, differentiation and metabolic functions of the epithelium in the gastrointestinal tract are regulated by the extracellular matrix. Different cell membrane binding components including the integrins for constituents of the extracellular matrix are expressed in the epithelial cells. These cell membrane binding components may be structural mediators of cell-matrix interaction in the gastrointestinal tract. A characterization of this interaction is of great importance, not only to understand physiological processes, such as epithelial migration and differentiation, but also for the pathogenesis of healing processes (ulcer healing), immunologically mediated processes (adhesion of immunocompetent cells), and especially for tumor pathology (invasion and metastasis). Gastrointestinal diseases are characterized by alterations in the expression of cell membrane binding components for different constituents of the extracellular matrix. In chronic inflammatory bowel disease, a changed expression can be identified on epithelial cells and, in especially malignant transformation of epithelial cells resulted in a pathologic expression of cell adhesion molecules. Oncogenes may modify the expression and function of these cell membrane binding components in the course of malignant transformation. In animal models, it was possible to reduce the frequency of tumor invasion and metastasis and to achieve longer survival times by blocking the cell membrane binding components on malignant cells. An increasing understanding of the role of cell membrane binding components in the epithelium-matrix interaction will certainly also be translated in the future into new therapeutic concepts.     

Low back pain

Low back pain is a major burden to society. Many people will experience an episode of low back pain during their life. Some people develop chronic low back pain, which can be very disabling. Low back pain is associated with high direct and indirect costs. Recent epidemiological data suggest that there is a need to revise our views regarding the course of low back pain. Low back pain is not simply either acute or chronic but fluctuates over time with frequent recurrences or exacerbations. Also, low back pain may frequently be part of a widespread pain problem instead of being isolated, regional pain. Although epidemiological studies have identified many individual, psychosocial and occupational risk factors for the onset of low back pain, their independent prognostic value is usually low. Similarly, a number of factors have now been identified that may increase the risk of chronic disability but no single factor seems to have a strong impact. Consequently, it is still unclear what the most efficient strategy is for primary and secondary prevention. In general, multi-modal preventative approaches seem better able to reflect the clinical reality than single-modal interventions.     

p40phox: the last NADPH oxidase subunit

The phagocytic NADPH-oxidase is a multiprotein system activated during the inflammatory response to produce superoxide anion (O2-), which is the substrate for formation of additional reactive oxygen species (ROS). The importance of this system for innate immunity is established by chronic granulomatous disease (CGD), a primary immunodeficiency caused by defects in the NADPH oxidase. In this review, we present and discuss recent knowledge about p40phox, the last NADPH oxidase component to be identified. Furthermore, its interaction with cellular pathways outside of the NADPH oxidase is discussed. Described in this review is evidence that p40phox participates in NADPH oxidase dynamics within cells, what is known about its role in the oxidase, the possibility that p40phox participates in non-NADPH oxidase processes in phagocytic and non-phagocytic cells and whether p40phox could mediate a similar function in other NADPH oxidases. An improved understanding of p40phox should provide new insights about NADPH oxidase, the physiology of phagocytic cells and the innate immune system.     

Maintenance of pathogenic Th2 cells in allergic disorders

Immunological memory is an important protective mechanism that enables host organisms to respond rapidly and vigorously to pathogens that have been previously encountered. In addition to the protective function, memory CD4⁺ T helper (Th) cells play a central role in the pathogenesis of chronic inflammatory disorders, including asthma. Recently, several investigators have identified phenotypically and functionally distinct memory Th2 cell subsets that produce IL-5. These memory Th2 cell subsets play an important role in the pathology of allergic inflammation and function as memory-type “pathogenic Th2 (Tpath2) cells” both in mice and humans. We review the role of lung Tpath2 cells in the development of allergic inflammation and, in the context of recent findings, propose a mechanism by which Tpath2 cells not only survive but also continue to function at the sites where antigens were encountered. A greater understanding of the functional molecules or signaling pathways that regulate the inflammatory niche for Tpath2 cells may aid in the design of more effective treatments for chronic inflammatory disorders.     

Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Human cytomegalovirus (CMV) infection has been linked to inflammatory diseases, including vascular disease and chronic transplant rejection, that involve vascular endothelial damage. We have previously shown that the host CD4(+) T-cell response to CMV antigen can produce IFNgamma and TNFalpha at levels sufficient to drive induction of fractalkine, a key marker of inflammation in endothelial cells. We have also observed a major pathogenic effect in which endothelial cell damage and loss follow the induction of fractalkine and up-regulation of cell adhesion markers in the presence of peripheral blood mononuclear cells (PBMCs) from donors with a high CMV-specific T-cell frequency. In this report, we show that the fractalkine-CX(3)CR1 interaction resulting in recruitment of natural killer (NK) cells and monocyte-macrophages plays an important role in mediating this endothelial damage. Supportive evidence for frac-talkine's key role is shown by the ability of specific antibody to CX(3)CR1 to reduce significantly CX(3)CR1(+)-bearing cell chemoattraction and to protect against endothelial damage. These findings support CMV as a member of a class of persistent pathogens in which a high T-cell response and chemokine-mediated effects are a risk factor for development of chronic inflammation and endothelial cell injury.