Bone homeostasis is maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoblasts not only play a central role in bone formation by synthesizing multiple bone matrix proteins, but regulate osteoclast maturation by soluble factors and cognate interaction, resulting in bone resorption. Osteoclast maturation requires stimulation by RANKL expressed on osteoblasts, and the cognate interaction is mediated by firm adhesion via ICAM-1. During the processes, pro-inflammatory cytokines such as IL-1 and TNF-alpha, cause an imbalance in bone metabolism, by favoring bone resorption via the induction of RANKL and ICAM-1 on osteoblasts. These inflammatory signals originate from the immune system, the largest source of cell-derived regulatory signals, and such immunological signals to the bone are transmitted primarily via osteoblasts to induce osteoclast maturation, resulting in secondary osteoporosis. Actually, such phenomena mainly occur at the interface between proliferating synovium and bone tissue in rheumatoid arthritis (RA). Thus, therapeutic strategies for these conditions, an anti-TNF-alpha antibody and an IL-1 receptor antagonist, effective for treating RA disease activity, also reduce secondary osteoporosis and joint destruction. Based on an improved understanding of immune signals, investigation of the suppression of cell functions may lead to improved understanding and better treatment of diseases of bone metabolism and osteoporosis.
At sites of inflammation, multiple inflammatory cells including eosinophils, neutrophils, and macrophages are capable of generating reactive oxygen species (ROS), which can contribute to development of various diseases. In case of allergic inflammation, for example, the lung cells obtained by bronchoalveolar lavage (BAL) following antigen challenge generates superoxide anion at nanomolar concentrations. Eosinophils obtained from BAL following a segmental allergen challenge generate more superoxide anion than eosinophils obtained from the peripheral circulation. Such ROS may contribute not only to tissue injury but also to inflammatory reactions. For example, hydrogen peroxide can stimulate both neutrophil and eosinophil adhesion as an autocrine or paracrine mediator via the upregulation of beta2 integrin. Furthermore, ROS may alter morphological or functional properties of endothelial cells, including permeability and adhesion molecule expression. Thus, ROS can promote adhesive interaction between inflammatory and endothelial cells, which could culminate in manifestations of inflammatory diseases such as bronchial asthma.
No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. However, several new treatments that target the inflammatory process are in clinical development. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include adhesion molecule and chemokine-directed therapy, as well as therapies to combat tumour necrosis factor-alpha and augment interleukin-10. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B4 receptor antagonists. Epidermal growth factor receptor kinase inhibitors and calcium-activated chloride channel inhibitors have potential to combat mucus overproduction. Therapy to inhibit fibrosis is being developed against transforming growth factor-beta1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.
Immune and inflammatory responses are governed by antigen-specific T cells, whose activation, differentiation and effector function are induced by signals delivered via the T cell antigen receptor (TCR) and by costimulatory and cytokine receptors. The molecular events leading to the activation of naïve T cells have been extensively studied and are well characterized. Much less is known about the molecular and biochemical events regulating the activation of T cells in chronic inflammatory diseases such as rheumatoid arthritis (RA). This review examines the current state of knowledge of T cell activation in chronic inflammation, focusing on RA, and summarizes experimental data which indicate that the chronic inflammatory process may profoundly affect TCR and cytokine signal transduction pathways. We present evidence suggesting that in chronic inflammation, the antigen-driven TCR-mediated processes are attenuated, while cytokine-driven effector responses are sustained or even enhanced. The possible implications of this inbalance are discussed.
Oxygen radicals including superoxide anion (O(2)(-)) and nitric oxide (NO) are involved in a variety of inflammatory diseases induced by viral infection. In this review, we focus on the role of oxygen radicals in allergic inflammation such as bronchial asthma induced by viral infection--specifically, with respiratory syncytial virus (RSV). This infection in early childhood is a risk factor for development of wheezing, significant decreases in pulmonary function, and increases in airway reactivity. RSV infection also exacerbates recurrent wheezing attacks in patients with established asthma. Recently, we have demonstrated that RSV enhanced superoxide production by human eosinophils stimulated with a lipid mediator such as platelet-activating factor. This response depends on a beta2 integrin, alphaMbeta2, which is critical for eosinophil effector functions. Our results suggest that eosinophils and their products promote RSV-induced airway inflammation in asthma. Close delineation of the mechanism by which RSV enhances eosinophilic inflammation in asthma should yield clues to more effective therapy.
Vasculitis is definitely associated with familial Mediterranean fever. This familial Mediterranean fever-associated vasculitis takes one of three forms: polyarteritis nodosa, with or without microscopic polyangiitis, and Henoch-Schonlein purpura. Behcet disease and inflammatory bowel diseases may also be associated with familial Mediterranean fever, though this is yet to be formally proven. The selective biological advantage, if any, for carriers of simple heterozygotic mutations in the gene responsible for familial Mediterranean fever, MEFV, is not known. Indirect arguments are given for a better defense against certain groups of bacterial pathogens and amongst intra-cellular bacteria, Mycobacterium tuberculosis.
In inflammatory airway diseases, granulocytes such as eosinophils and neutrophils infiltrate the tissue where they are thought to exert pathogenic activities. To avoid a catastrophic accumulation of activated granulocytes, their recruitment must be balanced by efficient cell clearance mechanisms. In this regard, the focus has been on elimination through apoptosis and subsequent engulfment of apoptotic cells by phagocytes. However, novel data suggest that in the airways, powerful non-apoptotic mechanisms are also critically involved in cell clearance. One such mechanism is transepithelial migration into the airway lumen where the mucociliary escalator executes the final elimination. The physiological clearance of tissue granulocytes is normally silent, but can under certain situations shift to become a pro-inflammatory event. For example, apoptotic cells that escape phagocytosis, disintegrate in a pro-inflammatory process called secondary necrosis. In other situations, granulocytes are triggered to undergo an active and violent cytolytic death. This delicate balance in vivo, between silent and violent properties of granulocyte demise, complicates the design of pro-apoptotic pharmacological interventions. On the other hand, this insight may also open possibilities to new exciting treatment strategies. In this context, promoting transepithelial migration, prevention of secondary necrosis, and boosting the macrophage phagocytic system appear as exciting treatment avenues.
The skin is exposed to endogenous and environmental pro-oxidant agents, leading to the harmful generation of reactive oxygen species (ROS). The resulting oxidative stress damages proteins, lipids, and DNA. An imbalance between ROS and antioxidants can lead to an elevated oxidative stress level. Some evidence indicates that allergic and inflammatory skin diseases like atopic dermatitis, urticaria and psoriasis are mediated by oxidative stress. For example, monocytes from patients with atopic dermatitis are primed to generate ROS in response to zymosan, a Toll-like receptor 2 (TLR2) ligand, suggesting that Staphylococcus aureus may damage lesional skin of the disease by production of ROS. Mast cells generate mainly intracellular ROS following the aggregation of FceRI; these ROS may act as secondary messengers in the induction of several biological responses. The present review summarizes the involvement of ROS in the pathogenesis of allergic and inflammatory skin diseases.
Endothelial cells are involved in leukocyte extravasation underlying inflammation. A number of adhesion molecules play a role in leukocyte-endothelial interactions. New vessel formation, termed angiogenesis, is also crucial for leukocyte extravasation. The outcome of neovascularization is highly dependent on the balance or imbalance between angiogenic mediators and inhibitors. There have been several attempts to therapeutically interfere with the cellular and molecular mechanisms, such as leukocyte-endothelial cell adhesion and angiogenesis. Most studies have been performed using animal models of various types of inflammation, such as arthritis. In addition, a very limited number of human clinical trials gave promising results. In this review, authors summarize the most relevant information on adhesion molecules, as well as angiogenic and angiostatic agents. In addition, further perspectives of anti-adhesive and anti-angiogenic therapy are also discussed. Specific targeting of pathological endothelial function including adhesion and angiogenesis, may be useful for the future management of various inflammatory diseases.
The prevalence of asthma and related allergic disorders has increased considerably over the last several decades. Since the genetic makeup of humans has not changed during this time, it is likely that environmental factors may have influenced this rise in allergic diseases. Furthermore, there is increasing evidence to suggest that many aspects of health and disease are determined during the perinatal period and that alterations in lifestyle and diet later in life are secondary to the effects of the immunological programming that occurs during pregnancy and early infancy. This is directly applicable to allergic disease where immune responses at birth implicate intrauterine exposure as a primary sensitization event. Moreover, infants who experience allergy early in life already have an altered immune response at birth and most therapeutic approaches focus on altering the expression of the disease. Therefore, a better understanding of the underlying mechanisms that shapes the immune response towards allergy development is fundamental to strengthening "natural" protective stimuli or developing preventative rather than treatment therapies.
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.
Autoinflammatory diseases are defined as recurrent “unprovoked” inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.
Lung represents a tissue that encounters a high oxidant burden but is also endowed with efficient protection against oxygen and reactive oxygen species (ROS). The oxidant stress experienced by the lung is enhanced by exogenous oxidant producing toxins most importantly pollutants and cigarette smoke, as well as by increased oxidant production during lung inflammation. The major oxidant generating enzymes present in human lung include NADPH oxidase, myeloperoxidase, eosinophil peroxidase and nitric oxide synthases, all of which are induced during inflammatory states. The antioxidant machinery of human lung against ROS is more versatile than often assumed. In addition to metal binding proteins, mucus components and small molecular weight antioxidants and vitamins, lung tissue possesses a highly cell specific and compartmentalized defense system containing several antioxidant enzymes with variable locations, inducibilities and kinetics. Inflammatory states like asthma, chronic obstructive lung disease (COPD) and parenchymal lung disorders have been shown to lead to serious disturbances in the oxidant/antioxidant balance of the lung with consequent oxidant mediated cell injury. Novel synthetic antioxidant mimetics may have the potential to slow or terminate the progression of lung diseases associated with free radicals.
Familial Mediterranean Fever (FMF, MIM 249100), or Periodic disease, is a recessively transmitted and ethnically restricted condition prevalent in population from the Mediterranean decent. FMF notoriously has been hard to diagnose until mutations in the MEFV gene have been identified and as a tremendous help are used for the diagnosis of difficult cases. Since FMF can be controlled by medication, it is extremely desirable to have a firm diagnosis. The aim of this study was to establish the frequency of the most common mutations and genotypes in Armenian population. Molecular analysis of MEFV gene mutations in 3000 Armenian patients has demonstrated direct correlation between the clinical severity and the molecular diagnostic criteria of the disease, including the development of renal amyloidosis with MEFV genotypes. MEFV genotyping performed in the framework of a genetic counseling may reveal and identify affected individuals in presymptomatic phase, providing the possibility of a precocious start of the therapy.
Amyloidosis remains currently a severe potential complication of many chronic inflammatory disorders. It is not exactly know why some patients develop a progressive amyloidosis, whereas others do not although latent deposits may be present. A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis. Genetic factors have however been recently emphasized. Among persistent or emerging causes of AA amyloidosis, hereditary periodic fever syndromes also known as auto-inflammatory syndromes are a group of diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases.
Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.
