Evidence of apoptosis in alcoholic cardiomyopathy

Apoptosis is a mechanism of cell death implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in the cardiac muscle, and there is evidence of skeletal muscle apoptosis in long-term high-dose alcohol consumers. The relation between skeletal and cardiac muscle damage in alcoholism led us to consider the pathogenic role of apoptosis in alcoholic dilated cardiomyopathy. We evaluated apoptosis in the hearts of individuals with long-term alcoholism (n = 19), of those with long-standing hypertension (n = 20), and of those with no known disease as control subjects (n = 7). Alcohol consumption measurement, heart function evaluation, and myocardial immunohistochemical and morphometric analysis were performed. Apoptosis was evaluated with deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay, and BAX and BCL-2 expressions were used to detect induction of and protection from proapoptotic mechanisms, respectively. Hearts from patients with a history of alcoholism showed apoptotic indexes similar to those of organs from hypertensive donors. Subjects with structural heart damage of alcoholic or hypertensive origin showed higher apoptotic indexes in deoxyribonucleotidyl transferase-mediated dUTP-biotin nick end-labeling, BAX, and BCL-2 assays as compared with control subjects (P < .001 for all). Moreover, New York Heart Association class I alcoholic patients displayed higher BAX and BCL-2 expressions as compared with control subjects. We conclude that apoptosis is present to a similar degree in the heart muscle of high-dose alcohol consumers and long-standing hypertensive subjects and is related to structural damage. Proapoptotic mechanisms are activated in alcoholic patients without heart damage.     

The role of Fas-mediated apoptosis in thyroid autoimmune disease.

Apoptosis is a carefully regulated mechanism of cell death that differs from necrosis and plays an important role in normal tissue development and homeostasis, as well as disease processes. Apoptosis also plays an important role in autoimmunity. Defective apoptosis can cause systemic autoimmunity by allowing the survival of autoreactive lymphocytes. It may also be involved in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors. One of these pathways employs the death receptor Fas and its ligand (FasL). Fas expression and death pathway signaling have been demonstrated in the thyroid, but there is controversy surrounding the expression of FasL and its role in thyroid autoimmunity. A number of proteins, including FAP-1, Bcl-2 and I-FLICE may regulate the Fas pathway in the thyroid and provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.     

Interleukin-18 overexpression as a hallmark of the activity of autoimmune inflammatory myopathies

The objective of this study was to explore the role of interleukin (IL)-18 in patients with inflammatory myopathies (IM) such as dermatomyositis (DM) and polymyositis (PM) in relation to the possible predominance of a Th1 immune response in their pathogenesis. Serum concentrations of IL-18, interferon (IFN)-gamma, IL-4 and IL-6 were measured in six patients by enzyme-linked immunosorbent assay (ELISA). IL-18 expression was evaluated by in situ hybridization (ISH), whereas CD68, CD8 and CD83 were investigated by immunohistochemistry (IHC) to define the main producers of IL-18. Lastly, the expression of both IL-18 receptor (IL-18R) and monocyte chemoattractant protein (MCP)-1 was also explored by IHC. High serum levels of IL-18 and IFN-gamma, and conversely low titres of IL-4 and IL-6, were demonstrated in both diseases. In addition, IL-18 was overexpressed in muscle biopsy specimens from patients with IM. Both macrophages and dendritic cells (DC) surrounding either perivascular and perimysium areas in DM or endomysium in PM were the main producers of IL-18. Endothelial cells (EC), smooth muscle cells (SMC) and CD8(+) T cells expressed a high content of IL-18R. Vessel cells overexpressed MCP-1 in parallel with IL-18R. High concentrations of serum IL-18 as well as muscular up-regulation of IL-18 and IL-18R suggest that deregulation of the IL-18/IL-18R pathway is a pathogenetic mechanism in IM. Measurement of IL-18 may thus predict the severity of both DM and PM.     

Evidence of apoptosis in chronic alcoholic skeletal myopathy

Apoptosis is a common mechanism of programmed cell death that has been implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in cardiac muscle. The relationship between skeletal and cardiac muscle damage in alcoholism led us to consider the possible role of apoptosis in the pathogenesis of skeletal myopathy. We prospectively evaluated apoptosis in skeletal muscle biopsies of 30 consecutively selected male high-dose well-nourished chronic alcohol consumers and 12 nonalcoholic controls. Alcohol consumption, evaluation of muscle strength by myometry, and deltoid muscle biopsy with immunohistochemical and morphometric analysis were performed. Apoptosis was assessed by TUNEL, BAX, and BCL-2 immunohistochemical assays. Chronic alcoholics compared with controls showed a significantly higher apoptotic index in TUNEL (2.35% +/- 0.25% versus 0.18% +/- 0.03%, P < 0.001), BAX (9.16% +/- 2.00% versus 0.66% +/- 0.22%, P < 0.001), and BCL-2 muscle assays (8.08% +/- 0.20% versus 0.83% +/- 0.20%, P = 0.001), respectively. In addition, these apoptotic indexes were higher in alcoholics with skeletal myopathy compared with in those without skeletal myopathy (3.04% +/- 0.36% versus 1.65% +/- 0.26%, P = 0.004 for TUNEL; 17.00% +/- 2.78% versus 1.33% +/- 0.22%, P < 0.001 for BAX; and 15.13% +/- 3.2% versus 1.03% +/- 0.33%, P < 0.001 for BCL-2 assays, respectively). We conclude that apoptosis is present in the skeletal muscle of high-dose alcohol consumers, mainly in those affected by myopathy. However, the specific pathogenic mechanism of apoptosis in chronic skeletal myopathy in alcoholics remains to be elucidated.     

Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders

When subjected to excessive oxidative stress, neurons may respond adaptively to overcome the stress, or they may activate a programmed cell death pathway called apoptosis. Apoptosis is characterized by alterations in mitochondria and the endoplasmic reticulum and activation of cysteine proteases called caspases. Increasing evidence suggests that apoptotic biochemical cascades are involved in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. Studies of normal aging, of genetic mutations that cause disease, and of environmental factors that affect disease risk are revealing cellular and molecular alterations that may cause excessive oxidative stress and trigger neuronal apoptosis. Accumulation of self-aggregating proteins such as amyloid beta-peptide, tau, alpha-synuclein, and huntingtin may be involved in apoptosis both upstream and downstream of oxidative stress. Membrane-associated oxidative stress resulting in perturbed lipid metabolism and disruption of cellular calcium homeostasis may trigger apoptosis in several different neurodegenerative disorders. Counteracting neurodegenerative processes are an array of mechanisms including neurotrophic factor signaling, antioxidant enzymes, protein chaperones, antiapoptotic proteins, and ionostatic systems. Emerging findings suggest that the resistance of neurons to death during aging can be enhanced by modifications of diet and lifestyle.     

Characterization of mononuclear exudates in idiopathic inflammatory myopathies

Summary Percentages of B-cells, T-cells and subsets Th, Ts, T activated, and macrophages were analyzed by using monoclonal antibodies in a series of 24 patients [19 dermatomyosis (DM) and 5 polymyositis (PM)]. Specific site of deposition of these cells was also identified (endomysial, perimysial and perivascular). We were able to find a greater number of endomysial T-cells in PM than in DM. However, B-cells were more frequent at perivascular sites in DM than in PM. These findings support the previous reported hypothesis that humorally-mediated immune damage in both vascular and muscle cells predominates in DM while cellular cytotoxic mediated damage is more marked in PM patients.     

The immune system in the elderly

Apoptosis is a complex cell-death process that allows cells to die in a controlled fashion. Our overall health relies to a great extent on the proper balance between the normal removal of damaged or unneeded cells via apoptosis and proliferation of the cells that comprise our body. Increasing evidence suggests that apoptosis is involved in many physiological processes and pathological conditions. It plays an important role during development, in maintaining tissue homeostasis, in responding to cellular damage, and in preventing neoplastic diseases. Apoptosis is a key regulator of clonotypic diversity generation during lymphocyte ontogenesis and is essential for the proper function of the immune system, controlling lymphocyte activation and clonal expansion following antigenic stimulation. There are various types of apoptosis, induced by different kinds of stimuli and in cells and tissues of different natures. On the basis of the nature of the apoptosis-inducing stimuli, two main apoptotic pathways can be identified: an activation-induced apoptosis, initiated by a variety of signals, such as the binding of ligands to their death-promoting receptors on the cell surface, and a damage-induced apoptosis, triggered by a damage to the nucleous or other cellular components. Apoptosis is markedly involved in many changes characteristic of immunosenescence, such as thymic involution, alteration of T-cell repertoire, accumulation of memory/effector cells, and autoimmunity. The intense investigation of the age-related changes occurring in cell-death phenomena and on their precise impact on aging has resulted in controversial data. During senescence, the activation-induced and damage-induced apoptotic pathways could be differentially modulated, with variable impacts on the aging process. Changes in either of these two main apoptotic networks that may occur during aging could lead to disease. A correct modulation of apoptosis may be useful for prolonging the lifespan or at least reducing age-related degenerative and inflammatory pathologies and neoplastic diseases whose incidence increases with age. Careful study of literature together with personal experience in the field of senescence causes us to propose a new reading register that better explains and integrates many of the apparently discordant results.     

The pathological diagnosis of specific inflammatory myopathies.

Pathological diagnosis of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) should be possible in almost all cases when an appropriately involved muscle is biopsied. DM shows characteristic patterns of muscle fiber damage and capillary damage. Lymphocytes and macrophages are seen in PM and IBM partially invading non-necrotic fibers. IBM is also characterized by rimmed vacuoles with membranous whorls, characteristic masses of filaments in cytoplasm and sometimes in nuclei, and grouped atrophic fibers. Muscle fiber damage in PM is more variable. Inflammatory myopathy can be associated with HTLV-1 and HIV infection. In the latter a strong resemblance to PM is reported. Separate, still less well characterized forms of inflammatory myopathy occur in young children.     

Apoptosis: the sculptor of development

Apoptosis is a programmed mechanism of cell death recognized by its characteristic morphological and biochemical changes. Over the last decade, our understanding of the biochemistry of apoptosis has flourished. However, the physiological relevance of apoptosis remains elusive. Here, I propose that the process of programmed cell death plays an essential role in structural development. From pioneering studies almost a century ago to recent findings using modern technology, similar conclusions have emerged that highlight the fundamental role of apoptosis in vascular development. This review will recount these classic and modern studies as I survey evidence that implicates apoptosis in other aspects of development and ask how cell death can possibly contribute to homeostasis and development of the immune system. I briefly consider the mechanisms that may determine the fate of cells within the vasculature and propose new roles for the contribution of apoptosis to development and differentiation. More provocatively, I explore the possibilities that arise from this growing field of study, including prevention of developmental defects and even abnormal development after birth, such as neoplastic development. To realize these end points, the biochemical bases of apoptosis must be thoroughly understood.     

T淋巴细胞凋亡及其调控机制的研究进展

T淋巴细胞凋亡是免疫系统维持稳定的一种重要机制,在多种疾病中起着重要作用.fas/FasL、Trail/trail受体等死亡受体信号传导可介导T淋巴细胞凋亡,线粒体在诱导细胞凋亡中也起着重要作用;而bcl-2家族、v-FLIP等抗细胞凋亡蛋白和转录因子Nur77等对T淋巴细胞凋亡起调控作用.     

Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity.

Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD). Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle alpha-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0-5+/5+ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle alpha-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.     

Molecular mechanisms of liver injury: Apoptosis or necrosis

Hepatic apoptosis is thought of as a prevalent mechanism in most forms of liver injury. However, the role of hepatic apoptosis is often intermixed with the cellular necrosis. It remains unknown how apoptosis is relevant to the progression of the liver injury. This review summarizes the characteristics of both hepatic apoptosis and necrosis in pathogenesis of liver diseases. Apoptosis and necrosis represent alternative outcomes of different etiology during liver injury. Apoptosis is a main mode of cell death in chronic viral hepatitis, but is intermingled with necrosis in cholestatic livers. Necrosis is the principal type of liver cell killing in acetaminophen-induced hepatotoxicity. Anti-apoptosis as a strategy is beneficial to liver repair response. Therapeutic options of liver disease depend on the understanding toward pathogenic mechanisms of different etiology.     

Altered RIG‐I/DDX58‐mediated innate immunity in dermatomyositis

We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments^? using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up‐regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid‐inducible gene 1 (RIG‐I, DDX58) and the novel antiviral factor DDX60, which promotes RIG‐I‐mediated signalling, were significantly up‐regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over‐expression of RIG‐I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG‐I produced a significant secretion of interferon‐β (IFNβ; p < 0.05) and up‐regulation of class I MHC, RIG‐I and TLR3 (p < 0.05) by IFNβ‐dependent and TLR3‐independent mechanisms. RIG‐I‐mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd     

"Tissue" transglutaminase in AIDS

Apoptosis or programmed cell death (PCD) is an active process of cellular self-destruction, essential for embryonic development and maintenance of homeostasis of multicellular organisms. Programmed cell death induction can serve as a defence mechanism of the host against intracellular microbes. Virus infections trigger host cell apoptosis, which can either limit virus production or contribute directly to viral pathogenesis.Several independent laboratories have identified "tissue" transglutaminase (tTG) as a potentially important player of the cell death program(s). This gene is specifically expressed in cells dying during mammalian development as well as in those undergoing apoptosis in various patho-physiological and experimental settings [Eur. J. Cell Biol. 56 (1991) 170; Piacentini, M., Davies, P.J.A., Fesus, L., 1994. Tissue transglutaminase in cells undergoing apoptosis. In: Tomei, L.D., Cope, F.O. (Eds.), Apoptosis II: The molecular basis of apoptosis in disease. Cold Spring Harbor Lab. Press, pp. 143-165.]. This chapter reviews recent studies concerning the expression and the possible role of "tissue" transglutaminase (tTG) in apoptotic cells; particular emphasis is given to its expression in the cell death pathways associated with HIV infection in the immune system.We propose here that the induction of the tTG gene in cells of the immune system, as well as the detection of the isodipeptide epsilon(gamma-glutamyl)lysine in plasma, are useful markers of apoptosis and might make it possible to monitor disease progression in HIV-infected individuals.     

Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world and exists as subtypes with very different clinical courses. CLL is generally described as a disease of failed apoptosis. Apoptosis resistance may stem from a combination of microenvironmental survival signals as well as from intrinsic alterations in the apoptotic machinery within the CLL cell. The molecular mechanism involved in controlling apoptosis in CLL is complex and is influenced by many factors, including Bcl-2 family proteins, which are critical regulators of cell death. Here we review the significance of apoptosis dysregulation in CLL, focusing on the role of Bcl-2 and related Bcl-2 family proteins, such as Bax and Mcl-1. The differential properties of the newly described subsets of CLL are also highlighted.     

Links between apoptosis, proliferation and the cell cycle

Many physiological processes, including proper tissue development and homeostasis, require a balance between apoptosis and cell proliferation. All somatic cells proliferate via a mitotic process determined by progression through the cell cycle. Apoptosis (programmed cell death) occurs in a wide variety of physiological settings, where its role is to remove harmful, damaged or unwanted cells. Apoptosis and cell proliferation are linked by cell-cycle regulators and apoptotic stimuli that affect both processes. This review covers recent developments in the field and examines new evidence of the interconnection between apoptosis and cell proliferation.     

Evidence for apoptosis in human atherogenesis and in a rat vascular injury model.

Apoptosis is a physiological cell death process important for normal development and involved in many pathological conditions. In atherosclerosis, pathological accumulation of cells in the intima has been attributed to the migration and proliferation of smooth muscle cells, macrophages, and lymphocytes. In this report, we explored the possibility that apoptosis may also contribute to the pathogenesis of this disease. We examined 35 human atherosclerotic lesion samples and identified a substantial number of cells undergoing apoptosis in 25 of the samples. Furthermore, in a rat vascular injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptotic cells was demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, nuclear staining with propidium iodide, and electron microscopy. Immunostaining with cell-type-specific markers and subsequent terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling analysis on the same sample revealed that the majority of the apoptotic cells were modulated smooth muscle cells as well as macrophages. These results indicate that apoptosis occurs in cells of the injured blood vessel as well as the advanced atherosclerotic lesion and that physiological cell death may have an important role in determining the course of atherogenesis.     

Update on idiopathic inflammatory myopathies

The inflammatory myopathies are a group of acquired diseases, characterized by an inflammatory infiltrate of the skeletal muscle. On the basis of clinical, immuno-pathological and demographic features, three major diseases can be identified: dermatomyositis (DM); polymyositis (PM); and inclusion body myositis (IBM). New diagnostic criteria have recently been introduced, which are crucial for discriminating between the three different subsets of inflammatory myopathies and for excluding other disorders. DM is a complement-mediated microangiopathy affecting skin and muscle. PM and IBM are T cell-mediated disorders, where CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I antigens, thus leading to fibre necrosis. In IBM, vacuolar formation with amyloid deposits are also present. This article summarizes the main clinical, laboratory, electrophysiological, immunological and histologic features as well as the therapeutic options of the inflammatory myopathies.     

Host-Cell Survival and Death During Chlamydia Infection

Different Chlamydia trachomatis strains are responsible for prevalent bacterial sexually-transmitted disease and represent the leading cause of preventable blindness worldwide. Factors that predispose individuals to disease and mechanisms by which chlamydiae cause inflammation and tissue damage remain unclear. Results from recent studies indicate that prolonged survival and subsequent death of infected cells and their effect on immune effector cells during chlamydial infection may be important in determining the outcome. Survival of infected cells is favored at early times of infection through inhibition of the mitochondrial pathway of apoptosis. Death at later times displays features of both apoptosis and necrosis, but pro-apoptotic caspases are not involved. Most studies on chlamydial modulation of host-cell death until now have been performed in cell lines. The consequences for pathogenesis and the immune response will require animal models of chlamydial infection, preferably mice with targeted deletions of genes that play a role in cell survival and death.     

Apoptosis in heart and skeletal muscle.

Apoptosis, or programmed cell death, is now recognized to be an important cellular event during normal development and in the progression of specific diseases. Apoptosis can be triggered by stimuli initiating outside of the cell, or within the mitochondria, leading to the activation of caspases and subsequent cell death. Although apoptosis has been widely studied in a variety of tissues over the last 5 years, skeletal muscle and heart have been relatively ignored in this regard. Research on apoptosis in cardiac muscle has recently taken on a higher profile as the recognition emerges that it may be an important contributor to specific cardiac pathologies, particularly in response to ischemia-reperfusion in which reactive oxygen species are formed. In skeletal muscle, very few studies have been done under specific physiological (e.g., exercise) and pathophysiological (e.g., dystrophies, denervation, myopathies) conditions. Skeletal muscle is unique in that it is multi-nucleated, and evidence suggests that it can undergo individual myonuclear apoptosis as well as complete cell death. This review discusses the basic cellular mechanisms of apoptosis, as well as the current evidence of this process in cardiac and skeletal muscle. The need for more work in this area is highlighted, particularly in exercise and training.