Unique protective function of Kupffer cells

Kupffer cells The most important function of Kupffer cells is defense against infections and tumor cells. Kupffer cells act as antigen presenting cells and as effector cells that act directly by phagocytosis, or indirectly by activation of other cells, e.g. NK cells. Though Kupffer cells are constantly acting as scavengers, they can be activated through different pathways. Firstly, soluble mediators can trigger their activation. IFN-γ is the prototypical macrophage activating factor. It is central to the development of Th1-dominated immune responses, and it affects not only macrophages in an autocrine fashion, but other immune cells as well.One of the key events during innate immune reactions is the production of IL-12, mainly by macrophages. IL-12 induces NK cells to rapidly secrete IFN-γ, which then in turn activates macrophages early in the immune response. It also induces IFN-γ production by T cells. IL- 18, which is produced by Kupffer cells and other cell types, is also involved in enhancing IFN-γ production by T cells. Macrophages also secrete IFN-γ upon stimulation with IL-12 and IL-18 together. It is known that IFN-γ is a possible reducer of metastasis of colon cancer in the liver. Macrophages can also be activated by direct interaction with micro-organisms or bacterial products such as lipopoly-saccharide, glucan, muramyl dipeptide and lipid A[52]. A pivotal role for IFN-γ in the clearance of various intracellular pathogens has been amply demonstrated. It has been described that macrophages release the cytotoxic radical, NO. In vitro studies suggested that NO induces mitochondrial dysfunction in tumor cells followed by membrane barrier dysfunction in the liver sinusoid. Another important cytotoxic factor released by activated macrophages is tumor necrosis factor alpha (TNF-α), which is produced in both soluble and membrane-bound forms. After binding to its receptor, apoptosis can be induced in the target cell.Cytotoxicity of macrophages can be classified into antibody-dependent and antibody-independent cell-mediated cytotoxicity. Both pathways are contact dependent and induce tumor cell death after a number of hours. Antibody-dependent cell-mediated cytotoxicity is based on the recognition of an antibody-coated target by Fc receptors on the effector cells. Upon cross-linking of the Fc receptor, secretion of cytotoxic mediators occurs. Secretion of reactive oxygen species, IL-1 and TNF-α are probably involved. Antibody-independent cell-mediated cytotoxicity involves binding to the macrophage followed by translocation of the lysosomal organelles to the target. Moreover, cytotoxicity towards tumor targets involves cytolysis and phagocytosis.In certain pathophysiologic conditions, apoptosis is chaotic and non-selective, may be massive and occurs persistently over an extended period of time. A large number of apoptotic bodies produced are phagocytosed by Kupffer cells. It has recently been reported that engulfment of apoptotic bodies results in the generation of death ligands, such as FasL and TNF-α on the membrane of the Kupffer cells, but engulfment of latex beads does not produce a similar response. This means that uptake of apoptotic bodies induces an additional immunologic response involving liver inflammation and fibrosis

Liver stellate cells: magnificent characteristics in human cell biology

Hepatic stellate cells (HSCs), a mesenchymal cell type in hepatic parenchyma, have unique features with respect to their cellular origin, morphology, and function. Normal, quiescent HSCs function as major vitamin A-storing cells containing over 80% of total vitamin A in the body to maintain vitamin A homeostasis. HSCs are located between parenchymal cell plates and sinusoidal endothelial cells, and extend well-developed, long processes surrounding sinusoids in vivo as pericytes. However, HSCs are known to be ‘activated’ or ‘transdifferentiated’ to myofibroblast-like phenotype lacking cytoplasmic lipid droplets and long processes in pathological conditions such as liver fibrosis and cirrhosis, as well as merely during cell culture after isolation. HSCs are the predominant cell type producing extracellular matrix (ECM) components as well as ECM degrading metalloproteases in hepatic parenchyma, indicating that they play a pivotal role in ECM remodeling in both normal and pathological conditions. Recent findings have suggested that HSCs have a neural crest origin from their gene expression pattern similar to neural cell type and/or smooth muscle cells and myofibroblasts. The morphology and function of HSCs are regulated by ECM components as well as by cytokines and growth factors in vivo and in vitro. Liver regeneration after partial hepatectomy might be an invaluable model to clarify the HSC function in elaborate organization of liver tissue by cell-cell and cell-ECM interaction and by growth factor and cytokine regulation

Fibroblastic cell subpopulations role during hepatic damаge

Accumulation of extracellular matrix observed in fibrosis and cirrhosis is due to the activation of fibroblasts, which acquire a myofibroblastic phenotype. Myofibroblasts are absent from normal liver. They are produced by the activation of precursor cells, such as hepatic stellate cells and portal fibroblasts. These fibrogenic cells are distributed differently in the hepatic lobule: the hepatic stellate cells resemble pericytes and are located along the sinusoids, in the Disse space between the endothelium and the hepatocytes, whereas the portal fibroblasts are embedded in the portal tract connective tissue around portal structures (vessels and biliary structures). Differences have been reported between these two fibrogenic cell populations, in the mechanisms leading to myofibroblastic differentiation, activation and “deactivation”, but confirmation is required. Second-layer cells surrounding centrolobular veins, fibroblasts present in the Glisson capsule surrounding the liver, and vascular smooth muscle cells may also express a myofibroblastic phenotype and may be involved in fibrogenesis. It is now widely accepted that the various types of lesion (e.g., lesions caused by alcohol abuse and viral hepatitis) leading to liver fibrosis involve specific fibrogenic cell subpopulations. The biological and biochemical characterisation of these cells is thus essential if we are to understand the mechanisms underlying the progressive development of excessive scarring in the liver. These cells also differ in proliferative and apoptotic capacity, at least in vitro. All this information is required for the development of treatments specifically and efficiently targeting the cells responsible for the development of fibrosis/cirrhosis

Histological Changes of Linear Scleroderma “en Coup de Sabre”

Introduction. Scleroderma is a chronic disease of unknown aetiology characterized by skin fibrosis and is divided into two clinical entities: localized scleroderma and systemic sclerosis. But the localized scleroderma is not accompanied by Raynaud’s phenomenon, acrosclerosis and internal organ involvement and the life prognosis of patients with localized scleroderma is good. Scleroderma “en coup de sabre” (ECDS) is considered a linear localized form of scleroderma or morphoea. It usually involves, unilaterally, the frontoparietal area, but may extend downwards to the face. Most cases begin before 10 years of age. The aim of our study was to investigate the histological characteristics and their clinical association in ECDS. Materials and methods. The present study was carried out at the Department of Dermatology and Venereology in Tbilisi State Medical University. 11 patients (2 men and 9 women) with lesions clinically and histologically diagnosed as ECDS were retrospectively included. Patients who were treated with immunomodulating agents, including systemic corticosteroids and immunosuppressants before presentation, or patients complicated with Parry – Romberg syndrome were excluded from the study. All patients were subjected to: history taking including: age, sex, duration of the disease, family history; clinical examination; skin biopsy – evaluated for epidermal atrophy, spongiosis, vacuolar degeneration of basal cell layer, satellite cell necrosis, basal pigmentation, melanin incontinence, perivascular infiltrate, perineural infiltrate, periappendageal infiltrate, vacuolar changes of follicular epithelium and dermal fibrosis. Results. All ECDS patients demonstrated epidermal lymphocytic infiltrate, tagging of lymphocytes along the dermo-epidermal junction and vacuolar changes, regardless of disease duration, clinical presentation and the intensity of perivascular lymphocytic infiltrate. Furthermore, when we defined patients with disease duration of < 3 years and of ≥ 6 years, respectively, the degrees of perivascular and/or peri-appendageal infiltrate and vacuolar changes of follicular epithelium were much greater, whereas epidermal atrophy was less frequently seen, in early ECDS patients than in late ECDS patients. The intensity of interface dermatitis in epidermis was comparable between early and late ECDS lesions. Also it’s important to mention, that in our study in early stage localized scleroderma the characteristic histological finding is not only perivascular lymphocytic infiltrate. Vacuolar changes in epidermis is also a common histological feature in the sites of damaged skin of ECDS patients and vacuolar changes in follicular epithelium and peri-appendageal infiltrate serve as a histological marker of early and active ECDS lesions in addition to perivascular infiltrate. Conclusions. Although the pathogenesis of localized scleroderma still remains unknown, the present observation and received results are useful to determine the activity of skin lesions in ECDS and provide us a new clue to further understand the pathogenesis of this disorder

Morphological basis of the aging erythrocytes deformability

Red blood cells are flexible and oval biconcave disks, they lack a cell nucleus and their disk diameter is 7–10 μm. Approximately 2.4 million new erythrocytes are produced per second and circulate for about 100–120 days in the body. Red blood cells are cells present in blood in order to transport oxygen, the aging red blood cell undergoes changes making it susceptible to selective recognition by macrophages and subsequent phagocytosis. The cytoplasm of erythrocytes is rich in hemoglobin, an iron-containing biomolecule that can bind oxygen and is responsible for the red colour of the cells. Immature red blood cells are lacking the red hemoglobin pigment so these cells are often shades of grayish blue, only mature cells are red.A glycophorin is a sialoglycoprotein of the membrane of a red blood cell, that contains N-acetylneuraminic acid. Ions such as Na+ and Ca2+ can diffuse rapidly through it and can be for 60% it`s negative charge of the plasma membrane. Typical human red blood cell has a diameter of approximately 6.2–8.2 μm, a thickness - 2 μm, circumference – 76-110 μm, speed no more than 2 cm/ sec that is enough to transport oxygen from hemoglobin toward myoglobin. Listed features are changed depending on the lifespan of red blood cells: 1. Decreases the percentage of hemoglobin content, within the part of it is broken down. 2. Changes occurs in the activities electronic change in oxidation and restoration of Fe. 3. As erythrocyte ages, it undergoes changes in its plasma membrane, in particular sialic acid activity. 4. Erythrocyte membrane becomes inflexible, less elastic and rough. 5. Worn-out red blood cells (100-120 day) have a limited functional significance.As a result of this research, both functional and physical indicators are strictly differentiated regarding to human age: 1. The length of erythrocyte life in the elderly (70-75) is twice longer than in younger people (25-30). 2. Red blood cells are remarkably deformable in younger than in elderly people. 3. Because of decreased deformability of the red blood cell, they have trouble to squeeze through capillaries which is the reason of hemodynamics local violations