Chronic.pdf

Chronic inflammation Objective 1. definition of chronic inflammation. 2. Identify the cells of chronic inflammation. 3.To know the processes of chronic inflammation. 4.Etiology and main features of granulomatous. 5. Recognition the sequence of events in tissue repair. 6. the processes of...

Chronic inflammation Objective 1. definition of chronic inflammation. 2. Identify the cells of chronic inflammation. 3.To know the processes of chronic inflammation. 4.Etiology and main features of granulomatous. 5. Recognition the sequence of events in tissue repair. 6. the processes of healing in first & second intension. 7. Factor affect healing process. 8.Understand the healing process of bone fracture. ‫زينب العلي‬.‫د‬.‫م‬.‫ا‬ Definition Inflammation of prolonged duration (weeks to months to years) in which active on inflammation , tissue injury , & healing proceed simultaneously Characters Chronic inflammation arises in settings of: Persistent infection Immune-mediated inflammation diseases Prolonged exposure to potentially toxic agents. Morphology of chronic inflammation Chronic inflammation is of prolong duration & microscopically characterized by Inflammation Tissue distraction Repair. Cells Involved in Chronic Inflammation Monocytes/Macrophages Plasma Cells Dendritic Cells Acute Inflammatory Cells Fibroblasts Monocytes/Macrophages Activated macrophages and their cytokines are central to initiating inflammation and prolonging responses that leadto chronic inflammation Activated macrophage produce variety of biologically activated product include: 1.acide &neutral proteases. 2. ROS & NO 3. arachidonic acid (AA )metabolites. 4. cytokines such as IL-1& TNF, variety of growth factors  Cells Involved in Chronic Inflammation Monocytes/Macrophages Plasma Cells Dendritic Cells Acute Inflammatory Cells Fibroblasts These cells are then diffusely scattered in various parts of the body, in the liver (Kupffer cells), spleen, lymph nodes (sinus histiocytes), lungs (alviolar macrophages), bone marrow, brain (microglia), skin(Langerhan’s cells), etc…. These cells constitute the mononuclear- phagocytic system. 􀂾 Macrophages are scavenger cells of the body. Macrophage-lymphocyte interactions in chronic inflammation. Activated lymphocytes and macrophages influence each other and also release inflammatory mediators that.affect other cells Granulomatous Inflammation A distinctive pattern of chronic inflammation characterized by aggregation of activated macrophages that have been modified but acquiring an enlarged squamous cell-like appearance ,these cell called epithelioid cells (granulomatous inflammation) Definition: Granulomatous inflammation is characterized by the presence ofgranuloma. A granuloma is a microscopic aggregate of epithelioid cells. Epithelioid cellis an activated macrophage, with a modified epithelial cell-like appearance (hence the name epithelioid). The epitheloid cells can fuse with each other & form multinucleated giant cells. So, even though, a granuloma is basically a collection of epithelioid cells, it also usually contains multinucleated giant cell & is usually surrounded by a cuff of lymphocytes and occasional plasma cells. There are two types of giant cells a. Foreign body-type giant cells which have irregularly scattered nuclei in presence of indigestible materials. b. Langhans giant cells in which the nuclei are arranged peripherally in a horse -shoe 2 pattern of multinucleated giant cell 1.Langhans giant cell 2.foreign A Langhansbody giantcell giant cellshows nuclei arranged on the periphery of an abundant.cytoplasm Major causes of granulomatious inflammation include: a) Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis b) Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis c) Helminthic: Schistosomiasis d) Protozoal: Leishmaniasis, Toxoplasmosis e) Chlamydia: Lymphogranuloma venerum f) Inorganic material: Berrylliosis g) Idiopathic: Acidosis, Cohn’s disease, Primary biliary cirrhosis Repair restoration of tissue architecture & function after an injury. Repair processes are critical for the maintenance of normal structure and function and survival of the organism. It either regeneration or healing that result in scar formation Regeneration refers to growth of cells and tissues to replace lost structures. Healing is the processes occurs when the injure tissues are incapable of complete restitution ,or if the supporting structures of the tissue are severely damaged ,repair laying down by connective (fibrous)tissue.  Regeneration requires an intact connective tissue scaffold,if it damage ,repair can only be accomplished by scar formation.ECM provide the framework for cell migration and maintain the correct cell polarity for the re-assembly of multilayer structures.& it a source of agents that are critical for tissue repair. Fibrosis extensive deposition of collagen that occur in many organe as consequence of chronic inflammation. organization it occur if the fibrosis occur in the tissue space. The figure shows the cell-cycle phases (G0 , G1 , G2 , S, and M), the location of the G1 restriction point, and the G1 /S and G2 /M cell-cycle checkpoints SIGNALING MECHANISMS IN CELL GROWTH All growth factors function by binding to specific receptors, which deliver signals to the target cells. The first event that initiates cell proliferation is, usually, the binding of a signaling molecule, the ligand, to a specific cell receptor. Types of effect of GF 1. Autocrine effect : effect on cell that secreted them. 2.Paracrine effect : near cells adjacent to it. 3.Endocrine effect : enter blood stream & reach target. 4.Synaptic effect : Seen in neural tissue & muscles. Repair by Healing, Scar Formation, and Fibrosis It is a complex but orderly phenomenon involving a number of processes: 1.heamostasis. 2. inflammation. 3.Prolifration. 4. Remolding an inflammatory process in response to the initial injury, with removal of damaged and dead tissue Proliferation and migration of parenchymal and connective tissue cells.  Formation of new blood vessels (angiogenesis) and granulation tissue.  Synthesis of ECM proteins and collagen deposition.(this control by PDGF,b- FGF& TGF ),deposition maily collagen type lll then replaced after several weeks by collagen l which response for strength .Tissue remodeling.  Wound contraction. Acquisition of wound strength. Not all of these events occur in every repair reaction. Staging the repair by time  Repair begins early in inflammation, as early as 24 hours after injury, if resolution has not occurred.  3-5 day fibroblasts and vascular endothelial cells begin proliferating to form a specialized type of tissue that is the hallmark of healing, called granulation tissue.(the hall make of healing  its pink, soft, granular appearance on the surface of wounds, histologic features are characteristic: the formation of new small blood vessels (angiogenesis) and the proliferation of fibroblasts. These new vessels are leaky, allowing the passage of proteins and red cells into the extravascular space. Thus, new granulation tissue is often edematous. A, Granulation tissue showing numerous blood vessels, edema, and a loose ECM containing occasional inflammatory cells. B, Trichrome stain of mature scar, showing dense collagen, with only scattered vascular channels. B.groos appearance pink soft & granular. Cutaneous Wound Healing Cutaneous wound healing is generally divided into three phases: (1) inflammation (early and late). (2) granulation tissue formation and re-epithelialization. (3) wound contraction, ECM deposition, and remodeling. Healing by primary intention. (4) An initial open, (5) incised wound with closely apposed wound edges held together with a suture and minimal tissue loss. (6) There is decreased granulation tissue. Such a wound requires only minimal cell proliferation and revascularization to heal. (7) The result is a narrow, linear scar. The narrow incisional space immediately fills with clotted blood ,dehydration of the surface clot forms the well-known scab that covers the wound. The healing process follows a series of sequential steps: Within 24 hours, neutrophils are seen at the incision Margin. Within 24 to 48 hours, epithelial cells from both edges have begun to migrate and proliferate along the dermis, depositing basement membrane components as they progress. By day 3, the neutrophils have been largely replaced by macrophages. Granulation tissue progressively invades the incision space. By day 5, the incisional space is filled with granulation tissue. Neovascularization is maximal. During the second week, there is continued accumulation of collagen and proliferation of fibroblasts.  By the end of the first month, the scar is made up of a cellular connective tissue devoid of inflammatory infiltrate, covered now by intact epidermis. Steps of healing by second intention (healing by second union): When tissue loss is more extensive the repair is more complex associated with: - more intense inflammatory reaction. - more abundant granulation tissue. - the wound contract by myo-fibroblasts. - followed by formation of large scar. This occur in these situations: A. Large wounds. B. Abscesses. C. Ulcerations. D. After infarction in paranchymal organs. HEALING BY SECOND INTENTION (WOUNDS WITH SEPARATED EDGES) Regeneration of parenchymal cells cannot completely restore the original architecture, and hence abundant granulation tissue grows in from the margin to complete the repair. Secondary healing differs from primary healing in several respects: large tissue defects generate a larger fibrin clot that fills the defect and more necrotic debris and exudate. the inflammatory reaction is more intense. Much larger amounts of granulation tissue are formed. wound contraction, which occurs in large surface wounds. COMPLICATIONS IN CUTANEOUS WOUND HEALING (1) deficient scar formation (2) excessive formation of the repair components(Aberrations of growth ) hypertrophic scar. keloid. exuberant granulation. (3) formation of contractures. Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in diabetic patients. The histology slides show B, a skin ulcer with a large gap between the edges of the lesion; C, a thin layer of epidermal reepithelialization and extensive granulation tissue formation in the dermis; and D, continuing reepithelialization of the epidermis and wound contraction  Factors That Retard Wound Healing Local Factors Blood supply Mechanical stress Denervation Necrotic tissue Local infection Protection (dressings) Foreign body Surgical techniques Hematoma Type of tissue Systemic Factors Age Malnutrition Anemia Obesity Drugs (steroids, cytotoxic medications, Systemic infection intensive antibiotic therapy) Temperature Trauma, hypovolemia, and hypoxia Genetic disorders (osteogenesis imperfecta, Ehlers-Danlos syndromes, Marfan syndrome) Uremia Vitamin deficiency (vitamin C) Hormones Trace metal deficiency (zinc, copper) Diabetes Malignant disease Fracture is defined as loss of bone integrity resulting from mechanical injury and/or diminished bone strength. Fractures are the most common pathologic conditions affecting bone. The following qualifiers describe fracture types and affect treatment: Simple: the overlying skin is intact Compound: the bone communicates with the skin surface Comminuted: the bone is fragmented Displaced: the ends of the bone at the fracture site are not aligned. Stress: a slowly developing fracture that follows a period of increased physical activity in which the bone is subjected to repetitive loads Greenstick: extending only partially through the bone, common in infants when bones are soft Pathologic: involving bone weakened by an underlying disease process, such as a tumor. Fracture is defined as loss of bone integrity resulting from mechanical injury and/or diminished bone strength. Fractures are the most common pathologic conditions affecting bone. fracture healing  Fracture healing shares many similarities with soft-tissue healing but its ability to be completed without the formation of a scar is unique.  Fracture healing involves complex processes of cell and tissue proliferation and differentiation.  Many players are involved, including growth factors, inflammatory cytokines, antioxidants, bone breakdown (osteoclast) and bone‐building (osteoblast) cells, hormones, amino acids, and uncounted nutrients. Healing of Fractures  Fracture repair involves regulated expression of a multitude of genes and can be separated into overlapping stages with particular molecular, biochemical, histologic, and biomechanical features.  Bone healing, or fracture healing, is a proliferative physiological process in which the body facilitates the repair of a bone fracture. Fracture healing can be divided into three phases:  Inflammatory phase  Repair phase  Remodeling phase   Schematic representation of inflammation and repair during fracture healing aes, Stefan Recknagel and Anita Ignatius. Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol. 8, 133–143 (201  Inflammatory phase:  The defect is initially filled with hematoma and there is intense inflammation Dominique J Griffon. Fracture healing Inflammatory  Immediately after fracture, rupture of blood vessels results in a hematoma, which fills the fracture gap and surrounds the area of bone injury.  The clotted blood provides a fibrin mesh, sealing off the fracture site and creating a scaffold for the influx of inflammatory cells and the ingrowth of fibroblasts and new capillaries  degranulated platelets and migrating inflammatory cells release PDGF, TGF-β, FGF, and other factors that activate osteoprogenitor cells in the periosteum, medullary cavity, and surrounding soft tissues and stimulate osteoclastic and osteoblastic activity 2. Repair phase: This is quickly replaced by granulation tissue.  By the end of the first week, a mass of predominantly uncalcified tissue— called soft callus or procallus—provides anchorage between the ends of the fractured bones.  After approximately 2 weeks, the soft callus is transformed into a bony callus The activated osteoprogenitor cells deposit woven bone. In some cases, the activated mesenchymal cells in the soft tissues and bone surrounding the fracture line also differentiate into chondrocytes that make fibrocartilage and hyaline cartilage. The newly formed cartilage along the fracture line undergoes endochondral ossification, forming a contiguous network of bone with newly deposited bone trabeculae in the medulla and beneath the periosteum.  In this fashion the fractured ends are bridged  Over the weeks a fibrocartilaginous callus is formed. Mineralization leads to formation of a hard callus 3. Remodeling phase: a hard callus becoming fusiform and slowly disappearing as Haversian remodeling progresses. As the callus matures and is subjected to weight bearing forces, portions that are not physically stressed are resorbed. This remodeling reduces the size of the callus until the shape and outline of the fractured bone are reestablished as lamellar bone. The healing process is complete with restoration of the medullary cavity. Factors that affect fracture healing  Many risk factors for impaired fracture healing exist:  Type of injury (fracture geometry, degree of open injury, mechanism of injury).  Fracture treatment (type of fixation, size of fracture gaps);  Gender, age.  Comorbidities (diabetes mellitus, malnutrition, peripheral vascular disease, hypothyroidism, polytrauma).  Medications (NSAIDs, corticosteroids, antibiotics, anticoagulants); smoking; and alcohol consumption.  Infection of the fracture site, especially common in open fractures, is a serious obstacle to healing  Inadequate immobilization permits movement of the callus and prevents its normal maturation, resulting in delayed union or nonunion. If a nonunion persists, the malformed callus undergoes cystic degeneration, and the luminal surface may become lined by synovial-like cells, creating a false joint or pseudoarthrosis.