Inflammation PDF

INFLAMMATON Prof. Dr. Rafal Al-Saigh MBChB, PhD, FIBMS Pathology Specialist Pathologist  Inflammation Host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage OR reaction of tissues to various injurious stimuli...

INFLAMMATON Prof. Dr. Rafal Al-Saigh MBChB, PhD, FIBMS Pathology Specialist Pathologist  Inflammation Host response to foreign invaders and necrotic tissue, but it is itself capable of causing tissue damage OR reaction of tissues to various injurious stimuli a protective response → remove the initial cause of cell injury, necrotic cells and tissues have harmful effects like anaphylactic shock, rheumatoid arthritis and atherosclerosis The main components of inflammation 1. Vascular reaction 2. Cellular response Both are activated by mediators derived from plasma proteins and various cells. The steps of the inflammatory response (1) recognition of the injurious agent, (2) recruitment of leukocytes, (3) removal of the agent, (4) regulation (control) of the response, (5) resolution (repair).  Features of Acute and Chronic Inflammation Feature Acute Chronic Onset Fast: minutes or hours Slow: days Cellular infiltrate Mainly neutrophils Monocytes/ macrophages and lymphocytes Tissue injury, fibrosis Usually mild and self-limited Often severe and progressive Local and systemic signs Prominent Less prominent; may be subtle Acute inflammation short duration (few minutes - few days) 1.Vascular changes leading to increased blood flow (hyperæmia). 2.Microvascular structural changes leading to leakage of plasma proteins (exudation). 3.Emigration of leukocytes (neutrophilic) towards the site of injury. The outcome of acute inflammation is either elimination of the noxious stimulus, followed by decline of the reaction and repair of the damaged tissue, or persistent injury resulting in chronic inflammation. ▪ heat (calor) ▪ redness (rubor) ▪ swelling (tumour) ▪ pain (dolor) ▪ loss of function (functio læsa)  Reaction of Acute Inflammation 1. Vasodilation is induced by chemical mediators such as histamine (described later) and is the cause of erythema and stasis of blood flow. 2. Increased vascular permeability is induced by histamine, kinins, and other mediators that produce gaps between endothelial cells; by direct or leukocyte- induced endothelial injury; and by increased passage of fluids through the endothelium. 3. This increased permeability allows plasma proteins and leukocytes to enter sites of infection or tissue damage; fluid leak through blood vessels results in edema. Leukocyte Recruitment to Sites of Inflammation Leukocytes are recruited from the blood into the extravascular tissue, where infectious pathogens or damaged tissues may be located, and are activated to perform their functions. Leukocyte recruitment is a multi-step process consisting of loose attachment to and rolling on endothelium (mediated by selectins); firm attachment to endothelium (mediated by integrins); and migration through interendothelial spaces. Various cytokines promote expression of selectins and integrin ligands on endothelium (TNF, IL-1), increase the avidity of integrins for their ligands (chemokines), and promote directional migration of leukocytes (also chemokines); many of these cytokines are produced by tissue macrophages and other cells responding to pathogens or damaged tissues. Neutrophils predominate in the early inflammatory infiltrate and are later replaced by macrophages. Leukocyte Effector Mechanisms Leukocytes can eliminate microbes and dead cells by phagocytosis, followed by their destruction in phagolysosomes. Destruction is caused by free radicals (ROS, NO) generated in activated leukocytes and lysosomal enzymes. Enzymes and ROS may be released into the extracellular environment. The mechanisms that function to eliminate microbes and dead cells (the physiologic role of inflammation) are also capable of damaging normal tissues (the pathologic consequences of inflammation). Major Cell-Derived Mediators of Inflammation Vasoactive amines—histamine, serotonin: Their main effects are vasodilation and increased vascular permeability. Arachidonic acid metabolites—prostaglandins and leukotrienes: Several forms exist and are involved in vascular reactions, leukocyte chemotaxis, and other reactions of inflammation; they are antagonized by lipoxins. Cytokines: These proteins, produced by many cell types, usually act at short range; they mediate multiple effects, mainly in leukocyte recruitment and migration; principal ones in acute inflammation are TNF, IL-1, IL-6, and chemokines. ROS: Roles include microbial killing and tissue injury. NO: Effects are vasodilation and microbial killing. Lysosomal enzymes: Roles include microbial killing and tissue injury. Plasma Protein–Derived Mediators of Inflammation Complement proteins: Activation of the complement system by microbes or antibodies leads to the generation of multiple breakdown products, which are responsible for leukocyte chemotaxis, opsonization and phagocytosis of microbes and other particles, and cell killing. Coagulation proteins: Activated factor XII triggers the clotting, kinin, and complement cascades and activates the fibrinolytic system. Kinins: Produced by proteolytic cleavage of precursors, this group mediates vascular reaction and pain. Sequence of Events in Acute Inflammation The vascular changes are characterized by increased blood flow secondary to arteriolar and capillary bed dilation (erythema and warmth). Increased vascular permeability, as a consequence of either widening of interendothelial cell junctions of the venules or direct endothelial cell injury, results in an exudate of protein-rich extravascular fluid (tissue edema). The leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules and then leave the microvasculature and migrate to the site of injury under the influence of chemotactic agents. Phagocytosis, killing, and degradation of the offending agent follow. Genetic or acquired defects in leukocyte functions give rise to recurrent infections. The outcome → removal of the exudate with restoration of normal tissue architecture (resolution); transition to chronic inflammation; or extensive destruction of the tissue resulting in scarring. Benificial Effects of Acute Inflammation 1. Dilution of toxins. 2. Exudation of protective antibodies. 3. Fibrin formation which delays bacterial spread. 4. Exudation of plasma mediators (complement, coagulation, fibrinolytic and kinin). 5. Exudation of nutrient materials. 6. Promotion of immunity. Outcomes of Acute Inflammation 1. Complete resolution to histologic and functional normality. 2. Fibrosis: Occurs in A. When inflammation in tissues that do not regenerate. B. After substantial tissue destruction. C. Extensive fibrinous exudates. 3. Abscess formation in pyogenic infection. 4. Progression to chronic inflammation Chronic inflammation longer duration (days or years) ❖ Infiltration by mononuclear cells (monocytes, lymphocytes & macrophages. ❖Tissue destruction. ❖Tissue repair. (vascular proliferation and fibrosis). Causes 1.Persistent infections like tuberculosis, syphilis. 2.Prolonged exposure to potentially toxic agents. 3.Autoimmune disorders. Features of Chronic Inflammation Prolonged host response to persistent stimulus Caused by microbes that resist elimination, immune responses against self and environmental antigens, and some toxic substances (e.g., silica); underlies many important diseases Characterized by persistent inflammation, tissue injury, attempted repair by scarring, and immune response Cellular infiltrate consisting of activated macrophages, lymphocytes, and plasma cells, often with prominent fibrosis. Mediated by cytokines produced by macrophages and lymphocytes (notably T lymphocytes), with a tendency to an amplified and prolonged inflammatory response owing to bidirectional interactions between these cells.  Cells Macrophages derived from monocytes → increasing in size, contents of lysosomes and more active metabolism. lymphocytes, plasma cells eosinophils Activation signals include IFN-γ secreted from T lymphocytes, Macrophages secrete: 1) Acid and neutral proteases. 2) Complement components. 3) Oxygen-free radicals and nitric oxide. 4) Cytokines (IL-1, TNF). Granulomatous Inflammation aggregation of activated macrophages as (epithelioid) appearance. 1.Bacterial infection: e.g. tuberculosis, leprosy, syphilis, cat scratch disease. 2.Parasitic: Bilharziasis. 3.Fungal: Histoplasmosis. 4.Inorganic metals: Silica, berylliosis. 5.Foreign body. Unknown: Sarcoidosis. Systemic Effects of Inflammation Fever: cytokines (TNF, IL-1) stimulate production of prostaglandins in hypothalamus Production of acute-phase proteins: C-reactive protein, stimulated by cytokines (IL-6, others) acting on liver cells Leukocytosis: cytokines (CSFs) stimulate production of leukocytes from precursors in the bone marrow. In severe infections, septic shock: fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF Cell Proliferation, the Cell Cycle, and Stem Cells Regeneration of tissues is driven by proliferation of uninjured (residual) cells and replacement from stem cells. Cell proliferation occurs when quiescent cells enter the cell cycle. The cell cycle is tightly regulated by stimulators and inhibitors and contains intrinsic checkpoint controls to prevent replication of abnormal cells. Tissues are divided into labile, stable, and permanent, according to the proliferative capacity of their cells. Continuously dividing tissues (labile tissues) contain mature cells that are capable of dividing and stem cells that differentiate to replenish lost cells. Stem cells from embryos (ES cells) are pluripotent; adult tissues, particularly the bone marrow, contain adult stem cells capable of generating multiple cell lineages. Induced pluripotent stem cells (iPS cells) are derived by introducing into mature cells genes that are characteristic of ES cells. iPS cells acquire many characteristics of stem cells Extracellular Matrix and Tissue Repair The ECM consists of the interstitial matrix between cells, made up of collagens and several glycoproteins, and basement membranes underlying epithelia and surrounding vessels, made up of nonfibrillar collagen and laminin. The ECM serves several important functions: It provides mechanical support to tissues; this is the role of collagens and elastin. It acts as a substrate for cell growth and the formation of tissue microenvironments. It regulates cell proliferation and differentiation; proteoglycans bind growth factors and display them at high concentration, and fibronectin and laminin stimulate cells through cellular integrin receptors. An intact ECM is required for tissue regeneration, and if the ECM is damaged, repair can be accomplished only by scar formation.  Morphologic Patterns of Acute And Chronic Inflammation 1.Serous Inflammation: Effusions of watery, protein-poor fluid derived from serum or mesothelial cells, lining peritoneal, pleural or pericardial cavities. 2.Fibrinous Inflammation: Occurs in severe injuries, appearing as a meshwork of threads or as an amorphous coagulum. Fibrinous exudates is either removed by macrophages or fibrinolysis or replaced by fibrosis (organization). 3.Suppurative (Purulent) Inflammation: Manifested by the presence of a large amount of purulent exudates (pus), consisting of neutrophils, necrotic cells and fluid, caused by bacteria (pyogenic) like staphylococci. Abscess is a focal collection of pus caused by deep seeding of MO in tissues or by secondary infection of necrotic areas, having large central necrotic region rimmed by preserved neutrophils and surrounded by dilated blood vessels and proliferated fibroblasts. 4.Ulceration: This refers when an epithelial surface becomes eroded by necrosis with associated subepithelial acute and chronic inflammation. Toxic or traumatic, e.g. peptic ulcer. Vascular e.g. foot ulcers of diabetes. Cutaneous Wound Healing and Pathologic Aspects of Repair Cutaneous wounds can heal by primary union (first intention) or secondary union (second intention); secondary healing involves more extensive scarring and wound contraction. Wound healing can be altered by many conditions, particularly infection and diabetes; the type, volume, and location of the injury are also important factors in healing. Excessive production of ECM can cause keloids in the skin. Persistent stimulation of collagen synthesis in chronic inflammatory diseases leads to fibrosis of the tissue.