CELL INJURY - Pathology PDF

CELL INJURY Prof. Dr/Basma Nasr Cell biology and histology-Faculty of science-Helwan university TABLE OF CONTENT: * what is pathology * Types of pathology * cell injury: 1. overview of cell injury 2. causes of cell injury 3. mechanism of cell injury 4. cell...

CELL INJURY Prof. Dr/Basma Nasr Cell biology and histology-Faculty of science-Helwan university TABLE OF CONTENT: * what is pathology * Types of pathology * cell injury: 1. overview of cell injury 2. causes of cell injury 3. mechanism of cell injury 4. cellular adaptation 5. necrosis & Apoptosis Introduction to Pathology The word pathology originates from the Greek words Pathos (suffering) and logos (study) and as its name implies it is a discipline devoted to the study of the cause, the pathogenesis, the morphological changes and functional derangement in cells, tissues and organs that underlie disease. With the advent of new technologies, pathologists are able to make diagnoses by examining a whole organ, a fragment of tissue, or even a few cells. They integrate data from gross and microscopic examination, cytological and molecular methods so that they can face common diseases such as cancer and inflammation Branches of Pathology Diagnostic pathology has many sub-specialty fields. Some are determined by the age of the patients, such as paediatric pathology. Others are related to the type of sample received, such as cytopathology. Some are related to the methods of analysis, such as molecular pathology. Most sub specialties, however, are according to organ systems, such as gastrointestinal pathology, liver pathology, gynaecological pathology or neuropathology Overview of Cell Injury Cells actively control the composition of their immediate environment and intracellular milieu within a narrow range of physiological parameters ("homeostasis") Under physiological stresses or pathological stimuli ("injury"), cells can undergo adaptation to achieve a new steady state that would be compatible with their viability in the new environment. -If the injury is too severe ("irreversible injury"), the affected cells die. There are 4 interrelated cell systems especially susceptible to injury: 1. Membranes (cellular and organellar) 2. Aerobic system 3. Protein synthesis (enzymes, structural proteins, etc) 4. Genetic apparatus (DNA, RNA, etc)  Causes of Cell Injury 1. Hypoxia (ischemia - block in blood flow, hypoxemia - decreased partial pressure of oxygen in blood, anemia - decreased oxygen carrying capacity) - Block in ventilation(foreign body), oxygen diffusion (pneumonia, pulmonary edema), perfusion (pulmonary embolus), decreased cardiac output 2.Free radical damage 3.Chemicals, drugs, toxins 4.Infections 5.Physical agents 6.Immunologic reactions 7.Genetics 8.Nutritional imbalance 9.Oxygen tension falls disrupts oxidative phosphorylation decreased ATP ▪ Na+/K+ ATPase increased intracellular Na+ swelling ▪ ATP-dependent Ca++ pumps increased cytosolic Ca++ ▪ Depletion of glycogen from altered metabolism ▪ Decreased pH from lactic acid accumulation ▪ Decreased protein synthesis from ribosome detachment from RER 10.End result-cytoskeletal disruption with loss of microvilli, bleb formation, etc Cellular Adaptation ❖ Hyperplasia -increase in NUMBER (not size) of cells in an organ or tissue -May be seen in combination with hypertrophy 1. Physiologic hyperplasia-mechanisms include increased DNA synthesis, growth inhibitors will halt hyperplasia after sufficient growth has occurred -Hormonal-hyperplasia of uterine muscle during pregnancy -Compensatory - hyperplasia in organ after partial resection 2- Pathological-not in itself neoplastic or preneoplastic, but the trigger may place patient at risk of sequelae (dysplasia, carcinoma) - Excess hormones - endometrial proliferation from over increased estrogen -Excess growth factor stimulation-warts arising from papillomavirus ❖ Hypertrophy increase in cell SIZE, leading to increase in organ size Usually in terminal cells which can no longer divide, so their only recourse is enlargement o End result is amount of increased work that each cell must perform is limited Physiologic hyperplasia-hormonal stimulation (hypertrophy of uterine wall during pregnancy) * Pathologic chronic cell stressors (stenotic valves, left ventricular hypertrophy from increased afterload) ❖ Chronic hypertrophy if stress that triggered hypertrophy is not resolves, likely result is organ failure o Hypertrophied tissue at increased risk for ischemia from metabolic demands outpacing blood supply ❖ Autotrophy shrinkage in cell size (may or may not include shrinkage of organ size) o Cells are smaller than normal, but are still viable. They do not normally undergo apoptosis or necrosis o Physiologio autotrophy tissues/structures present in embryo or childhood may undergo autotrophy as growth and development process progresses * Pathologic decreased workload, loss of innervation, decreased supply, inadequate nutrition, decreased hormonal stimulation, pain, physical pressure ❖ Metaplasia Reversible change in which one type of adult cell (epithelial or mesenchymal) is replaced by another type - if stress/injury abates, metaplastic tissue may revert to original cell type: -Bronchial (pseudostratifie, ciliated columnar) to squamous epithelium - smokers -Endocervical (columnar) to squamous - chronic cervicitis -Esophageal (squamous) to gastric or intestinal - barret esophagous (acid reflux)  Free Radical injury (acetaminophen-Tylenol overdose) o Lipid peroxidation - damage to cellular and organellar membranes o Protein crosslinking/fragmentation from oxidative modification of amino acids and proteins o DNA damage from free radical reaction with thymine Types Chemical Inflammation/microbial killing Irradiation Oxygen Age-related Free Radical Derivations: o Superoxide - O2 - produced by cellular oxidases o H2O2-produced by superoxide mutase or catalase o OH-produced by ionizing radiation, H2O2 and O2, and fenton reaction  Morphological changes follow functional changes 1/ Reversible injury * Light microscope - cell swelling, fatty change * Ultrastructural changes-cell membrane alterations, swelling and small deposits of mitochondria, RER and attached ribosome swelling 2/ Irreversible injury * Light microscope 1. Loss of RNA (which is basophilic) - increased cytoplasmic eosinophilia (pink colour) 2. Cytoplasmic vacuolization 3. Nuclear chromatin clumping * Ultrastructural 1. Membrane breakage 2. Large amorphous densities in mitochondria 3. Nuclear changes Pyknosis-nuclear shrinkage, increased basophilia (blue colour) Karyorrhexis - fragmentation of pyknotic nucleus Karyolysis - fading of basophilia of chromatin  Types of Cell Death 1. Apoptosis - usually regulated, may be pathogenic, has a role in embryogenesis 2. Necrosis - always pathologic, many causes Apoptosis o Programmed cell death in embryogenesis o Hormone dependent involution of adult organs (thymus) o Cell deletion in proliferative populations o Cell death in tumors o Cell injury in some viral diseases (hepatitis)  Necrosis Causes: 1. Coagulative (most common) * Cells basic outlines are preserved * Homogenous, glassy eosinophilic appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular) * Nucleus may show any of pyknosis, karyorrhexis, or karyolysis 2. Liquefactive-most often in CNS and abscess usually from enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils) 3. Caseous -Gross form - resembles cheese -Micro form - amorphous, granular eosinophilic material surrounded by rim of inflammatory cells (no visible cell outlines, tissue architecture is obliterated) -Usually seen in infections (mycobacterial and fungal) 4. Enzymatic fat necrosis * Hydrolytic action of lipases on fat, most often in and around pancreas, can also be seen in other fatty body areas (usually via trauma) * Fatty acids released via hydrolysis - react with Ca++ to form chalky white areas - "saponification" 5. Gangrenous necrosis * Most often in extremities via trauma/physical injury * Dry gangrene - no bacterial superinfection, looks dry * Wet gangrene - has bacterial superinfection, looks wet and liquefactive 6. Fibrinoid necrosis * Usually seen in walls of vessels (vasculitides) * Glassy, eosinophilic fibrin-like material deposited within vascular walls * Immune disorders  TISSUE REPAIR Process of healing - restoration of tissue architecture and function after an injury, set in motion by the inflammatory response. This occurs in 2 ways: regeneration and scarring, both involving cell proliferation and cell-matrix interactions. Mammals have limited capacity for regeneration of most tissues and organs; both regeneration and scar formation therefore contribute to repair REGENERATION Replacement of damaged components to return to normal state via cell proliferation of differentiated cells that still retain the capacity to proliferate, or via tissue stem cells / progenitors. Restoration of normal tissue structure can only occur if the residual tissue is structurally intact e.g. after partial surgical resection, in contrast to damage by infection or inflammation whereby scarring will also occur CELL PROLIFERATION Driven by growth factors, and critically dependent on the integrity of the extracellular matrix (ECM): Growth factors are typically produced by cells nears the site of damage, mostly by activated macrophages but also epithelial and stromal cells. All growth factors activate signaling pathways that stimulate DNA replication and also changes in cell metabolism to promote biosynthesis of other cellular components for replication Cells also bind to ECM proteins via integrins; signals from integrins can also stimulate cell proliferation CELL PROLIFERATION The capacity for regeneration depends on the tissues' intrinsic proliferative capacity and the presence of tissue stem cells: #Labile (continuously dividing) tissues: Cells of these tissues are continuously being lost and replaced by maturation from tissue stem cells and proliferation of mature cells e.g. haematopoietic cells, surface epithelial cells e.g. skin epidermis, mucosal lining of gastrointestinal tract. These tissues can readily regenerate after injury as long as the stem cells are preserved Stable tissues: Cells of these tissues are quiescent (in the GO stage of the cell cycle) with minimal proliferative activity in the normal state, but can divide in response to injury or loss of tissue mass e.g. parenchyma of most solid organs e.g. liver, kidney; also endothelial cells, fibroblasts, smooth muscle cells. Generally limited capacity to regenerate after injury except for liver # Permanent tissues: Cells of these tissues are generally terminally differentiated and non proliferative e.g. majority of neurons and cardiomyocytes. Repair is therefore typically dominated by scar formation SCARRING Deposition of connective tissue (fibrosis), when the tissues are incapable of regeneration or supporting structure is too damaged to support regeneration alone. ❖ Aim is to provide enough structural stability for the injured tissue to function, not restoration ❖ This process is also known as organization when the fibrosis occurs in a tissue space occupied by inflammatory exudate (e.g. organizing pneumonia in the lung) Following tissue injury, sequential processes occur, starting with a hemostatic plug composed of platelets to stop the bleeding and provide a scaffold for fibrin deposition. After inflammation occurs and resolves, various cell types (epithelial cells, endothelial cells and pericytes, fibroblasts) proliferate and migrate to close the now clean wound, initially via formation of granulation tissue (loose connective tissue with new thin-walled delicate capillaries and often admixed inflammatory cells) and subsequent replacement by increasing amounts of collagen to form a fibrous scar Macrophages (mainly the M2 alternatively activated type) are central to the repair process, by clearing the offending agents and dead tissue, secreting growth factors for cellular proliferation and cytokines that stimulate fibroblast proliferation, connective tissue synthesis and deposition STEPS IN SCAR FORMATION (CONNECTIVE TISSUE REPAIR) Angiogenesis Deposition of connective tissue Remodeling of connective tissue Deposition of connective tissue: Deposition of connective tissue: involves 1) migration and proliferation of fibroblasts into site of injury, and 2) deposition of ECM proteins produced by these cells, mediated by locally produced cytokines and growth factors produced by M2 macrophages and inflammatory cells, esp. TGF-β As healing progresses and the scar matures, there is increased ECM deposition and vascular regression with decreasing proliferating fibroblasts Some fibroblasts may also transform into myofibroblasts (acquiring features of smooth muscle cells) that contribute to scar contraction FACTORS THAT INFLUENCE TISSUE REPAIR: Local factors Infection: Clinically one of the most important causes of delayed healing. Prolongs inflammation and likely increases local tissue injury Mechanical factors: e.g. Increased local pressure, torsion, causing wound dehiscence Poor vascular perfusion: e.g. due to peripheral vascular disease, arteriosclerosis, diabetes, obstructed venous drainage in varicose veins Foreign bodies: perpetuates chronic inflammation Type, extent and location of tissue injury: Injury to permanent tissues will always result in scarring Location of injury: in tissue spaces e.g. serous cavities, inflammation results in extensive exudates, which can either undergo resolution (via proteolytic digestion and resorption) or organisation (when granulation tissue grows into the exudate and fibrous scarring occurs) Systemic factors Diabetes: Metabolic disease causing impaired tissue healing for various reasons (macro and microangiopathy, prone to infections) Nutritional status: Protein deficiency and vitamin C deficiency inhibit collagen synthesis and retard healing Glucocorticoids (steroids): Anti-inflammatory effects may cause scar weakness due to inhibition of TGF-ẞ, although may be useful in certain circumstances e.g. to reduce scarring Age: Younger patients generally heal better EXAMPLES OF TISSUE REPAIR AND FIBROSIS CUTANEOUS WOUND HEALING Healing occurs via first or second intention depending on the nature and size of wound HEALING BY FIRST INTENTION (PRIMARY UNION): When the injury is relatively limited (with closely apposed wound edges), involving mostly the epithelial layer, with only focal disruption of the epithelial basement membrane and death of relatively few epithelial and connective tissue cells e.g. a clean uninfected surgical incision FIBROSIS IN PARENCHYMAL ORGANS Mechanism of fibrosis (excessive deposition of collagen and other ECM components in tissue) is basically similar to scar formation in the skin during tissue repair. However, fibrosis can be responsible for substantial organ dysfunction / failure e.g. liver cirrhosis, fibrosing diseases of the lung  Inflammation INTRODUCTION Inflammation is a normal response of the body to protect tissues from infection, injury or disease. The inflammatory response begins with the production and release of chemical agents by cells in the infected, injured or diseased tissue. These agents cause redness, swelling, pain, heat and loss of function. Inflamed tissues generate additional signals that recruit leukocytes to the site of inflammation. Leukocytes destroy any infective or injurious agent, and remove cellular debris from damaged tissue. This inflammatory response usually promotes healing but, if uncontrolled, may become harmful. Recognition: of the initiating stimulus for inflammation via cell receptors that recognize microbial products and other released substances, leading to production of mediators of inflammation that trigger subsequent steps of the inflammatory response (see "Recognition of microbes and damaged cells" below) Recruitment: of leukocytes and plasma proteins from the circulation into tissue Removal: of the stimulus for inflammation, mostly by phagocytic cells that ingest and destroy microbes and dead cells Regulation: of the inflammatory response to terminate the reaction when objective is achieved Repair: to heal damaged tissue by regeneration and/or replacement by connective tissue (scarring) Meant to be a beneficial survival response, mediated by response of blood vessels, phagocytic leukocytes, antibodies and complement proteins. However, there is also often accompanying local tissue damage and its signs and symptoms (e.g. pain, functional impairment). While this is often self-limited and resolves with no sequelae misdirection or inadequate control of this inflammatory reaction can become the cause of both acute and chronic diseases e.g. in autoimmune diseases or in allergies CAUSES OF INFLAMMATION Infections: Most common cause. Different microbial organisms and toxins elicit varying inflammatory responses from mild to severe or acute to chronic reactions. Outcome depends largely on type of pathogen, host response and host characteristics Tissue necrosis: Elicits inflammation regardless of the cause of cell death (e.g. ischaemia, trauma, thermal/chemical injury) Foreign bodies: Can be due to their presence and/or the trauma they cause / associated microbes. Can be endogenous e.g. urate crystal deposits in gout When the normally protective immune system is inappropriately directed against self-antigens or environmental substances, damaging the individual's own tissues e.g. autoimmune diseases and allergies. As these stimuli cannot be eliminated, the inflammation tends to be persistent and difficult to cure, causing significant morbidity and mortality  Mediator Source Stimull Action Vasoactive amines: important actions on blood vessels Histamine Mast cells, basophils, 1.Physical injury, 1.Vasodilation of platelets cold/ heat arterioles Stored preformed> among 2.Binding of antigens 2.Increased the first mediators to be to IgE antibodies on permeability of released via mast cell the surfaces of mast venules degranulation cells 3.Anaphylatoxins (complement products C3a and C5a), cytokines, neuropeptides Arachidonic acid (AA) metabolites: lipid products Prostaglandins Mast cells, leukocytes, Mechanical, Eicosanoids bind to G endothelial cells, platelets chemical, physical protein- coupled Produced from AA in stimuli or other receptors on many membrane phospholipids mediators eg. Csa cells and generally via phospholipase As. AA- cause vasodilation, derived mediators pain and fever (eicosanoids) are then PGD, and PGE, synthesized by vasodilation, cyclooxygenases (COX) increases vascular (for prostaglandins) and permeability. PGD, Spoxygenases (for is also a neutrophil leukotrienes) chemoattractant, COX-1 constitutively while PGE, is expressed in most cells hyperalgesic COX-2 inducible mainly in Prostacyclin (PGI): cells involved in vasodilator, inflammation inhibitor of platelet aggregation Thromboxane A2 (TA): vasoconstrictor, platelet- aggregating agent, rapidly inactivated Leukotrienes Increased vascular permeability. 5-lipoxygenase: chemotaxis, leukocyte predominant lipoxygenase adhesion and in neutrophils activation esp. LTB, Note: Lipazins are also as well as generated by lipoxygenase bronchospasm from AA, but suppress inflammation instead Cytokines and chemokines: proteins that mediate and regulate immune and inflammatory reactions TNF and IL-1 Macrophages, also: Microbial products, Local TNF: mast cells, T- dead cells, immune -Endothelial activation lymphocytes IL-1: complexes, foreign (increased expression endothelial cells and some bodies, physical of adhesion molecules epithelial cells injury, other that promote TNF production is induced inflammatory stimuli leukocyte recruitment, by signals through TLRS increased production IL-1 production is of other similarly induced but also cytokines/chemokines, depends on the and increased inflammasome procoagulant activity of the endothelium) -Activation of leukocytes and other cells (TNF augments neutrophil and macrophage responses; IL-1 activates fibroblasts to synthesize collagen and Th17 responses) Systemic: -Acute phase response: Fever, metabolic abnormalities, hypotension (shock) esp. IL-6 II. ACUTE INFLAMMATION Involves both a vascular and cellular response: (1) Increased blood flow and vascular permeability: Vascular changes are designed to maximise exudation i.e. the movement of plasma proteins and leucocytes (mediators of host defence) out of the circulation and into the site of infection or injury. Exudate = extravascular fluid with high protein concentration and contain cellular debris. Implies presence of a process causing increased vascular permeability Pus = purulent exudate rich in leukocytes (mostly neutrophils), dead cellular debris +/- microbes Transudate = extravascular fluid with low protein concentration (mostly albumin), little/no cells and low specific gravity. Usually produced as a result of osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability Oedema = excess fluid in interstitial tissue; or serous cavities (effusion). Can be either exudate or transudate Changes in vascular flow and caliber (vasodilatation and stasis) Vasodilatation: One of the earliest manifestations of acute inflammation, first involving arterioles and then opening of new capillary beds o Induced by several mediators (histamine in particular) on vascular smooth muscle Resulting increased blood flow causes heat and redness (erythema This together with the subsequent increased vascular permeability (and fluid extravasation) leads to stasis i.e. engorgement of small vessels by increased concentration of slowly moving red blood cells Manifests as vascular congestion and localized redness (erythema) Blood leukocytes (primarily neutrophils) marginate along the vascular endothelium and subsequently migrate through the vascular wall into the interstitium (see "Leukocyte recruitment to sites of inflammation") Recognition of microbes and damaged cells: Initiating step in inflammatory reactions. This can occur via: Cellular receptors for microbes (e.g. Toll-like receptors (TLRs)): Receptors can be expressed in the plasma membrane (for extracellular microbes), endosomes (for ingested microbes) and cytosol (for intracellular microbes). Expressed on many cell types including epithelial cells, dendritic cells, macrophages and other leukocytes. Engaged receptors triggers production of molecules involved in inflammation e.g. cytokines Circulating proteins: e.g. complement proteins, mannose-binding lectin (recognizes microbial sugars), collectins Sensors of cell damage (e.g. NOD-like receptors (NLRs)): All cell types have cytosolic receptors that recognize molecules released or altered due to cell damage e.g. uric acid (from DNA breakdown), ATP (from damaged mitochondria), reduced intracellular K+ concentrations (due to plasma membrane injury). The receptors activate the inflammasome (a multiprotein cytosolic complex) which induces production of cytokine interleukin-1 (IL-1) that recruits leukocytes and induces inflammation Other cellular receptors involved in inflammation: Many leukocytes express receptors for the Fc tails of antibodies and complement proteins which coat microbes (opsonization). This then promotes ingestion and destruction of microbes as well as inflammation Morphologic patterns of acute inflammation General morphologic features: Vascular dilation and congestion, oedema, inflammatory cellular infiltrate within the extravascular tissue Specific morphologic patterns: Additional features that may be seen depending on site and tissue involved, cause and severity of the reaction: 1. Serous inflammation: Exudation of cell-poor fluid into mesothelial-lined body cavities (pleural, peritoneal, pericardial cavities) forming an effusion, or into spaces created by cell injury (e.g. in skin blisters) 2. Fibrinous inflammation: Eosinophilic (pink) meshwork of threads / amorphous proteinaceous material that accumulates when vascular leaks are large enough for large molecules like fibrinogen to pass through the vessel wall, or there is local procoagulant stimulus. Usually seen in inflammation of lining of body cavities e.g. meninges, pericardium, pleura. If not removed by fibrinolysis or macrophages, can organize into scar tissue and lead to fibrous thickening / obliteration of the body cavity space 3. Suppurative (purulent) inflammation: Characterised by production of pus (exudate containing neutrophils, liquefied necrotic debris and oedema fluid) e.g. acute appendicitis. Usually caused by pyogenic (pus-producing) bacterial infection >>>Abscess: Localised collection of pus caused by suppuration within tissue, organ or confined space, due to seeding of pyogenic bacteria into the tissue. Central liquefied zone of necrotic tissue surrounded by neutrophils, granulation tissue and fibrosis (indicating chronic inflammation and repair) - eventually the abscess cavity can undergo complete fibrosis 4. Ulcers: Local defect of a skin/mucosal surface caused by the sloughing/shedding of inflamed necrotic tissue e.g. gastric/duodenal peptic ulcer Outcomes of acute inflammation Typically 3 possible outcomes ensue: 1. Complete resolution: Ideal outcome. Usually only if injury is limited or short- lived with little tissue destruction, allowing removal of cellular debris and microbes by macrophages, resorption of oedema fluid and regeneration of damaged cells. 2. Scarring / fibrosis: Healing by connective tissue replacement (organization). Occurs after substantial tissue destruction, the damaged tissue cannot regenerate or fibrinous exudate cannot be cleared adequately 3. Progression to chronic inflammation: Occurs when the acute inflammatory response cannot be resolved due to persistence of injurious agent or other interference with the normal healing process  CELLS AND MEDIATORS OF CHRONIC INFLAMMATION: Macrophage Dominant cell in most chronic inflammatory reactions, by secreting cytokines and growth factors that act on various cells (in particular, activating T lymphocytes), eliminating foreign invaders, causing accompanying tissue injury and also initiating tissue repair Some tissues have a resident macrophage population (e.g. Kupffer cells in the liver, microglia in the brain). Most connective tissues also have scattered macrophages, which arise from circulating monocytes in the blood that migrate into the tissues and differentiate into macrophages CELLS AND MEDIATORS OF CHRONIC INFLAMMATION: In inflammatory reactions, monocytes begin to emigrate into extravascular tissues (via processes similar to neutrophils) to form the predominant cell type within 48 hours Macrophage functions include: o Phagocytosis: ingest and eliminate microbes and dead tissues o Secretion of cytokines and eicosanoids (mediators of inflammation): initiate and propagate inflammatory reactions o Initiation of tissue repair: involved in scar formation and fibrosis o Interaction with T-lymphocytes: important in cell-mediated immune responses II-CHRONIC INFLAMMATION Prolonged host response (weeks or months) to persistent stimuli in which inflammation, tissue injury and attempts at repair coexist in varying combinations Causes of chronic inflammation: May follow acute inflammation, or begin insidiously as a low-grade response without evidence of preceding acute inflammation: Persistent infections: Unresolved acute inflammation with persistent infection can evolve into chronic inflammation e.g. chronic abscess. Microorganisms that are difficult to eradicate e.g. mycobacteria, certain fungi, parasites or viruses can sometimes cause a type of chronic inflammation called granulomatous reaction, which may involve a delayed-type hypersensitivity immune reaction Hypersensitivity diseases: Excessive and inappropriate activation of the body's immune system results in chronic inflammation and tissue damage e.g. rheumatoid arthritis, inflammatory bowel disease. These diseases may show a mixed acute and chronic inflammatory patterns as they are characterized by recurring bouts of inflammation. Prolonged exposure to potentially toxic agents: Exogenous agents include silica (can result in silicosis). Endogenous agents include cholesterol and other lipids (causing atherosclerosis) Lymphocytes T and B lymphocytes are activated by microbes and other environmental antigens, which can lead to generation of long-lived memory cells causing a more persistent and severe inflammatory reaction CD4+ T-cells: secretes cytokines that promotes various types of inflammation Th1 cells: produce IFN-y → activates macrophages via classical pathway Th2 cells: produce IL-4, IL-5 and IL-13→ alternative macrophage activation; also recruits and activates eosinophils (important in parasites and allergic inflammation) Th17 cells: produce IL-17 and other cytokines induces secretion of chemokines to recruit neutrophils and monocytes Other cell types - Eosinophils: abundant in immune reactions mediated by IgE and parasitic infections. Granules contain major basic protein that is toxic to helminths but may also injure host epithelial cells e.g. in allergies Mast cells: participates in both acute and chronic inflammatory reactions e.g. immediate hypersensitivity reactions Neutrophils: although characteristic of acute inflammatory, can persist in many forms of chronic inflammation (acute on chronic inflammation) * GRANULOMATOUS INFLAMMATION Form of chronic inflammation characterized by granulomas (aggregates of activated macrophages, often with T lymphocytes and sometimes associated with necrosis) Cellular attempt to contain a difficult to eradicate offending agent Different types of granulomas may be induced by different causes: Foreign body granulomas: incited by inert (non-immunogenic) foreign bodies (e.g. talc, sutures) too large for phagocytosis, in the absence of T-cell mediated immune response As only a limited number of conditions cause granulomatous inflammation, recognition of granulomas and exclusion of treatable conditions (e.g. tuberculosis) is important. Ancillary investigations include special stains for organisms (Ziehl- Neelson stain for acid-fast bacilli), cultures, molecular techniques and serology Microscopy: Activated macrophages in granulomas may have abundant cytoplasm resembling epithelial cells (epithelioid histiocytes) and fuse (multinucleated giant cells). The macrophage aggregates may be surrounded by a collar of lymphocytes or fibroblasts. Granulomas may have a central zone of necrosis (classically seen in Mycobacterium tuberculosis infection) which appears as amorphous eosinophilic granular debris. This is called caseous necrosis due to its resemblance to cheese on gross appearance. Granulomas in Crohn disease, sarcoidosis and foreign body reaction tend to be non-necrotizing / non-caseating. Granulomas generally heal by fibrosis, which can be extensive SYSTEMIC EFFECTS OF INFLAMMATION: Inflammation (even if localized) is associated with cytokine-induced systemic reactions called the acute-phase response. The cytokines produced in response to bacterial products and other inflammatory stimuli, in particular TNF, IL-1, IL-6 and interferons are important mediators of this response. The systemic reactions include: Fever: elevation of body temperature, often when associated with infection. Thought to be a protective host response. Pyrogens are substances that induce fever, and include bacterial products (exogenous pyrogens e.g. lipopolysaccharides) and cytokines (endogenous pyrogens e.g. IL-1, TNF) o Exogenous pyrogens act by stimulating release of endogenous pyrogens IL-1 and TNF Exogenous pyrogens act by stimulating release of endogenous pyrogens IL-1 and TNF IL1- and TNF upregulate cyclooxygenases to synthesize prostaglandins Prostaglandins (esp. PGE2) synthesized by the vascular and perivascular cells of the hypothalamus stimulate the production of neurotransmitters by the hypothalamus to reset the body's steady- state temperature to a higher level, which is accomplished by vasoconstriction (to reduce heat loss) and effects on brown fat and skeletal muscle (to increase heat generation) Leukocytosis: especially high in bacterial infections. Extreme elevations that mimic leukemia are called leukemoid reactions Occurs initially due to accelerated release of both mature and immature granulocytes from bone marrow by cytokines Prolonged infection also induces proliferation of precursors in the bone marrow (via production of colony-stimulating factors by macrophages and marrow stromal cells) 1. Bacterial infections usually cause neutrophilia, viral infections lymphocytosis, allergies and helminth infestations eosinophilia. However, certain infections e.g. typhoid fever are associated with leukopenia instead partly due to sequestration of activated leukocytes in vascular spaces and tissues Symptoms and signs such as elevated pulse and blood pressure, decreased sweating (blood flow is redirected from cutaneous to deep vascular beds to minimize heat loss), chills, rigors, anorexia, malaise, somnolence Septic shock: a severe often fatal form of systemic inflammatory response syndrome (SIRS) in severe bacterial infections (sepsis), whereby the large amounts of bacteria and their products in the blood stimulate production of high blood levels of cytokines (esp. TNF and IL-1), causing disseminated intravascular coagulation (DIC), hypotensive shock and metabolic  Questions 1. Write on scaring formation during tissue repair? 2. Give an account on role of leukocytes in site of injury 3. Illustrate the role of mediators of acute inflammation 4. Compare between Acute and Chronic inflammation in four main points 5. write on mechanism of tissue repair 6. Write on cellular morphological changes during injury ‫اجابة السؤال التاني‬ Leukocytes (white blood cells) play a crucial role in the body's immune response at the site of injury. Their involvement is central to controlling infection, promoting tissue repair, and maintaining homeostasis. Here's an account of their role: 1. Detection of Injury When tissue is injured, damaged cells and activated platelets release signals, including cytokines (e.g., interleukins, tumor necrosis factor-alpha) and chemokines. These signals alert leukocytes and initiate their recruitment to the site. 2. Migration to the Injury Site Vasodilation and Increased Permeability: Histamine and other mediators increase blood vessel permeability, allowing leukocytes to exit the bloodstream. Chemotaxis: Leukocytes follow a gradient of chemotactic signals (e.g., C5a, leukotrienes) to the site of injury. 3. Key Functions of Leukocytes at the Injury Site a. Neutrophils (First Responders) Phagocytosis: Engulf and digest pathogens, necrotic tissue, and debris. Degranulation: Release enzymes like myeloperoxidase and defensins to kill microbes. Formation of NETs (Neutrophil Extracellular Traps): Trap and neutralize pathogens. b. Macrophages and Monocytes Phagocytosis: Clear debris and dead cells. Release of Cytokines: Modulate inflammation and attract other immune cells. Tissue Repair: Secrete growth factors like VEGF and TGF-β to promote healing. c. Lymphocytes Coordinate the adaptive immune response if the injury involves infection. T cells: Target specific pathogens. B cells: Produce antibodies to neutralize microbes. d. Eosinophils and Basophils Play roles in parasitic infections and allergic responses at injury sites, if applicable. 4. Resolution of Inflammation As pathogens and debris are cleared, anti-inflammatory signals (e.g., IL-10, TGF- β) ensure leukocytes reduce their activity. Apoptotic neutrophils are phagocytosed by macrophages, promoting a return to tissue homeostasis ‫اجابة السؤال الثالث‬  ‫اجابة السؤال الرابع‬ inflammation is a normal part of your body’s response to injuries and invaders (like germs). It promotes healing and helps you feel better. But inflammation that happens when there’s no injury or invader can harm healthy parts of your body and cause a range of chronic diseases Give an account for mechanism of tissue injury?