Pathology

Features of Acute Inflammation Local signs • vascular events • exudate • neutrophils • systemic response • laboratory and pathology clues Acute inflammation has recognizable local, microscopic and systemic features. They arise from rapid changes in blood flow and endothelial permeability followed by leukocyte recruitment and activation. Learning the sequence allows students to translate a red, swollen, painful area or a septic patient’s laboratory results into underlying physiology. Learning outcomes Explain the five cardinal signs and their mechanisms. Recognise the vascular, exudative and cellular features of acute inflammation. Describe neutrophil recruitment, phagocytosis and the typical microscopic appearance. Differentiate exudate from transudate and identify major exudative patterns. Recognise systemic features and laboratory changes, including atypical presentations. Use features to identify red-flag inflammation requiring emergency action. 1. The cardinal local signs Sign Mechanism Clinical example Rubor (redness) Arteriolar dilation and increased blood flow. Red cellulitic skin or inflamed conjunctiva. Calor (heat) Hyperaemia and local/systemic temperature rise. Warm, tender joint. Tumor (swelling) Protein-rich exudate, endothelial gaps and cellular accumulation. Oedematous wound or joint effusion. Dolor (pain) Bradykinin, prostaglandins, ATP, nerve compression and tissue acidosis. Pain on palpation or movement. Functio laesa Pain, oedema, tissue destruction and altered organ physiology. Reduced joint movement or impaired breathing. 2. Vascular features Brief vasoconstriction: may occur immediately after injury. Arteriolar vasodilation: histamine, NO and prostaglandins increase flow. Capillary bed recruitment: more surface area is perfused. Increased venular permeability: protein-rich fluid exits vessels. Haemoconcentration and stasis: red cells become concentrated and flow slows. Margination: leukocytes move toward the endothelial surface. 3. Exudate and oedema 3.1 Exudate Exudate is protein-rich inflammatory fluid with leukocytes and debris. Its high protein content reflects endothelial permeability. Fibrinogen can polymerise into fibrin; neutrophils and bacteria create purulent exudate. 3.2 Transudate Transudate is protein-poor fluid from increased hydrostatic pressure or reduced plasma oncotic pressure. Heart failure, cirrhosis and nephrotic syndrome cause transudative oedema without primary endothelial inflammation. Feature Exudate Transudate Protein High. Low. Cells Often many leukocytes. Few cells. Cause Inflammatory permeability. Hydrostatic/oncotic imbalance. Examples Pneumonia, abscess, inflammatory pleuritis. Heart-failure pleural effusion, cirrhotic ascites. 4. Cellular features 4.1 Neutrophil predominance Neutrophils arrive within minutes to hours and dominate early bacterial and necrotic inflammation. They have multilobed nuclei, granular cytoplasm and strong phagocytic/oxidative capacity. A left shift or bandemia suggests increased marrow release. 4.2 Rolling and adhesion Selectins mediate rolling; integrins binding ICAM-1/VCAM-1 mediate firm adhesion; PECAM-1 supports diapedesis. Defects produce recurrent bacterial infections and poor healing. 4.3 Chemotaxis and activation C5a, LTB4, IL-8/CXCL8 and bacterial peptides direct leukocytes to the focus. Activation produces degranulation, respiratory burst, NETs and cytokine release. 4.4 Monocyte transition Monocytes become more prominent after 24–48 hours and differentiate into macrophages. Their persistence supports debris clearance and repair but can drive chronic inflammation and fibrosis if the stimulus continues. 5. Microscopic and gross features Level Features Gross Redness, warmth, swelling, pus, fibrin, ulceration, haemorrhage or tissue softening. Light microscopy Dilated vessels, oedema, endothelial activation, neutrophils, fibrin and tissue necrosis. Abscess Central liquefied necrotic debris, neutrophils, bacteria and a peripheral inflammatory wall. Serosal inflammation Watery, fibrinous or haemorrhagic exudate on pleura, pericardium or peritoneum. Airway/lung Mucosal oedema, mucus, bronchoconstriction or alveolar exudate. 6. Systemic features Fever or hypothermia: IL-1, TNF and PGE2 alter the hypothalamic set point. Malaise, anorexia and somnolence: cytokines act on the brain. Tachycardia and tachypnoea: increased metabolic demand and compensation for acidosis. Leukocytosis: neutrophilia in bacterial disease, lymphocytosis in many viral infections and eosinophilia in allergy/helminths. Acute-phase response: CRP, fibrinogen, serum amyloid A and hepcidin rise. Sepsis physiology: hypotension, mottling, oliguria, confusion, lactate elevation and organ dysfunction. 7. Laboratory clues and limitations Test What it suggests Limitations CRP/ESR Systemic inflammatory activity. Non-specific; may lag or remain low in immunosuppression. FBC/differential Leukocytosis, neutrophilia, lymphocytosis or eosinophilia. Normal counts do not exclude serious infection. Lactate Hypoperfusion or altered metabolism. Not specific for inflammation or sepsis. Procalcitonin May support bacterial systemic infection in selected settings. Interpret with clinical context; not a stand-alone rule-out test. Fluid analysis Exudate, cells, Gram stain and culture. Prior antibiotics and sampling error can produce false negatives. 8. Features that signal dangerous inflammation Airway swelling, stridor, wheeze or rapidly falling oxygen saturation. Hypotension, altered mental state, mottled skin, oliguria or rising lactate. Rapidly expanding erythema, pain out of proportion, bullae, skin anaesthesia or crepitus. Severe headache, focal neurology, meningism or reduced consciousness. Rigid abdomen, peritonism, severe chest pain or new ECG changes. Hyperkalaemia, acidosis or dark urine after crush injury. 9. Outcomes reflected in features Outcome Typical feature Resolution Signs fade, neutrophils clear, oedema drains and function returns. Abscess Persistent focal pain, fluctuant mass, pus and fever. Fibrosis Firm scar, stricture, adhesions or reduced organ compliance. Chronic inflammation Long duration, weight loss, anaemia, persistent inflammatory markers and tissue remodelling. Systemic failure Shock, hypoxia, coagulopathy, renal injury or encephalopathy. 10. Clinical examples Cellulitis Red, warm, tender, swollen skin with advancing margins represents local acute inflammation. Look for abscess, lymphangitis, necrotising infection and systemic toxicity. Pneumonia Alveolar exudate causes crackles, hypoxia and consolidation. The inflammatory response may be protective or cause ARDS and sepsis. Anaphylaxis Rapid mediator release produces urticaria, angioedema, bronchospasm and vasodilation. IM adrenaline is time-critical. Acute gout Crystal-triggered neutrophilic synovitis causes exquisitely painful swelling. Infection must be excluded in a hot joint. 11. Quick self-test What causes redness and heat?Answer: Arteriolar vasodilation and hyperaemia. What causes inflammatory swelling?Answer: Protein-rich exudate, oedema and cellular accumulation. What is the predominant cell in early acute inflammation?Answer: Neutrophils. What is the difference between exudate and transudate?Answer: Exudate is protein-rich due to inflammation; transudate is protein-poor due to hydrostatic/oncotic imbalance. Name three red flags for dangerous inflammation.Answer: Airway compromise, shock, altered consciousness, rapid tissue spread, severe hypoxia, crepitus or organ dysfunction. Why can a normal white count be misleading?Answer: Early disease, immunosuppression, marrow failure or overwhelming sepsis may blunt leukocytosis. 12. Take-home summary Acute inflammation produces cardinal signs through vasodilation, permeability and leukocyte recruitment. Exudate is protein-rich inflammatory fluid; transudate reflects hydrostatic or oncotic imbalance. Neutrophils dominate early, while monocytes/macrophages become more prominent later. Laboratory markers support but do not

Stimuli of Acute Inflammation What starts the rapid response • infectious and sterile triggers • danger signals • clinical recognition Acute inflammation begins when resident cells detect an immediate threat. The stimulus may be a microorganism, necrotic tissue, physical injury, chemical exposure, foreign material, immune reaction or crystal. The trigger determines the dominant receptors, mediators, cells and treatment, so identifying it is the first step in safe management. Learning outcomes List major stimuli of acute inflammation and classify them as infectious or sterile. Explain how PAMPs, DAMPs, immune complexes, complement, crystals and toxins activate inflammatory pathways. Recognise the clinical clues and emergency risks associated with each stimulus. Distinguish the stimulus from the downstream morphologic pattern. Choose targeted investigations and initial management priorities. 1. Stimulus versus response Term Meaning Example Stimulus/trigger The initiating event that disturbs tissue homeostasis. Bacterial invasion, infarction or a burn. Recognition signal PAMP, DAMP, immune complex or crystal sensed by a receptor. Lipopolysaccharide activates TLR4. Inflammatory response Vascular change, mediator release and leukocyte recruitment. Neutrophilic exudate in bacterial pneumonia. Outcome Resolution, abscess, fibrosis, chronic inflammation or organ failure. Scar after myocardial infarction. 2. Infectious stimuli 2.1 Bacteria Bacterial surfaces and toxins trigger TLRs, NOD-like receptors and inflammasomes. Pyogenic organisms produce neutrophil-rich suppuration; invasive organisms may cause necrosis, thrombosis and sepsis. Extracellular bacteria: complement, antibodies and neutrophils dominate. Intracellular bacteria: macrophages, NK cells and T cells become important. Exotoxins: direct cytotoxicity, pore formation or systemic neurotoxicity. Endotoxin: TLR4-driven cytokines, endothelial activation and shock. 2.2 Viruses Viral RNA/DNA is detected by endosomal or cytosolic sensors. Type I interferons restrict replication; cytotoxic T cells and NK cells kill infected cells. Acute viral inflammation may cause bronchiolitis, hepatitis, encephalitis or myocarditis. 2.3 Fungi Beta-glucans and mannans activate C-type lectin receptors. Neutrophils are critical for mould killing, while granulomas contain some deep fungal infections. Invasive fungal disease can produce haemorrhage and infarction. 2.4 Parasites Helminths stimulate IgE, mast cells and eosinophils; tissue migration can cause urticaria, bronchospasm, obstruction and granulomatous inflammation. Protozoa may cause macrophage or cytotoxic T-cell responses. 2.5 Microbial patterns and acute emergencies Sepsis and septic shock. Meningitis/encephalitis and raised intracranial pressure. Necrotising soft-tissue infection and gas gangrene. Severe pneumonia with respiratory failure. Invasive fungal disease in neutropenia or immunosuppression. 3. Tissue necrosis and DAMP stimuli Dead or severely injured cells release DAMPs that produce sterile inflammation. Important settings include: Necrotic stimulus Examples Clinical risks Ischaemic infarction Heart, brain, kidney, spleen or bowel. Reperfusion injury, arrhythmia, oedema, organ failure. Crush injury Muscle compression, compartment syndrome. Rhabdomyolysis, hyperkalaemia, acute kidney injury. Pancreatic enzyme injury Acute pancreatitis. Shock, hypocalcaemia, respiratory/renal failure. Burns/frostbite Thermal injury and reperfusion. Airway oedema, fluid loss, tissue loss. Traumatic necrosis Blunt injury, blast, surgery. Haemorrhage, compartment syndrome, infection. DAMPs include extracellular ATP, HMGB1, mitochondrial DNA, uric acid, heat-shock proteins and exposed phospholipids. They activate TLRs, NLRP3 inflammasomes and complement even when no organism is present. 4. Physical stimuli Heat and burns: protein denaturation, endothelial injury, DAMP release and fluid loss. Cold/frostbite: vasoconstriction, ice crystals, thrombosis and reperfusion inflammation. Mechanical injury: cell rupture, haemorrhage and oedema after trauma or surgery. Radiation: DNA damage, ROS and endothelial injury. Electricity/lightning: thermal necrosis, arrhythmia and muscle injury. Pressure/barotrauma: tissue disruption and ischaemia during decompression or ventilation. Ultraviolet light: keratinocyte damage and sunburn inflammation. 5. Chemical and drug stimuli Stimulus Acute inflammatory mechanism Clue Corrosive acid/alkali Direct protein and membrane destruction. Oropharyngeal burns, dysphagia, airway oedema. Smoke/irritants Epithelial injury, ROS and bronchial mediator release. Cough, wheeze, hypoxia or delayed lung injury. Paracetamol toxicity Reactive metabolite, glutathione depletion and hepatocyte necrosis. Overdose history, later liver failure. Drug hypersensitivity IgE, immune complexes or T-cell injury. Rash, eosinophilia, hepatitis, nephritis or anaphylaxis. Heavy metals/pesticides Enzyme inhibition, oxidative stress and cell injury. Neurologic, gastrointestinal or renal syndrome. 6. Foreign-body stimuli Splinters, sutures, talc, silica, asbestos, prosthetic debris and keratin trigger inflammation because they cannot be cleared. Macrophages surround the material, fuse into giant cells and release cytokines and ROS. The response may remain local or cause granulomatous fibrosis. In the emergency setting, remove penetrating material when safe, image retained foreign bodies and consider infection in a draining sinus or non-healing wound. 7. Immune and allergic stimuli 7.1 IgE-mediated allergy Allergen cross-linking of IgE on mast cells produces histamine, tryptase, prostaglandins and leukotrienes. Urticaria, angioedema, bronchospasm, vomiting and hypotension can develop within minutes. 7.2 Immune complexes Deposited antigen–antibody complexes activate complement and neutrophils, causing vasculitis, glomerulonephritis, arthritis and serum sickness. 7.3 Cytotoxic lymphocytes CD8 cells and NK cells kill infected or abnormal cells through perforin/granzyme and death receptors. The resulting apoptosis may be accompanied by secondary inflammation. 7.4 Autoimmune stimulation Persistent self-antigen drives chronic disease with acute flares. Examples include rheumatoid synovitis, inflammatory bowel disease, lupus and autoimmune hepatitis. 8. Crystal and metabolic stimuli Crystal/metabolic signal Response Clinical example Monosodium urate NLRP3/IL-1β, neutrophils and intense synovitis. Acute gout. Calcium pyrophosphate Crystal phagocytosis and neutrophilic inflammation. Pseudogout. Cholesterol crystals Macrophage inflammasome activation and plaque inflammation. Atherosclerotic plaque rupture. Silica crystals Lysosomal injury, inflammasome activation and fibrosis. Silicosis. Calcium oxalate Tubular injury and crystal nephropathy. Ethylene glycol toxicity or oxalosis. Free fatty acids Lipotoxicity and low-grade cytokine activation. Obesity-associated inflammation and fatty liver. 9. Neoplastic and treatment-related stimuli Tumours generate inflammation through necrosis, invasion, cytokines and immune recognition. Chemotherapy, radiotherapy, immunotherapy and targeted drugs can produce tumour-cell death or immune-related inflammation. Tumour lysis: rapid cell death releases potassium, phosphate and nucleic acids. Checkpoint-inhibitor toxicity: T-cell activation may cause colitis, hepatitis, pneumonitis, myocarditis or endocrinopathy. Radiation injury: DNA damage and endothelial inflammation can be acute or delayed. 10. Clinical method for identifying the stimulus Timeline: minutes suggests anaphylaxis or toxin; hours suggests infection/trauma; weeks to months suggests autoimmune or foreign-body disease. Exposure: drug, food, occupation, travel, trauma, surgery, transfusion or device. Distribution: focal, dermatomal, joint-specific, pulmonary, gastrointestinal or systemic. Fluid/tissue: pus, blood, clear blister fluid, fibrin, necrosis or granuloma. Host factors: diabetes, neutropenia, immunosuppression, pregnancy, age and vascular disease. Tests: cultures/PCR, imaging, toxicology, autoantibodies, biopsy and serial organ-function markers. 11. Emergency priorities Stimulus suspected First priorities Anaphylaxis IM adrenaline, airway/oxygen/circulation

Acute Inflammation Rapid vascular response • exudate • neutrophil recruitment • phagocytosis • mediators • outcomes • emergency recognition Acute inflammation is the rapid response to infection or tissue injury. It develops over minutes to hours and is dominated by changes in blood flow and vascular permeability followed by recruitment of neutrophils and other innate immune cells. Its purpose is to deliver plasma proteins and leukocytes, eliminate the trigger and begin repair. The same mechanisms can become dangerous when they are excessive, delayed in resolution or systemic. Pulmonary oedema, airway obstruction, sepsis, anaphylaxis, cerebral swelling and tissue necrosis are examples of acute inflammation becoming an emergency. Learning outcomes Describe the vascular and cellular phases of acute inflammation in sequence. Explain arteriolar dilation, endothelial contraction, direct injury, leukocyte-mediated injury and delayed permeability. Describe exudate, transudate, stasis, margination, rolling, adhesion, transmigration and chemotaxis. Explain phagocytosis, opsonisation, killing and the causes of leukocyte-mediated collateral injury. Identify major acute inflammatory mediators and their effects. Recognise morphologic patterns and outcomes: resolution, abscess, fibrosis and chronic inflammation. Apply the pathway to sepsis, pneumonia, burns, anaphylaxis and acute limb injury. 1. Sequence at a glance Phase Main event Visible/clinical result Recognition Macrophages, mast cells, dendritic cells and endothelium detect PAMPs/DAMPs. Mediator release begins. Vascular change Arteriolar dilation and increased permeability. Redness, heat, swelling and exudate. Haemodynamic stasis Protein-rich fluid leaves vessels; flow slows. Leukocyte margination. Leukocyte recruitment Rolling, adhesion, transmigration and chemotaxis. Neutrophils arrive at the focus. Elimination Phagocytosis, degranulation, ROS and extracellular traps. Microbial killing and debris removal. Termination/repair Mediator decay, efferocytosis, drainage and repair. Resolution, scar, abscess or chronic inflammation. 2. Recognition and mediator release Resident macrophages, mast cells and epithelial cells detect PAMPs and DAMPs through toll-like, NOD-like, C-type lectin and cytosolic nucleic-acid receptors. They release preformed histamine and newly synthesised lipid mediators and cytokines. Complement, kinins and coagulation pathways in plasma amplify the response. 3. Vascular changes 3.1 Transient vasoconstriction A brief arteriolar constriction may occur immediately after injury. It is usually short and clinically unimportant compared with the later dilation. 3.2 Vasodilation Histamine, nitric oxide and prostaglandins relax arteriolar smooth muscle. Blood flow rises, producing redness and heat. Capillary beds open, increasing hydrostatic pressure and favouring fluid movement into tissue. 3.3 Increased permeability and exudation Mechanism Onset/duration Typical triggers Endothelial contraction Immediate, short-lived. Histamine, bradykinin, leukotrienes. Junctional retraction Delayed, prolonged. TNF and IL-1; cytoskeletal rearrangement. Direct endothelial injury Immediate or delayed, long-lasting. Severe burns, toxins, necrotising infection. Leukocyte-mediated injury Delayed after leukocyte adhesion. Venules and pulmonary capillaries in severe inflammation. Increased transcytosis Rapid, mediator-dependent. VEGF and selected cytokines. New-vessel leak Persistent until maturation. Angiogenesis during repair and chronic inflammation. 3.4 Exudate versus transudate An exudate is protein-rich inflammatory fluid containing leukocytes and debris. A transudate is protein-poor fluid caused by hydrostatic or oncotic imbalance without primary endothelial injury. The distinction helps separate inflammation from heart failure, cirrhosis and nephrotic oedema. 4. Haemodynamic stasis and margination Loss of plasma concentrates red cells and increases blood viscosity. Slower flow pushes leukocytes from the central axial stream toward the endothelial surface (margination). Activated endothelium expresses selectins, integrin ligands and chemokines that prepare leukocytes for arrest. 5. Leukocyte recruitment 5.1 Rolling Endothelial E-selectin and P-selectin bind transient carbohydrate ligands on leukocytes. The bonds form and break rapidly, so cells roll along the vessel wall. Histamine and thrombin rapidly mobilise P-selectin from endothelial stores; TNF and IL-1 induce E-selectin over hours. 5.2 Firm adhesion Endothelial chemokines activate leukocyte integrins (LFA-1, Mac-1 and VLA-4), increasing their affinity. Integrins bind ICAM-1 and VCAM-1 on endothelium. Defects in integrins or their ligands cause recurrent infections and poor wound healing. 5.3 Transmigration (diapedesis) Leukocytes squeeze between endothelial cells in post-capillary venules. PECAM-1 (CD31) and junctional molecules help the cell cross the basement membrane. Matrix metalloproteinases and proteases facilitate passage. 5.4 Chemotaxis Leukocytes move along chemical gradients toward the highest concentration of attractant. Chemoattractant Source/importance Bacterial peptides (N-formyl-methionyl peptides) Directly signal microbial products. C5a Complement-derived chemotactic and activating fragment. LTB4 Potent neutrophil chemoattractant and activator. Chemokines (e.g. CXCL8/IL-8) Endothelial and leukocyte-derived recruitment signals. Platelet-activating factor Promotes adhesion, chemotaxis and degranulation. 6. Phagocytosis and killing 6.1 Recognition and attachment Phagocytes bind microbes directly through pattern-recognition receptors or through opsonins. Important opsonins include IgG, C3b, collectins and pentraxins. Opsonisation greatly increases the speed and efficiency of engulfment. 6.2 Engulfment Pseudopods surround the particle and fuse to form a phagosome. The phagosome fuses with lysosomes to create a phagolysosome. Actin rearrangement, small GTPases and cytoskeletal motors are required. 6.3 Killing and degradation Respiratory burst: NADPH oxidase generates superoxide and hydrogen peroxide. Myeloperoxidase: H2O2 plus chloride forms hypochlorous acid. Reactive nitrogen species: inducible nitric oxide synthase produces NO and peroxynitrite. Non-oxidative mechanisms: defensins, lysozyme, proteases, lactoferrin and acidic lysosomes. Macrophage processing: antigens may be presented to T cells after digestion. 6.4 Leukocyte-mediated tissue injury Neutrophils release enzymes and ROS into extracellular space when they encounter immune complexes, crystals, large particles or frustrated phagocytosis. Collateral damage causes emphysema, vasculitis, acute lung injury, pancreatitis and reperfusion injury. 7. Major acute inflammatory mediators Mediator Main effects Histamine Immediate vasodilation and venular permeability; bronchoconstriction in allergy. Prostaglandins Vasodilation, pain, fever and platelet modulation. Leukotrienes Bronchoconstriction, permeability and chemotaxis. Bradykinin Pain, permeability, vasodilation and smooth-muscle contraction. Complement C3a/C5a Mast-cell activation, chemotaxis, opsonisation and membrane attack complex. TNF/IL-1 Endothelial activation, fever, leukocyte recruitment and systemic effects. IL-6 Hepatic acute-phase response and fever. PAF Platelet activation, permeability, bronchoconstriction and leukocyte adhesion. NO Vasodilation and microbial killing; excessive levels contribute to shock. Chemokines Selective, directed leukocyte recruitment. 8. Morphologic patterns of acute inflammation Pattern Main content Examples Serous Watery, relatively cell-poor fluid. Burn blister, viral serositis. Fibrinous Fibrin-rich exudate. Fibrinous pericarditis. Suppurative Neutrophils, bacteria and liquefied debris. Abscess, bacterial pneumonia. Catarrhal Mucus-rich mucosal response. Viral rhinitis and bronchitis. Haemorrhagic Red cells mixed with exudate. Severe vascular injury, necrotising infection. Ulcerative Loss of epithelium with inflamed base. Peptic ulcer or pressure sore. 9. Outcomes of acute inflammation 9.1 Resolution Resolution is likely when injury is limited, the tissue can regenerate and the cause is

Benefits and Harmful Effects of Inflammation Why inflammation protects • when it becomes destructive • resolution • fibrosis • systemic complications • treatment balance Inflammation is an essential defence and repair response, but it is a double-edged process. A proportionate response contains infection, removes dead tissue and prepares healing. An excessive, persistent or misdirected response damages healthy cells, blocks microcirculation, causes fibrosis and may produce shock or multi-organ failure. The clinical skill is not to eliminate all inflammation. It is to preserve the benefits while controlling the cause, limiting collateral damage and supporting resolution. Learning outcomes Explain the protective benefits of local and systemic inflammation. Describe how neutrophils, macrophages, complement, antibodies, fibrin and cytokines cooperate. Explain harmful effects including oedema, bystander injury, thrombosis, fibrosis, adhesions, pain, fever and systemic shock. Describe resolution as an active process and identify reasons it fails. Balance antimicrobial/anti-inflammatory treatment in emergencies. Apply the concepts to sepsis, anaphylaxis, infarction, asthma, autoimmune disease and chronic inflammation. 1. Protective benefits 1.1 Recognition and containment Pattern-recognition receptors detect pathogens and tissue damage. Vasodilation and increased permeability deliver plasma proteins, antibodies and complement. Fibrin and oedema can wall off a local focus, reducing spread through tissue planes and lymphatics. 1.2 Elimination of pathogens Opsonisation: complement C3b, antibodies and collectins coat microbes for phagocytosis. Phagocytosis: neutrophils and macrophages engulf organisms and debris. Oxidative killing: the respiratory burst produces superoxide, hydrogen peroxide and hypochlorous acid. Non-oxidative killing: lysosomal enzymes, defensins, lactoferrin and low pH damage microbes. Extracellular traps: neutrophil chromatin can immobilise organisms, although excessive NETs injure endothelium. Adaptive coordination: T cells and antibodies provide specificity and memory. 1.3 Removal of dead tissue and foreign material Macrophages recognise apoptotic cells and necrotic debris, digest them and transport soluble material through lymphatics. This clears the field for regeneration or scar formation. 1.4 Initiation of repair Macrophages, platelets, endothelial cells and fibroblasts release growth factors. Angiogenesis restores oxygen, fibroblasts deposit matrix and epithelial cells migrate over a wound. Controlled inflammation therefore prepares tissue reconstruction. 1.5 Systemic coordination Fever can inhibit some pathogens and enhance immune reactions. The liver produces CRP, complement and fibrinogen; bone marrow releases leukocytes; iron is sequestered through hepcidin. These changes support host defence but become harmful when severe or prolonged. 2. How inflammation causes tissue injury 2.1 Bystander damage from leukocytes Activated neutrophils and macrophages cannot always distinguish microbes from adjacent host tissue. ROS, proteases, elastase, myeloperoxidase products, NETs and cytokines destroy extracellular matrix, epithelium, endothelium and parenchymal cells. 2.2 Oedema and pressure Protein-rich exudate increases tissue volume and interstitial pressure. In the brain, lungs, airways, renal tubules and closed fascial compartments, oedema compromises perfusion or ventilation. 2.3 Thrombosis and microvascular obstruction Activated endothelium expresses tissue factor and adhesion molecules. Platelets, NETs and fibrin form microthrombi that worsen ischaemia. This is important in sepsis, COVID-like viral inflammation, vasculitis and atherosclerotic plaque rupture. 2.4 Pain and loss of function Bradykinin, prostaglandins, ATP and nerve compression sensitise nociceptors. Pain limits movement and protects the injured region but can produce immobility, atelectasis and deconditioning when prolonged. 3. Local harmful effects Effect Mechanism Possible consequence Persistent swelling Permeability, sodium/water retention and lymphatic overload. Compartment syndrome, airway obstruction or nerve compression. Suppuration Neutrophil enzymes digest tissue and form pus. Abscess, fistula, bacteraemia and scarring. Ulceration Surface necrosis and loss of epithelium. Bleeding, perforation and impaired absorption. Fibrosis Persistent macrophage/TGF-β signalling activates fibroblasts. Strictures, adhesions, cirrhosis or lung fibrosis. Thrombosis Endothelial activation and platelet–leukocyte interaction. Ischaemia, infarction or embolism. Destruction of specialised tissue ROS, proteases and cytotoxic lymphocytes. Loss of neurons, nephrons, beta cells or myocytes. 4. Systemic harmful effects 4.1 Fever and metabolic stress IL-1, TNF and prostaglandin E2 reset the hypothalamic temperature set point. Fever increases metabolic rate, oxygen demand and insensible fluid loss. It can worsen myocardial ischaemia, delirium or seizures in vulnerable patients. 4.2 Acute-phase and haematologic effects IL-6 induces CRP and fibrinogen; hepcidin sequesters iron; thrombopoietin and marrow signals change blood counts. Chronic inflammation produces anaemia of inflammation, thrombocytosis and cachexia. 4.3 Hypotension and shock TNF, IL-1, nitric oxide and endothelial injury cause vasodilation and capillary leak. Plasma leaves the circulation, venous return falls and microvascular perfusion becomes heterogeneous. Severe dysregulation produces septic or cytokine-mediated shock. 4.4 Acute respiratory distress Neutrophils and endothelial injury disrupt the alveolar–capillary barrier. Protein-rich fluid fills alveoli, reducing compliance and oxygenation. Mechanical ventilation and fluid strategy must be carefully balanced. 4.5 Disseminated coagulation Inflammatory tissue factor, platelet activation and endothelial damage can consume clotting factors and platelets while producing microthrombi. Bleeding and organ ischaemia may coexist. 4.6 Multi-organ dysfunction Persistent cytokines, hypoperfusion, microthrombi and mitochondrial dysfunction injure kidneys, liver, brain, heart and lungs. The clinical trajectory depends on early source control and restoration of perfusion. 5. Resolution: an active biological programme Resolution is not simply “inflammation running out.” It requires coordinated termination and repair. Remove or neutralise the inciting stimulus. Stop recruitment signals and degrade short-lived mediators. Neutrophils undergo apoptosis rather than releasing further enzymes. Macrophages perform efferocytosis and switch toward pro-resolution functions. Lymphatics drain protein-rich oedema and debris. Lipoxins, resolvins, protectins, maresins, IL-10 and TGF-β restrain further leukocyte recruitment. Regeneration restores tissue when the matrix and stem-cell reserve are intact; otherwise fibrosis provides structural closure. 5.1 Why resolution fails Persistent infection or biofilm. Retained foreign body or crystal. Ongoing toxin, smoking or metabolic stress. Defective efferocytosis or lymphatic drainage. Repeated injury and poor perfusion. Autoimmune stimulation and failure of tolerance. 6. Benefits and harms by clinical setting Setting Protective benefit Potential harm Pneumonia Neutrophils and antibodies remove organisms. Alveolar leak, ARDS and fibrosis. Myocardial infarction Macrophages clear necrotic myocytes and initiate scar. Peri-infarct injury, arrhythmia, ventricular rupture. Anaphylaxis Rapid defence against a perceived allergen. Airway oedema, bronchospasm and shock. Gout Crystals are recognised and cleared. Severe sterile synovitis and joint damage. Wound healing Debris removal and repair signalling. Hypertrophic scar, keloid or chronic ulcer. Autoimmunity Normally protects against infection. Persistent self-tissue destruction. 7. Anti-inflammatory treatment: preserve benefit, limit harm Intervention Benefit Risk or limitation Antimicrobials Remove infectious stimulus. Resistance, allergy, microbiome injury; do not

Causes of Inflammation Infectious • sterile injury • physical and chemical agents • immune disease • foreign bodies • metabolic triggers Inflammation begins when cells and tissues detect a threat to homeostasis. The trigger may be an invading organism, a damaged cell, a toxin, an abnormal immune response, a foreign material or a metabolic crystal. Correctly identifying the cause is more important than simply naming the inflammatory pattern because treatment differs radically: antibiotics help infection, reperfusion helps ischaemia, adrenaline treats anaphylaxis, surgery controls a necrotic focus and immunosuppression may help autoimmunity but worsen infection. Learning outcomes Classify inflammatory causes into infectious, traumatic/physical, chemical, immune, foreign-body, metabolic and neoplastic categories. Explain how PAMPs, DAMPs, crystals, antibodies, complement and cytokines initiate inflammation. Use clinical clues to distinguish infection from sterile inflammation. Recognise common emergency triggers such as sepsis, anaphylaxis, burns, infarction, necrotising infection and toxic exposure. Choose appropriate confirmatory tests and identify when source control or antidote therapy is urgent. 1. Cause-to-response framework Question Why it matters What was the trigger? Determines antimicrobial, antitoxin, reperfusion, surgical or immunologic therapy. Is it still present? Persistent infection, foreign body or obstruction prevents resolution. Is tissue necrotic? Necrosis releases DAMPs and may require debridement or drainage. Is the response sterile or infectious? Inflammation alone cannot distinguish infection; cultures and imaging may be required. Is inflammation local or systemic? Systemic organ dysfunction requires resuscitation and urgent escalation. 2. Infectious causes 2.1 Bacteria Bacterial PAMPs (lipopolysaccharide, peptidoglycan, lipoteichoic acid, flagellin and bacterial DNA) activate toll-like and NOD-like receptors. Exotoxins, pore-forming toxins, enzymes and direct invasion add tissue injury. Pyogenic bacteria: neutrophil-rich suppuration and abscess formation. Intracellular bacteria: macrophage and T-cell responses; granulomas or chronic inflammation. Toxin-mediated disease: systemic cytokine release, endothelial injury or neuromuscular dysfunction. Biofilms: persistent low-grade inflammation around catheters, prostheses and chronic wounds. 2.2 Viruses Viral RNA or DNA activates endosomal and cytosolic sensors, inducing type I interferons and inflammatory cytokines. Tissue damage can result from viral cytolysis, apoptosis, pyroptosis or cytotoxic T-cell killing. Viral infection may therefore produce either acute inflammation or chronic immune-mediated injury. 2.3 Fungi Fungal cell-wall components such as beta-glucans and mannans activate C-type lectin receptors. Neutrophils, macrophages and granulomas are important. Invasive fungi may cause vascular thrombosis, infarction and necrotising inflammation, especially in neutropenic or immunosuppressed patients. 2.4 Parasites Helminths trigger type 2 inflammation with IL-4, IL-5, IL-13, IgE and eosinophils. Protozoa may cause macrophage, cytotoxic T-cell or neutrophil responses. Tissue migration, obstruction and chronic antigen release lead to fibrosis or granulomas. 2.5 Prions Misfolded prion protein produces progressive neurodegeneration with minimal classic inflammation. This illustrates that tissue damage can be severe even when inflammatory cells are sparse. 2.6 Infection-associated emergencies Sepsis and septic shock. Meningitis/encephalitis with raised intracranial pressure. Necrotising fasciitis and gas gangrene. Severe pneumonia and acute respiratory distress. Invasive fungal disease with haemorrhage or infarction. 3. Tissue injury and necrosis Dead or injured cells release DAMPs including ATP, HMGB1, mitochondrial DNA, uric acid and heat-shock proteins. Sterile inflammation develops after: Infarction: myocardial, cerebral, renal, splenic or bowel ischaemia. Crush injury: muscle necrosis, rhabdomyolysis and hyperkalaemia. Burns and frostbite: thermal injury and reperfusion. Pancreatitis: enzyme-mediated fat and pancreatic necrosis. Surgery and tissue handling: controlled injury followed by repair. Sterile inflammation may coexist with infection later; an infarcted bowel or necrotic tumour can become secondarily infected. 4. Physical causes Physical agent Mechanism Inflammatory examples Emergency priority Heat Protein denaturation, dehydration, vascular damage. Burn wound, heat stroke. Airway, fluid/electrolyte support, cooling and burn referral. Cold Vasoconstriction, ice crystals, ischaemia and reperfusion. Frostbite and hypothermia. Rewarming when safe, perfusion and tissue assessment. Mechanical trauma Cell rupture, haemorrhage, oedema and DAMP release. Crush injury, fractures and compartment syndrome. Bleeding control, perfusion, fasciotomy assessment. Radiation DNA breaks and ROS. Radiodermatitis, marrow injury, radiation pneumonitis. Decontamination, specialist and supportive care. Electricity/lightning Thermal injury, arrhythmia, muscle necrosis. Electrical burns and rhabdomyolysis. ECG, trauma survey, electrolytes and renal monitoring. Pressure/barotrauma Mechanical disruption, gas bubbles or ischaemia. Decompression sickness, ventilator injury. Oxygen, pressure management and specialist referral. 5. Chemical and toxic causes 5.1 Direct irritants Acids, alkalis, solvents, smoke and concentrated disinfectants damage membranes and proteins at the contact site. Corrosive ingestion may cause airway oedema, oesophageal necrosis, perforation and mediastinitis. 5.2 Systemic toxins and metabolic activation Exposure Mechanism/inflammatory injury Clues Paracetamol overdose NAPQI depletes glutathione and causes centrilobular hepatic necrosis. Delayed nausea, rising AST/ALT, INR and encephalopathy. Cyanide Blocks cytochrome oxidase and cellular oxygen use. Severe lactic acidosis, cardiovascular collapse. Carbon monoxide Carboxyhaemoglobin and mitochondrial dysfunction. Neurologic symptoms, headache, multiple exposed people. Organophosphates Acetylcholinesterase inhibition; secretions and bronchospasm. Cholinergic toxidrome, fasciculations, bradycardia. Heavy metals Protein binding, enzyme inhibition and ROS. Neuropathy, abdominal symptoms, renal injury. Drug hypersensitivity Immune-mediated tissue injury and eosinophilic inflammation. Rash, fever, hepatitis, nephritis or anaphylaxis. 5.3 Occupational and environmental exposures Silica, asbestos, coal dust, tobacco smoke, air pollution and pesticides cause persistent macrophage activation, oxidative stress, fibrosis or malignancy risk. A detailed occupational history is often more revealing than a routine laboratory test. 6. Immune-mediated causes 6.1 Autoimmunity Loss of tolerance produces antibodies, immune complexes or T cells that attack host tissue. Examples include rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis, vasculitis, inflammatory bowel disease and autoimmune encephalitis. 6.2 Hypersensitivity reactions Type Main mechanism Examples I (immediate) IgE, mast cells, histamine, leukotrienes. Anaphylaxis, allergic asthma, urticaria. II (antibody-mediated) IgG/IgM against cell or matrix; complement, phagocytosis or receptor effects. Autoimmune haemolysis, Goodpasture disease, Graves disease. III (immune complex) Deposited antigen–antibody complexes activate complement and neutrophils. SLE, serum sickness, some vasculitides. IV (T-cell mediated) Th1/Th17 cytokines, cytotoxic T cells and macrophage activation. Contact dermatitis, tuberculosis, type 1 diabetes. 6.3 Allograft and transplant injury Antibodies and T cells recognise donor antigens, causing acute or chronic rejection. Vascular inflammation can produce thrombosis and organ infarction. Immunosuppression reduces rejection but increases infection and malignancy risk. 7. Foreign bodies and persistent material Macrophages cannot easily digest splinters, sutures, talc, silicone, keratin, silica or retained surgical material. Frustrated phagocytosis produces giant cells, fibrosis and chronic inflammation. Remove the material when feasible; persistent “sterile abscess” or draining sinus warrants

Definition and Types of Inflammation How inflammation is classified • acute versus chronic • local versus systemic • exudative, suppurative and granulomatous patterns Inflammation is a protective response of vascularised living tissue to infection, injury or abnormal stimulation. It recruits plasma proteins and leukocytes, removes the cause and initiates repair. Classification helps predict the dominant cells, mediators, time course, tissue appearance and complications. No single classification is enough. A patient may have acute, local, suppurative inflammation caused by bacteria, or chronic, systemic, granulomatous inflammation caused by tuberculosis. Always describe the time course, distribution, cause and morphology together. Learning outcomes State a complete definition of inflammation and explain the role of vascularised tissue. Classify inflammation by duration, distribution, cause, immune mechanism and morphology. Compare acute and chronic inflammation, including cells, mediators, outcomes and clinical examples. Recognise serous, fibrinous, suppurative, catarrhal, pseudomembranous, ulcerative, haemorrhagic, necrotising and granulomatous patterns. Distinguish local inflammation from systemic inflammatory response and sepsis. Use a structured description in clinical notes, pathology reports and exam answers. 1. Complete definition Inflammation is a coordinated response of vascularised tissue involving recognition of danger, mediator release, altered blood flow and permeability, recruitment/activation of leukocytes, elimination of the inciting stimulus, and termination with resolution or repair. The response is protective when it is proportionate and self-limited. It is pathologic when excessive, misdirected, persistent or directed against self. Avascular tissues cannot generate the classic vascular exudate but may show adjacent inflammatory responses through surrounding vessels. 2. Classification by duration 2.1 Acute inflammation Feature Acute pattern Onset/duration Minutes to hours; usually resolves within days. Vascular response Vasodilation, increased permeability and protein-rich exudate. Dominant cells Neutrophils, mast cells and early platelets. Main mediators Histamine, prostaglandins, leukotrienes, bradykinin, complement, TNF and IL-1. Typical causes Trauma, burns, bacterial infection, acute allergy, infarction and foreign bodies. Possible outcomes Resolution, abscess, fibrosis or transition to chronic inflammation. 2.2 Chronic inflammation Feature Chronic pattern Onset/duration Days to years; persistent or recurrent. Cells Macrophages, lymphocytes, plasma cells, eosinophils and fibroblasts. Tissue changes Ongoing injury, angiogenesis, fibrosis and remodelling alongside repair. Typical causes Persistent infection, autoimmunity, prolonged toxin exposure, foreign bodies and metabolic disease. Examples Tuberculosis, rheumatoid arthritis, chronic hepatitis, atherosclerosis and inflammatory bowel disease. Acute and chronic are not mutually exclusive. A chronic ulcer may have an acute neutrophilic flare, and an unresolved acute infection can become chronic. 3. Classification by distribution 3.1 Local inflammation Local inflammation is confined predominantly to one tissue or organ. It produces redness, heat, swelling, pain and loss of function when visible or palpable. Examples include cellulitis, appendicitis, arthritis and local dermatitis. 3.2 Regional inflammation Regional inflammation extends along tissue planes, lymphatics or a contiguous organ system. Lymphangitis, spreading cellulitis and regional lymphadenitis are examples. The border may advance rapidly, so serial examination is important. 3.3 Systemic inflammation Systemic inflammation affects multiple organs through circulating cytokines, complement, acute-phase proteins and endothelial activation. Fever, tachycardia, malaise, leukocyte changes and raised CRP may occur. Severe dysregulation causes organ dysfunction and shock. 3.4 Sepsis is not a synonym for inflammation Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Sterile trauma, pancreatitis and burns can produce systemic inflammation without sepsis, while infection may be severe even when classic inflammatory signs are absent in an immunosuppressed patient. 4. Classification by cause Cause Examples Typical pattern Infectious Bacterial, viral, fungal and parasitic disease. Acute suppurative or chronic granulomatous; organism-specific changes. Ischaemic/necrotic Infarction, tissue torsion, crush injury. Acute sterile inflammation around necrotic tissue. Physical Heat, cold, radiation, electricity and trauma. Acute inflammation, oedema and tissue destruction. Chemical Corrosives, smoke, drugs, toxins and irritants. Acute or chronic toxic inflammation. Immune-mediated Autoimmunity, hypersensitivity, immune complexes and graft rejection. Acute, chronic, granulomatous or vasculitic. Foreign-body Splinters, sutures, talc, silica and crystals. Persistent macrophage and giant-cell response. Metabolic Urate, cholesterol, obesity and atherosclerosis. Chronic low-grade or crystal-triggered inflammation. 5. Classification by immune mechanism Innate inflammation: rapid, pattern-recognition driven response involving macrophages, neutrophils, mast cells, complement and innate lymphoid cells. Adaptive inflammation: antigen-specific T cells, B cells and antibodies; usually slower but more targeted and memory-forming. Type 1 inflammation: macrophages and IFN-γ-dominant responses against intracellular organisms. Type 2 inflammation: IL-4/IL-5/IL-13, eosinophils and IgE in allergy and helminth disease. Type 3 inflammation: IL-17/IL-22 and neutrophils against extracellular bacteria and fungi. Sterile inflammation: DAMP-driven response to injury, crystals, metabolic stress or necrosis without an infectious organism. 6. Morphologic patterns of acute inflammation 6.1 Serous inflammation Serous inflammation produces a watery, relatively cell-poor fluid derived from plasma or mesothelial secretions. It forms blisters after burns or viral infection and can cause serous pleuritis or pericarditis. It usually resolves if the cause is removed. 6.2 Fibrinous inflammation More severe vascular leakage allows fibrinogen to escape and polymerise into fibrin. Fibrinous exudate appears as eosinophilic strands or a shaggy surface on serosal membranes. It may be removed by fibrinolysis or organise into adhesions and scar. Examples: fibrinous pericarditis after myocardial infarction or uraemia, and fibrinous pleuritis. Complication: constrictive scarring or adhesions if organisation is extensive. 6.3 Suppurative (purulent) inflammation Suppurative inflammation contains abundant neutrophils, liquefied necrotic debris, bacteria and protein-rich fluid. A local collection is an abscess; diffuse pus in tissue is cellulitis or phlegmon. Abscess centres are hypoxic and poorly penetrated by antibiotics. Drainage and source control are often necessary. Untreated pus may spread to blood, bone, brain or body cavities. 6.4 Catarrhal inflammation Catarrhal inflammation affects mucosal surfaces and is dominated by mucus hypersecretion. It occurs in viral rhinitis, bronchitis and some allergic conditions. Mucus retention can obstruct small airways or sinuses. 6.5 Pseudomembranous inflammation Severe mucosal injury produces a surface membrane of fibrin, necrotic epithelium, mucus and inflammatory cells. It can occur in Clostridioides difficile colitis, diphtheria and severe chemical injury. Removal may reveal an ulcerated, bleeding surface. Consider infection control, stool testing and urgent treatment when severe colitis is suspected. 6.6 Haemorrhagic inflammation Extensive endothelial damage or necrosis allows red cells to escape with the inflammatory exudate. Haemorrhagic inflammation occurs in severe viral disease, necrotising infections, pancreatitis and some vasculitides. It signals more destructive

Overview of Inflammation Definition • purpose • types • causes • benefits • harmful consequences • acute and chronic patterns • clinical recognition Inflammation is the coordinated protective response of vascularised tissue to infection, injury or tissue stress. It delivers plasma proteins and leukocytes to the affected site, removes the initiating cause and starts repair. Inflammation is therefore a defence mechanism, not automatically a disease. It becomes harmful when it is excessive, misdirected, persistent or unable to resolve. Emergency medicine relies on recognising both the protective and dangerous sides of inflammation: a local response can contain infection, while uncontrolled systemic inflammation can produce shock, capillary leak, thrombosis and multi-organ dysfunction. Learning outcomes Define inflammation and explain why vascularised tissues are required for a classic inflammatory response. Distinguish acute, chronic, granulomatous, serous, fibrinous, suppurative and systemic inflammation. List infectious, physical, chemical, immune, necrotic and metabolic causes. Explain the protective benefits and the mechanisms of inflammatory tissue damage. Describe the sequence from recognition to mediator release, vascular change, leukocyte recruitment, clearance and resolution/repair. Recognise local cardinal signs and systemic acute-phase responses. Apply the framework to sepsis, anaphylaxis, trauma, autoimmune disease and chronic inflammatory conditions. 1. Definition and essential components Inflammation is a response of living, vascularised tissue involving: Recognition: sensors detect pathogens (PAMPs) or tissue damage (DAMPs). Vascular reaction: arteriolar dilation, increased endothelial permeability and altered blood flow. Cell recruitment: leukocytes leave the circulation, migrate to the focus and become activated. Elimination: microbes, toxins and dead cells are neutralised or removed. Termination and repair: mediators decline, debris is cleared and tissue returns toward homeostasis or forms scar. Avascular tissues may show immune or degenerative responses but cannot mount the complete vascular-leukocyte sequence without adjacent vessels. 2. Why inflammation is beneficial Benefit How it helps Clinical example Containment Fibrin, oedema and leukocytes limit spread of microbes or toxins. Abscess wall limits bacterial infection. Microbial killing Neutrophils, macrophages, complement and antibodies destroy pathogens. Neutrophil killing of pyogenic bacteria. Removal of debris Phagocytes clear necrotic cells and foreign material. Macrophages remove infarcted tissue. Initiation of repair Growth factors stimulate angiogenesis, fibroblasts and re-epithelialisation. Granulation tissue in a healing wound. Systemic coordination Fever, acute-phase proteins and leukocytosis support host defence. Fever and CRP rise during infection. 3. When inflammation becomes harmful Excessive intensity: cytokine storm, anaphylaxis, acute respiratory distress and septic shock. Mis-targeting: autoimmunity, immune-complex vasculitis and inflammatory bowel disease. Persistence: chronic inflammation causes fibrosis, organ remodelling and malignancy risk. Inappropriate timing: inflammation after reperfusion or trauma expands tissue injury. Failure to resolve: retained microbes, foreign bodies or defective efferocytosis maintain the response. 4. Causes of inflammation Cause Examples Dominant signals Infections Bacteria, viruses, fungi, parasites and prions. PAMPs, complement, cytokines, inflammasomes. Necrosis/tissue injury Infarction, trauma, burns, crush injury and pancreatitis. DAMPs, ATP, HMGB1, mitochondrial DNA. Physical agents Heat, cold, radiation, pressure, electricity and ultraviolet light. Cell injury, ROS and DAMPs. Chemicals/toxins Corrosives, irritants, drugs, smoke and pollutants. Direct injury, oxidative stress and immune activation. Immune reactions Autoantibodies, T cells, immune complexes and allergic responses. Complement, Fc receptors, cytokines, mast-cell mediators. Foreign bodies Splinters, sutures, crystals, dust and prosthetic material. Macrophages, giant cells and persistent pattern-recognition signals. Metabolic stress Urate crystals, cholesterol crystals, obesity and insulin resistance. NLRP3 inflammasome, adipokines and low-grade cytokines. 5. Acute and chronic inflammation Feature Acute inflammation Chronic inflammation Onset Minutes to hours. Days to years. Dominant cells Neutrophils early; mast cells and platelets contribute. Macrophages, lymphocytes and plasma cells. Vascular response Prominent exudation and oedema. Less dramatic but persistent angiogenesis and remodelling. Tissue outcome Resolution, abscess, scar or progression. Destruction, fibrosis, angiogenesis and ongoing repair. Typical causes Trauma, bacterial infection, early allergic reaction. Tuberculosis, autoimmune disease, chronic viral infection, atherosclerosis. Acute and chronic inflammation can coexist. A chronic lesion may contain acute flares, and unresolved acute inflammation can transition into chronic inflammation. 6. Recognition of danger 6.1 PAMPs and pattern-recognition receptors Pathogen-associated molecular patterns include lipopolysaccharide, peptidoglycan, flagellin and viral nucleic acids. Toll-like receptors, NOD-like receptors, RIG-I-like receptors and C-type lectins detect them on immune cells, epithelium and endothelium. 6.2 DAMPs Damage-associated molecular patterns include extracellular ATP, HMGB1, mitochondrial DNA, uric acid crystals, heat-shock proteins and exposed phospholipids. They activate sterile inflammation after infarction, trauma, surgery and crystal disease. 6.3 Inflammasomes NLRP3 and related inflammasomes activate caspase-1, which matures IL-1β and IL-18 and may induce pyroptosis. Inflammasomes link infection, cellular stress, cholesterol crystals, silica and metabolic disease to inflammation. 7. The inflammatory sequence Recognition: resident macrophages, mast cells, dendritic cells and epithelial cells detect danger. Mediator release: histamine, prostaglandins, leukotrienes, complement fragments, cytokines and chemokines are produced. Vasodilation: arterioles dilate, increasing blood flow and producing warmth/redness. Permeability increase: endothelial gaps or injury permit protein-rich exudate and leukocytes to leave vessels. Stasis: plasma loss concentrates red cells and slows flow; leukocytes move to the endothelial margin. Leukocyte recruitment: rolling, adhesion, transmigration and chemotaxis bring cells to the focus. Activation: phagocytes ingest and kill microbes, release enzymes and produce ROS. Termination: anti-inflammatory mediators, efferocytosis, lymphatic drainage and repair resolve the response. 8. Local clinical signs Sign Mechanism Clinical observation Rubor (redness) Arteriolar dilation and increased blood flow. Red skin around a wound. Calor (heat) Increased blood flow and systemic/local temperature rise. Warm, tender joint. Tumor (swelling) Protein-rich exudate and cellular infiltration. Oedema or joint effusion. Dolor (pain) Bradykinin, prostaglandins, pressure and nerve sensitisation. Tenderness and pain on movement. Functio laesa (loss of function) Pain, swelling, tissue destruction and altered organ physiology. Reduced joint movement or impaired organ function. 9. Exudate, transudate and oedema Feature Exudate Transudate Cause Inflammatory endothelial permeability. Hydrostatic or oncotic imbalance without primary inflammation. Protein High. Low. Cells Often present. Few cells. Examples Pneumonia, cellulitis, inflammatory effusion. Heart failure, cirrhosis, nephrotic syndrome. Fibrin-rich exudate can organise into scar if not removed. Purulent exudate contains neutrophils, necrotic debris and often bacteria. 10. Inflammatory mediators: functional map Mediator Main source Important effect Histamine Mast cells, basophils, platelets. Rapid arteriolar dilation and venular permeability. Prostaglandins Leukocytes, endothelium and mast cells. Pain, fever, vasodilation and platelet effects. Leukotrienes Leukocytes and mast cells. Bronchoconstriction,

Cellular Aging Senescence • telomere attrition • genomic instability • proteostasis • mitochondrial dysfunction • stem-cell exhaustion • clinical relevance Cellular aging is the progressive decline in a cell’s ability to maintain homeostasis, repair damage, adapt to stress and preserve tissue function. It is not a single disease and it is not identical to apoptosis. Some aged cells remain alive but enter a durable growth-arrested state called senescence; others die, accumulate lipofuscin, lose proliferative reserve or alter their secretory behaviour. Ageing is a major risk factor for atherosclerosis, cancer, diabetes, neurodegeneration, infection, frailty and poor recovery after trauma. Emergency clinicians encounter its consequences when older tissues tolerate hypoxia poorly, regenerate slowly and develop exaggerated inflammatory or thrombotic complications. Learning outcomes Define cellular ageing, replicative senescence, quiescence and apoptosis. Explain the major biological mechanisms of ageing: genomic instability, telomere attrition, epigenetic change, loss of proteostasis, mitochondrial dysfunction, nutrient-sensing changes, stem-cell exhaustion and altered intercellular communication. Describe the role of DNA damage, ROS, autophagy, mTOR, AMPK, sirtuins, p53/p21 and p16/RB pathways. Recognise morphology and laboratory markers of senescent and aged cells. Explain how senescence-associated secretory phenotype (SASP) contributes to inflammation, fibrosis, cancer and tissue dysfunction. Relate ageing mechanisms to organ-specific disease and emergency presentations. Distinguish evidence-based prevention from unproven “anti-ageing” claims. 1. Core concepts State Meaning Can proliferation resume? Example Quiescence Reversible resting state caused by lack of growth signals or nutrients. Usually yes when stimulation returns. Hepatocytes after the liver reaches normal mass. Senescence Durable cell-cycle arrest with altered metabolism and secretory behaviour after stress or repeated division. Generally no under physiologic conditions. Replicative senescence of fibroblasts. Apoptosis Regulated cell death with caspase activation and phagocytic clearance. No; the cell is dead. Removal of irreparably damaged cells. Cellular ageing Cumulative decline in repair, energy, proteostasis and adaptation, with or without senescence. Capacity declines variably. Ageing cardiomyocytes with lipofuscin and mitochondrial damage. 2. The major hallmarks of cellular ageing The modern hallmarks framework groups interconnected processes. A cell rarely ages through one pathway alone; DNA damage can impair mitochondria, mitochondrial ROS can damage DNA, and chronic SASP inflammation can exhaust stem cells. Hallmark Cellular change Clinical consequence Genomic instability DNA mutations, strand breaks, defective repair and chromosomal rearrangements. Cancer, cell-cycle arrest, organ dysfunction. Telomere attrition Progressive shortening of chromosome ends with repeated replication or stress. Stem-cell exhaustion, marrow failure and pulmonary/liver disease in telomere syndromes. Epigenetic alterations Changed DNA methylation, histone modification, chromatin remodelling and transposable-element activity. Abnormal gene expression and loss of cell identity. Loss of proteostasis Misfolding, impaired chaperones, defective ER quality control and reduced proteasome/autophagy. Neurodegeneration, ER stress and inclusion bodies. Disabled autophagy Damaged organelles and proteins accumulate because recycling is inadequate. Mitochondrial dysfunction, inflammation and loss of reserve. Mitochondrial dysfunction Reduced oxidative phosphorylation, mtDNA mutations, altered dynamics and ROS. Energy failure, sarcopenia, cardiac dysfunction and poor stress tolerance. Deregulated nutrient sensing Altered insulin/IGF-1, mTOR, AMPK and sirtuin signalling. Metabolic syndrome, impaired repair and accelerated ageing phenotypes. Mitochondrial communication Damaged mitochondria release DAMPs and inflammatory signals. Chronic inflammation and immune dysfunction. Cellular senescence Stable growth arrest with SASP production. Fibrosis, tumour suppression initially, tissue dysfunction if persistent. Stem-cell exhaustion Reduced self-renewal and regenerative capacity. Poor wound healing, anaemia, sarcopenia and organ failure. Altered intercellular communication Chronic low-grade inflammatory, endocrine and neural changes. Frailty, atherosclerosis and immunosenescence. 3. Genomic instability and DNA damage DNA is damaged continuously by replication errors, ROS, ultraviolet radiation, toxins, inflammation and spontaneous chemical changes. Young cells use nucleotide excision repair, base-excision repair, mismatch repair, homologous recombination and non-homologous end joining. With age, repair capacity declines and mutations accumulate. 3.1 DNA-damage response ATM/ATR kinases sense double- and single-strand damage. p53 induces p21, pauses the cell cycle and coordinates repair. If damage is irreparable, p53 can activate BAX/PUMA and apoptosis. Persistent damage activates p16INK4a/RB and stable senescence. Chromosome mis-segregation, micronuclei and cytosolic DNA can activate cGAS–STING inflammation. 3.2 Clinical links Defective repair causes premature ageing syndromes and cancer predisposition. In older patients, a lower reserve of intact cardiomyocytes, neurons, renal tubular cells and stem cells means that a short episode of hypoxia or infection may produce a disproportionate functional decline. 4. Telomere attrition Telomeres are repetitive DNA–protein structures that protect chromosome ends. Most somatic cells lack sufficient telomerase, so telomeres shorten with repeated replication. Critically short telomeres activate DNA-damage signalling, p53/p21 and p16/RB pathways, producing senescence or apoptosis. 4.1 Telomerase Telomerase maintains telomeres in germ cells, many stem cells and most cancers. Excess telomerase supports unlimited tumour-cell proliferation; insufficient telomerase causes premature exhaustion of regenerative compartments. 4.2 Telomere biology disorders Bone-marrow failure and cytopenias. Pulmonary fibrosis and liver disease. Short stature, premature greying and mucocutaneous findings. Increased risk from infection, bleeding and organ failure during acute stress. 5. Epigenetic and chromatin changes Ageing alters DNA methylation (“epigenetic clock”), histone acetylation/methylation, nucleosome positioning and chromatin organisation. Heterochromatin loosens, repetitive DNA becomes active and gene expression drifts. These changes can silence repair pathways, alter inflammation and make cells more vulnerable to environmental stress. Loss of heterochromatin: reduces genome stability and cell identity. Altered histone marks: change repair, metabolism and inflammatory gene expression. Non-coding RNAs: microRNAs and long non-coding RNAs alter translation and senescence signalling. Transposable elements: reactivation can generate DNA breaks and innate immune activation. 6. Loss of proteostasis Proteostasis is the balance of protein synthesis, folding, trafficking and degradation. Ageing reduces molecular chaperones, proteasome activity, ER quality control and autophagy. Misfolded proteins aggregate and activate chronic unfolded-protein responses. Defect Result Example ER stress PERK, IRE1 and ATF6 pathways initially slow translation and increase chaperones; persistent stress activates CHOP and apoptosis. Pancreatic beta-cell failure, neurodegeneration. Proteasome decline Oxidised and ubiquitinated proteins accumulate. Inclusion bodies in neurodegenerative disease. Autophagy decline Damaged mitochondria and protein aggregates persist. Sarcopenia, cardiac ageing and liver injury. Extracellular aggregation Misfolded proteins deposit in tissue and alter architecture. Amyloid diseases. 7. Mitochondrial dysfunction and oxidative stress Mitochondria age through mtDNA mutations, altered fusion/fission, impaired mitophagy and electron-transport-chain defects. Less ATP is produced, while electron leakage generates ROS. Damaged mitochondria release mitochondrial DNA and cardiolipin, which

Intracellular Accumulations Abnormal substances inside cells • mechanisms • lipid, protein, glycogen and pigment storage • stains • clinical significance Intracellular accumulation occurs when a cell stores an abnormal amount of a substance that it cannot metabolise, fold, transport, degrade or export normally. The material may be endogenous (lipid, protein, glycogen, pigment) or exogenous (carbon, silica, tattoo pigment). Some accumulations are harmless markers of previous injury; others disrupt organelles, trigger inflammation, cause cell death or reveal an inherited metabolic disease. This pathology lesson connects the microscopic appearance to the biochemical defect and the clinical problem. A storage pattern is not a diagnosis by itself: the student must ask what material is present, why it accumulated, which organ is affected and whether the process is reversible. Learning outcomes Define intracellular accumulation and list the four major mechanisms by which it develops. Classify accumulations into lipids, proteins, glycogen, pigments and selected minerals. Explain fatty change, cholesterol accumulation, protein droplets, glycogen storage and major endogenous/exogenous pigments. Recognise important histologic stains and their limitations. Distinguish benign adaptive storage from inherited storage disease, toxic injury and premalignant change. Interpret organ-specific examples in liver, kidney, heart, macrophages, lung, skin and nervous system. Apply the concepts to clinical presentations and emergency complications such as acute liver failure, metabolic decompensation and haemolysis. 1. Definition and the four mechanisms Accumulation reflects an imbalance between production or uptake and the cell’s ability to use, package, degrade or export a substance. Robbins-style classification recognises four broad mechanisms: Mechanism What fails? Examples Abnormal metabolism or uptake A normal substance is produced or delivered in excess of normal processing capacity. Triglyceride accumulation in fatty liver; cholesterol in atherosclerotic macrophages. Defective folding, transport or export A normal or abnormal protein cannot fold, move through the ER/Golgi or leave the cell. Alpha-1-antitrypsin in hepatocyte ER; immunoglobulin in plasma cells. Inherited enzyme deficiency A metabolite cannot be degraded and accumulates in lysosomes or cytoplasm. Gaucher, Tay-Sachs, Pompe and other lysosomal storage diseases. Inability to degrade ingested material Phagocytes internalise substances that resist digestion. Carbon pigment, silica, tattoo ink and some microorganisms. Reversibility is context-dependent Alcohol-related steatosis may regress after abstinence, while a lysosomal storage disease persists until the metabolic defect is treated. Lipofuscin may simply record previous oxidative injury; iron or copper accumulation can become directly toxic. Always interpret the material, burden, organ and clinical setting together. 2. Lipid accumulations 2.1 Triglyceride accumulation (steatosis) Steatosis is abnormal storage of triglycerides within parenchymal cells, especially hepatocytes. The liver receives fatty acids from diet and adipose tissue, synthesises fatty acids, oxidises them and packages them into VLDL. Steatosis develops when delivery or synthesis exceeds oxidation and export. Mechanisms in the liver Increased free-fatty-acid delivery from adipose tissue during starvation, obesity, insulin resistance or catecholamine excess. Increased de novo lipogenesis, often related to insulin resistance and metabolic syndrome. Reduced fatty-acid oxidation from hypoxia, mitochondrial injury or toxins. Impaired apoprotein synthesis or VLDL assembly, as with protein malnutrition or some toxins. Blocked lipoprotein secretion from hepatocytes. Causes Cause Mechanism/clinical context Alcohol NADH excess from ethanol metabolism inhibits fatty-acid oxidation and promotes triglyceride synthesis; acetaldehyde and oxidative stress add injury. Obesity and type 2 diabetes Insulin resistance increases free-fatty-acid flux and de novo lipogenesis. Starvation and severe malnutrition Adipose mobilisation increases hepatic fatty-acid delivery; protein deficiency limits VLDL export. Hypoxia/ischaemia Mitochondrial oxidation falls. Toxins and drugs Carbon tetrachloride, tetracycline, valproate, corticosteroids and some antiretrovirals can impair oxidation or export. Pregnancy and metabolic disease Acute fatty liver of pregnancy and metabolic disorders can produce rapid hepatocellular dysfunction. Morphology Microvesicular steatosis: many small lipid vacuoles, central nucleus; seen in acute fatty liver, Reye syndrome, valproate toxicity and mitochondrial disorders. Macrovesicular steatosis: one or a few large clear vacuoles displace the nucleus to the cell periphery; common in alcohol-associated and metabolic fatty liver. Gross liver: enlarged, yellow, soft and greasy in substantial steatosis. Stain: routine processing dissolves lipid, leaving clear vacuoles. Oil Red O or Sudan stains demonstrate neutral lipid in frozen sections. Clinical progression Steatosis may be asymptomatic or cause hepatomegaly and mild transaminase elevation. Persistent metabolic injury can progress to steatohepatitis, hepatocyte ballooning, Mallory-Denk bodies, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. Alcohol-associated disease adds acetaldehyde toxicity and gut-derived inflammatory signalling. 2.2 Cholesterol and cholesteryl ester accumulation Cells accumulate cholesterol when uptake is excessive, synthesis is increased or efflux is impaired. Atherosclerosis: macrophages take up oxidised LDL through scavenger receptors and become foam cells; smooth-muscle cells also accumulate lipid. Cholesterol crystals and necrotic debris form the atheromatous core. Xanthomas: dermal macrophages filled with lipid produce yellow plaques or nodules in hyperlipidaemia. Cholesterolosis: macrophages accumulate cholesterol in the gallbladder wall, producing a “strawberry gallbladder.” Niemann-Pick disease: sphingomyelin or cholesterol-related lysosomal storage causes foam cells, organomegaly and neurologic disease in some subtypes. 2.3 Phospholipid accumulation Some drugs (for example, amiodarone and certain cationic amphiphilic agents) inhibit lysosomal phospholipases and cause phospholipid-rich lamellar bodies. The process may produce phospholipidosis in lung, liver, kidney or eye. It often improves after the drug is withdrawn, but organ dysfunction can occur. 3. Protein accumulations 3.1 Reabsorption droplets in renal tubules Proteinuria causes proximal tubular cells to endocytose filtered albumin and immunoglobulin. The proteins accumulate in eosinophilic cytoplasmic droplets. Treating the glomerular leak reduces the load; persistent heavy proteinuria causes tubular injury and interstitial fibrosis. 3.2 Alpha-1-antitrypsin deficiency Mutant alpha-1-antitrypsin (especially the Z variant) misfolds and polymerises in hepatocyte ER, forming periodic acid–Schiff (PAS)-positive, diastase-resistant globules. Loss of circulating inhibitor predisposes to emphysema, while hepatic accumulation causes hepatitis, cirrhosis and hepatocellular carcinoma. 3.3 Immunoglobulin and Russell bodies Plasma cells synthesising large amounts of immunoglobulin may accumulate eosinophilic globules called Russell bodies. Numerous bodies produce Mott cells. They occur in chronic inflammation and plasma-cell neoplasms and are not by themselves diagnostic of malignancy. 3.4 Mallory-Denk bodies These are cytoplasmic aggregates of damaged intermediate filaments (keratins 8 and 18) in hepatocytes. They are seen in alcohol-associated hepatitis, metabolic steatohepatitis and some cholestatic or Wilson-related diseases. They indicate cellular stress but are not specific for alcohol. 3.5 Amyloid Amyloid is extracellular rather

Apoptosis Programmed cell death • mitochondrial and death-receptor pathways • caspases • morphology • clearance • disease and emergency medicine Apoptosis is a regulated, energy-dependent form of cell death in which a cell dismantles itself into membrane-bound fragments that are rapidly cleared by phagocytes. It is essential for development, immune regulation and tissue turnover. It becomes pathologic when too many cells die (for example, in neurodegeneration or viral disease) or when damaged cells escape death (for example, in cancer and autoimmunity). Apoptosis is usually non-inflammatory because the plasma membrane remains intact and apoptotic bodies are engulfed. It is not, however, always harmless: large-scale apoptosis can cause organ atrophy, and secondary necrosis can occur if clearance fails. Learning outcomes Define apoptosis and distinguish it from necrosis and other regulated lytic pathways. Explain the intrinsic mitochondrial and extrinsic death-receptor pathways. Describe BCL-2 family control, mitochondrial outer-membrane permeabilisation, cytochrome c, apoptosome formation and caspase activation. Explain initiator versus executioner caspases and the role of inhibitor-of-apoptosis proteins. Recognise apoptotic morphology, apoptotic bodies, phosphatidylserine exposure and efferocytosis. List physiologic and pathologic examples and understand how cancer, autoimmunity, infection and drugs alter apoptosis. Interpret laboratory and histology findings and apply the concepts to emergency and clinical cases. 1. Definition and distinguishing features Apoptosis is a tightly controlled form of cell death mediated by proteolytic caspases. It removes individual cells or small groups without spilling intracellular contents. The process requires enough ATP and cellular organisation to execute signalling, dismantling and phagocytic recognition. Feature Apoptosis Necrosis Cell size Shrinks and becomes dense. Swells and becomes pale or eosinophilic. Membrane Intact, with blebbing and apoptotic-body formation. Permeability fails and membrane ruptures. Nucleus Chromatin condensation and orderly fragmentation. Pyknosis, karyorrhexis, karyolysis and loss of architecture. Cell contents Packaged into membrane-bound bodies. Leak into interstitium and circulation. Inflammation Usually absent or minimal. Usually prominent. Energy Requires ATP and regulated signalling. Severe energy failure predominates. Typical scale Single cells or small clusters. Contiguous areas of tissue. Important qualification “Programmed” and “non-inflammatory” are not synonyms. Apoptosis is programmed and usually quiet, whereas necroptosis and pyroptosis are programmed but lytic and inflammatory. If apoptotic bodies are not cleared, they can undergo secondary necrosis and release DAMPs. 2. Physiologic roles 2.1 Development and morphogenesis Separates fingers and toes by removing interdigital tissue. Shapes the nervous system by deleting excess neurons and synapses. Removes transient embryonic structures such as Müllerian or Wolffian remnants. Controls organ size by balancing proliferation with death. 2.2 Homeostatic turnover Intestinal epithelial cells die at the villus tip and are replaced from crypt stem cells. Endometrial cells undergo hormone-withdrawal apoptosis during menstruation. Skin, liver and immune tissues remove aged or damaged cells without disrupting the barrier. Neutrophils undergo apoptosis at the end of an acute inflammatory response. 2.3 Immune regulation Apoptosis deletes autoreactive lymphocytes during central tolerance, contracts an immune response after pathogen clearance and removes infected or tumour cells through cytotoxic lymphocytes. Failure of this balance can produce autoimmunity, immunodeficiency or cancer. 3. The central control system: BCL-2 family proteins The intrinsic pathway is governed by the balance between pro-survival and pro-death BCL-2 family proteins at the mitochondrial outer membrane. Group Representative proteins Function Pro-survival BCL-2, BCL-xL, MCL-1, A1. Keep mitochondrial membranes intact and restrain BAX/BAK. Multi-domain pro-apoptotic BAX, BAK. Oligomerise to form pores in the mitochondrial outer membrane. BH3-only sensors BIM, BID, BAD, PUMA, NOXA, BMF. Sense growth-factor withdrawal, DNA damage, ER stress, toxins and cytokines; inhibit survival proteins or activate BAX/BAK. Cell survival depends on growth factors, intact metabolism and anti-apoptotic proteins. DNA damage, hypoxia, loss of attachment or trophic signals increase BH3-only activity. When BAX/BAK-mediated permeabilisation exceeds the anti-apoptotic reserve, the point of no return for intrinsic apoptosis is reached. 4. Intrinsic (mitochondrial) apoptosis pathway 4.1 Triggers Irreparable DNA damage from radiation, cytotoxic drugs, ROS or replication stress. Growth-factor or hormone withdrawal. Severe ER stress and accumulation of misfolded proteins. Loss of cell-matrix attachment (anoikis). Some viral infections and intracellular toxins. 4.2 Molecular sequence Stress activates BH3-only proteins and weakens BCL-2-mediated survival. BAX and BAK oligomerise in the mitochondrial outer membrane. Mitochondrial outer-membrane permeabilisation (MOMP) releases cytochrome c and other pro-death factors. Cytochrome c binds APAF-1 and procaspase-9 in an ATP-dependent apoptosome. Caspase-9 activates executioner caspases-3 and -7. Executioner caspases cleave cytoskeletal proteins, nuclear lamins, DNA-repair proteins and endonuclease inhibitors. The cell fragments into apoptotic bodies and exposes “eat-me” signals for efferocytosis. 4.3 Mitochondrial factors beyond cytochrome c Smac/DIABLO and Omi/HtrA2 neutralise inhibitor-of-apoptosis proteins (IAPs). Apoptosis-inducing factor (AIF) can contribute to caspase-independent DNA damage in severe injury. The balance of these factors determines whether a stressed cell remains viable, executes apoptosis or progresses to necrosis when ATP becomes inadequate. 5. Extrinsic (death-receptor) apoptosis pathway 5.1 Death receptors and ligands Death receptors are members of the TNF receptor superfamily and contain intracellular death domains. Receptor Ligand/source Clinical role Fas (CD95) Fas ligand on activated T cells and other cells. Deletion of immune cells; cytotoxic T-cell killing; autoimmune lymphoproliferation when defective. TNFR1 TNF from macrophages and other inflammatory cells. Can activate NF-κB survival signals, apoptosis or necroptosis depending on adaptor and caspase activity. TRAIL receptors TRAIL on immune cells. Surveillance against infected and malignant cells. 5.2 Molecular sequence Ligand binds a death receptor and causes receptor trimerisation. FADD adaptor proteins attach to the receptor death domain. Procaspase-8 and/or procaspase-10 are recruited into the death-inducing signalling complex (DISC). Initiator caspase-8 becomes active and directly activates executioner caspases-3 and -7. Caspase-8 can cleave BID to tBID, which engages the mitochondrial pathway and amplifies death. 5.3 Caspase-8 checkpoint When caspase-8 activity is inhibited, TNF or toll-like receptor signalling may shift from apoptosis to necroptosis through RIPK1/RIPK3/MLKL. Thus the same external signal can produce quiet apoptosis or inflammatory lytic death depending on intracellular conditions. 6. Caspases: the execution machinery Class Examples Role Initiator caspases Caspase-8, -9, -10, -2. Activated on signalling platforms such as the DISC or apoptosome; activate executioner caspases. Executioner caspases Caspase-3, -6, -7. Cleavage of structural and regulatory proteins; nuclear fragmentation and apoptotic-body formation. Inflammatory caspases Caspase-1, -4, -5, -11.