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1. Vascular and Cellular Events of Inflammation

Vascular Reactions

Vasodilation

• One of the earliest changes; responsible for erythema and warmth.
• The primary mediator is histamine, acting on arteriolar smooth muscle.
• Vasodilation slows blood flow, setting the stage for leukocyte margination.

Increased Vascular Permeability

• Follows vasodilation rapidly.
• The principal mechanism is contraction of endothelial cells, creating interendothelial gaps. Triggered by histamine, bradykinin, and leukotrienes; occurs within 15-30 minutes.
• In burns/severe injury, direct endothelial damage causes immediate, sustained leakage.
• Results in the escape of protein-rich fluid (exudate) into the extravascular space.
• The difference between exudate and transudate:
  • Exudate: high protein, cellular debris, implies increased permeability (inflammatory).
  • Transudate: low protein, essentially ultrafiltrate of plasma (non-inflammatory, from hydrostatic/osmotic imbalance).
• Edema = excess fluid in interstitial tissue; Pus = purulent exudate rich in neutrophils.

Stasis and Congestion

• Loss of fluid + increased vessel diameter → slower blood flow, elevated blood viscosity.
• Red cells concentrate centrally, leukocytes peripheralize (margination).
• Lymph flow increases to drain edema; lymphangitis and lymphadenitis may follow.

Cellular Events (Leukocyte Recruitment)

Steps in Leukocyte Emigration

1. Margination: Slowed blood flow causes leukocytes to move to the vessel periphery.
2. Rolling: Leukocytes loosely bind and tumble along the endothelium via selectins (E-selectin, P-selectin on endothelium; L-selectin on leukocytes) binding sialylated oligosaccharide ligands.
3. Firm Adhesion: Mediated by integrins on leukocytes (LFA-1, Mac-1) binding ICAM-1 and VCAM-1 on activated endothelium. Chemokines (IL-8, etc.) activate leukocyte integrins to high-affinity state.
4. Transmigration (Diapedesis): Leukocytes squeeze between endothelial cells through PECAM-1 (CD31) interactions at cell junctions.
5. Chemotaxis: Directed migration toward the offending agent along chemical gradients of:
   • Exogenous: bacterial products (fMLP peptides)
   • Endogenous: C5a, LTB4, IL-8 (CXCL8), arachidonic acid metabolites

Sequence of Leukocyte Appearance

• Neutrophils (PMNs) predominate in the first 6-24 hours (short-lived; respond to bacterial chemotactic signals rapidly).
• Macrophages replace neutrophils at 24-48 hours (longer-lived; derived from blood monocytes).
• In viral infections, lymphocytes may predominate from early on.

Leukocyte Activation

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2. Phagocytosis

Steps of Phagocytosis

Recognition and Opsonization

• Mannose receptor (recognizes terminal mannose in microbial glycoproteins).
• Scavenger receptors.
• Opsonin receptors: greatly enhanced efficiency when microbes are coated with opsonins:
  • IgG (Fc portion binds Fc receptors).
  • C3b cleavage product of complement (binds CR1).
  • Plasma lectins (collectins).

Engulfment

• Phagocyte membrane surrounds the particle → phagosome formed.
• Phagosome fuses with lysosomes → phagolysosome.

Killing and Degradation

• Phagocyte oxidase (NADPH oxidase) is assembled in the phagolysosome membrane.
• Converts O₂ → superoxide (O₂⁻) → H₂O₂.
• Myeloperoxidase (MPO) in neutrophil azurophilic granules converts H₂O₂ + Cl⁻ → hypochlorite (OCl⁻) - the most potent bactericidal agent.
• The H₂O₂-MPO-halide system is the most efficient bactericidal system of neutrophils.
• This oxygen consumption = respiratory burst.
• Defect in NADPH oxidase → Chronic Granulomatous Disease.

• iNOS in macrophages (activated by IFN-γ) generates NO from arginine.
• NO + O₂⁻ → peroxynitrite (ONOO⁻), which damages microbial lipids, proteins, and nucleic acids.

• Specific granules of neutrophils: lactoferrin, collagenase, lysozyme, B12-binding protein.
• Azurophilic granules: MPO, defensins, elastase, cathepsins.
• Bactericidal/permeability-increasing protein (BPI) binds LPS of gram-negative bacteria.

Neutrophil Extracellular Traps (NETs)

• Activated neutrophils extrude nuclear chromatin complexed with granule proteins (elastase, histones) into the extracellular space.
• These trap and kill bacteria but may also contribute to tissue damage and thrombosis.

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3. Chemical Mediators of Inflammation (in Detail)

A. Vasoactive Amines

Histamine

• Source: Mast cells (granules), blood basophils, platelets.
• Release triggers: Physical injury, C3a/C5a (anaphylatoxins), IgE-mediated reactions, neuropeptides.
• Actions: Vasodilation of arterioles; increased vascular permeability of venules (endothelial contraction); endothelial activation.
• Acts via H1 receptors on smooth muscle and endothelium.

Serotonin (5-HT)

• Source: Platelets, certain neuroendocrine cells (GI tract).
• Primarily a vasoconstrictor; its role in human inflammation is less established.

B. Arachidonic Acid Metabolites (Eicosanoids)

Prostaglandins (via Cyclooxygenase - COX)

• COX-1 (constitutive) and COX-2 (inducible at inflammatory sites) convert AA → PGG₂ → PGH₂ → various prostaglandins.
• PGI₂ (Prostacyclin): Vasodilation, inhibits platelet aggregation.
• PGE₁, PGE₂, PGD₂: Vasodilation; sensitize pain receptors (hyperalgesia); cause fever (act on hypothalamic thermostat via cAMP).
• Thromboxane A₂ (TxA₂): Vasoconstriction, promotes platelet aggregation (produced in platelets via COX-1).

Leukotrienes (via 5-Lipoxygenase)

• 5-LO converts AA → LTA₄:
  • LTB₄: Potent chemotactic factor for neutrophils; promotes leukocyte adhesion.
  • LTC₄, LTD₄, LTE₄ (cysteinyl leukotrienes): Increase vascular permeability; bronchoconstriction (important in asthma); vasoconstriction.

Lipoxins

• Generated from AA via 15-LO.
• Act as negative regulators of inflammation: inhibit neutrophil recruitment and promote resolution.

Pharmacologic Inhibitors

• NSAIDs/Aspirin: Block COX-1 and COX-2; reduce prostaglandins (antipyretic, analgesic). Aspirin irreversibly acetylates COX.
• Selective COX-2 inhibitors (celecoxib): Anti-inflammatory without GI side effects; risk of cardiovascular events (reduced PGI₂).
• Zileuton: 5-LO inhibitor; used in asthma.
• Zafirlukast/Montelukast: Leukotriene receptor antagonists.
• Corticosteroids: Reduce COX-2, phospholipase A₂, pro-inflammatory cytokines (IL-1, TNF), iNOS gene transcription.

C. Cytokines and Chemokines

TNF and IL-1

• Produced mainly by activated macrophages and dendritic cells.
• Local effects: Promote leukocyte adhesion to endothelium (upregulate E-selectin, ICAM, VCAM); stimulate prostaglandin synthesis; amplify cytokine production.
• Systemic (acute-phase response):
  • Fever: Act on hypothalamic endothelium → COX → PGE₂ → reset thermostat.
  • Acute-phase protein synthesis (CRP, fibrinogen, SAA) in liver (also via IL-6).
  • Leukocytosis: Mobilize neutrophils from bone marrow.
  • In high doses → Septic shock: Hypotension, DIC, vascular leakage.
  • TNF-neutralizing agents (infliximab, adalimumab) used in RA and IBD.

IL-6

• Produced by macrophages, endothelium, fibroblasts.
• Stimulates acute-phase protein production (CRP, fibrinogen) from the liver.

Chemokines

• Small proteins that direct leukocyte migration.
• CC chemokines (e.g., MCP-1/CCL2): Attract monocytes, eosinophils, basophils.
• CXC chemokines (e.g., IL-8/CXCL8): Attract neutrophils primarily.
• CX3C chemokines (fractalkine): Attract monocytes and T cells.
• Also involved in angiogenesis (e.g., CXCL8).

D. Platelet-Activating Factor (PAF)

• Derived from phospholipids of mast cells, leukocytes, endothelium, platelets.
• Causes vasodilation; increases vascular permeability (100-1000× more potent than histamine); promotes leukocyte adhesion, chemotaxis, and degranulation; stimulates AA metabolism (prostaglandins and leukotrienes).

E. Complement System

• Pathways of activation:
  • Classical: Antigen-antibody complexes activate C1.
  • Alternative: Microbial surfaces (LPS) directly activate complement.
  • Lectin: Mannose-binding lectin (MBL) binds microbial carbohydrates.
• All three generate C3 convertase → C3a + C3b → C5 convertase → C5a + C5b.
• C5b-9 (MAC): Membrane attack complex; lyses bacteria.
• C3a, C4a, C5a (anaphylatoxins): Stimulate mast cell degranulation → histamine release → increased permeability and vasodilation.
• C5a: Chemotactic; activates neutrophils.
• C3b: Opsonin; coats microbes for phagocytosis.
• Hereditary C1 inhibitor deficiency → Hereditary angioedema.

F. Kinin System (Bradykinin)

• Hageman factor (factor XII) activates the kinin system.
• Kallikrein cleaves kininogens → Bradykinin.
• Actions: Increases vascular permeability; causes smooth muscle contraction; vasodilation; pain (acts on B₂ receptors; important in pain of inflammation).
• Short-lived (inactivated by kininases).

G. Coagulation System / Thrombin

• Activated by injured tissue (tissue factor).
• Thrombin cleaves fibrinogen → fibrin (contributes to fibrinous exudate).
• Thrombin also stimulates endothelial cells and leukocytes to produce mediators → amplifies inflammation.

Summary Table

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4. Tissue Regeneration and Repair

Outcomes of Acute Inflammation

1. Complete resolution: Limited injury, minimal cell death, tissue capable of regeneration. Macrophages remove debris; edema fluid is reabsorbed via lymphatics.
2. Healing by connective tissue replacement (fibrosis/scarring): Occurs when:
   • Substantial tissue destruction occurs.
   • Non-regenerating tissues are involved (e.g., cardiac muscle, neurons).
   • Fibrin exudate cannot be cleared.
   • Fibrous tissue fills the area → scar.
3. Progression to chronic inflammation: When the injurious agent persists or healing is impaired.

Regeneration

Labile Cells

• Continuously cycling; replaced throughout life by stem cells.
• Examples: Hematopoietic cells, gut epithelium, skin epidermis.
• High regenerative capacity.

Stable Cells

• Quiescent; re-enter the cell cycle when stimulated by injury.
• Examples: Hepatocytes, renal tubular cells, smooth muscle, endothelium.
• Good regenerative capacity.

Permanent Cells

• Cannot proliferate postnatally; lost cells are replaced by scar.
• Examples: Neurons, cardiac muscle, skeletal muscle.
• Minimal regenerative capacity.

Repair by Connective Tissue

Granulation Tissue Formation

• Within days of injury: angiogenesis + fibroblast proliferation → pink, granular, soft tissue visible at the base of healing wounds.
• Angiogenesis: Driven by VEGF (vascular endothelial growth factor), FGF. New capillaries are leaky (explains wound edema).
• Fibroblast proliferation and migration: Driven by PDGF, EGF, FGF, TGF-β from platelets and macrophages.

ECM Deposition and Remodeling

• Fibroblasts deposit collagen (types I and III), fibronectin, proteoglycans.
• TGF-β is the most potent stimulator of fibrosis.
• Over time, granulation tissue matures → scar.
• MMP (matrix metalloproteinases) remodel and degrade ECM; balanced by TIMPs.

Wound Healing

• Narrow fibrin clot → thin scar with minimal granulation tissue.

• Abundant granulation tissue fills the defect.
• Wound contraction by myofibroblasts.
• More prominent scar.

Factors Affecting Healing

• Local: Infection (most important), poor blood supply, foreign bodies, size/location of wound.
• Systemic: Malnutrition (especially vitamin C deficiency impairs collagen synthesis), diabetes, glucocorticoids (inhibit TGF-β and fibroblast activity), genetic disorders (Ehlers-Danlos syndrome).

Abnormal Wound Healing

• Hypertrophic scar: Raised scar confined to the wound site; may regress.
• Keloid: Scar tissue extends beyond the wound margins; more common in dark-skinned individuals; does not regress.
• Excessive fibrosis (fibrosis/cirrhosis): Persistent TGF-β activity → organ fibrosis (e.g., hepatic cirrhosis, pulmonary fibrosis).
• Deficient healing (dehiscence, ulceration): From infection, malnutrition, immunosuppression.

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5. Edema - Definition, Classification, Pathogenesis, Morphology, and Clinical Significance

Definition

• Anasarca: Severe, generalized edema with profound subcutaneous swelling and accumulation of fluid in multiple body cavities.
• Fluid in pleural cavity = hydrothorax; pericardial = hydropericardium; peritoneal = ascites (hydroperitoneum).

Classification

Pathogenesis of Each Type

1. Increased Hydrostatic Pressure

• Fluid movement across capillaries is governed by Starling forces.
• Normally: Hydrostatic pressure (~32 mmHg at arteriolar end, ~12 mmHg at venular end) is balanced by plasma colloid osmotic pressure (~25 mmHg).
• Elevated venous pressure → raised hydrostatic pressure at the venular end → fluid stays in the interstitium.
• Example - CHF: Left heart failure → pulmonary edema (increased pulmonary venous pressure). Right heart failure → peripheral/dependent edema.
• Example - Cirrhosis: Portal hypertension → splanchnic and peritoneal fluid accumulation (ascites). Also combined with low albumin.
• Example - DVT: Venous obstruction in lower limb → unilateral leg edema.

2. Reduced Plasma Osmotic Pressure (Hypoproteinemia)

• Low serum albumin → ↓ oncotic pressure → fluid not drawn back into the venular end → edema.
• Simultaneously, reduced plasma volume triggers RAAS → sodium retention → worsens edema.
• Nephrotic syndrome: Massive proteinuria (>3.5 g/day) → hypoalbuminemia → generalized edema (periorbital edema prominent in children).
• Liver disease (cirrhosis): Reduced albumin synthesis → hypoalbuminemia.
• Protein malnutrition (Kwashiorkor): Severe dietary protein deficiency → hypoalbuminemia → "pot-belly" (ascites) with peripheral edema.

3. Lymphatic Obstruction

• Normal lymphatics drain ~8 L/day of interstitial fluid back to the bloodstream.
• Obstruction prevents drainage → lymphedema.
• Filariasis (Bancroft's filariasis): Wuchereria bancrofti larvae obstruct lymphatics → massive lymphedema of the scrotum and lower limbs = elephantiasis.
• Post-mastectomy lymphedema: Axillary lymph node dissection → arm lymphedema.
• Tumor infiltration of lymph nodes → regional lymphedema.

4. Sodium and Water Retention

• Primary renal inability to excrete sodium → osmotic water retention → expansion of plasma volume → increased hydrostatic pressure → edema.
• Renal failure: Reduced GFR → Na+ and water retention.
• SIADH, hyperaldosteronism: Secondary sodium and water retention.
• All types of edema (except pure lymphedema) involve secondary RAAS activation and sodium retention, which perpetuates the edema.

5. Inflammatory Edema

• Increased vascular permeability from histamine, bradykinin, LTs, VEGF.
• Protein-rich exudate leaks into tissue → contributes to edema (though inflammation's primary goal is leukocyte delivery, not edema per se).
• Examples: Angioedema, acute infection, anaphylaxis, burns.

Morphological Features

• Subcutaneous edema: Pits on pressure (pitting edema in gravity-dependent areas - ankles, sacrum). Histologically: sparse, pale, vacuolated interstitium.
• Pulmonary edema: Heavy, wet, congested lungs (often >1000 g each). Frothy pink fluid in airways. Micro: alveolar spaces filled with pink granular fluid; alveolar macrophages laden with hemosiderin ("heart failure cells") in chronic left heart failure.
• Brain edema: Gyri flattened, sulci narrowed, brain herniation. May be cytotoxic (cellular swelling) or vasogenic (↑ permeability).
• Liver (cardiac) edema: "Nutmeg liver" - alternating pale and hemorrhagic areas, reflecting centrilobular hepatic congestion and necrosis.

Clinical Significance

• Pulmonary edema → impaired gas exchange → hypoxemia, respiratory failure.
• Cerebral edema → ↑ intracranial pressure → herniation, death.
• Anasarca → impairs wound healing, predisposes to infection.
• Chronic lymphedema predisposes to lymphangiosarcoma (Stewart-Treves syndrome after mastectomy).
• Edema is a marker of the underlying disease (CHF, nephrotic syndrome, cirrhosis) and guides treatment strategy.

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6. Thrombosis

Definition

Etiopathogenesis - Virchow's Triad

1. Endothelial Injury

• Most important factor in arterial and cardiac thrombosis.
• Exposes subendothelial ECM (von Willebrand factor [vWF], collagen) → platelet adhesion via GpIb-vWF interaction.
• Endothelial "activation/dysfunction" (by LPS, cytokines, hypercholesterolemia, homocysteine, hypertension, cigarette toxins, physical injury) shifts gene expression to a prothrombotic phenotype:
  • Downregulation of: thrombomodulin, protein C receptor, tissue factor pathway inhibitor (TFPI).
  • Upregulation of: tissue factor (TF), PAI-1 (inhibits fibrinolysis).
• Classic examples: Myocardial infarction → endocardial injury → mural thrombus; atherosclerosis → plaque rupture → arterial thrombosis.

2. Abnormal Blood Flow (Stasis and Turbulence)

• Turbulence (in arteries): causes endothelial injury; disrupts laminar flow; creates pockets of stasis. Seen in atherosclerotic plaques (disrupted flow), aneurysms, ulcerated plaques.
• Stasis (in veins): prevents dilution of activated clotting factors; impedes inflow of inhibitors; allows prolonged contact of platelets with endothelium.
• Clinical settings: Mitral stenosis + atrial fibrillation (stasis in left atrium → mural thrombus → stroke), immobility (DVT), polycythemia (hyperviscosity).

3. Hypercoagulability

• Factor V Leiden (most common; Arg506Glu mutation → factor V resistant to protein C): Heterozygotes - 3 to 4× risk; homozygotes - 25 to 50× risk. Found in 60% of recurrent DVT cases.
• Prothrombin G20210A mutation (1%-2% of population): Increased prothrombin expression → ↑ clot formation.
• Antithrombin III deficiency.
• Protein C or S deficiency.
• Elevated factor VIII, IX, or XI.

• Prolonged bed rest/immobilization.
• Oral contraceptives/estrogen therapy (increase fibrinogen and factors II, VII, X).
• Advanced cancer (tumor-derived procoagulants, Trousseau syndrome - migratory thrombophlebitis).
• Antiphospholipid antibody syndrome (primary: thrombosis alone; secondary: associated with SLE - "lupus anticoagulant").
• Heparin-induced thrombocytopenia (HIT): antibodies against heparin-PF4 complexes → platelet activation → thrombocytopenia + paradoxical thrombosis.
• DIC, nephrotic syndrome, pregnancy.

Morphology of Thrombi

• Lines of Zahn: Alternating pale layers (platelets + fibrin) and dark layers (red cells); characteristic of thrombi formed in flowing blood; distinguish antemortem thrombus from postmortem clot.
• Arterial thrombi: Rich in platelets (white/pale thrombus); often occlusive; attached at sites of endothelial injury (atherosclerotic plaque rupture).
• Venous thrombi (phlebothrombosis): Red/stasis thrombus; contain more enmeshed red cells; almost always occlusive; most common in lower extremity deep veins.
• Mural thrombi: In heart chambers (overlying infarct, fibrillating atrium) or the aortic lumen (atherosclerosis, aneurysm).
• Vegetations: Infected thrombi on heart valves (infective endocarditis); sterile (Libman-Sacks in SLE, marantic endocarditis in cancer).

Fate of Thrombus

1. Propagation: Enlarges, worsens occlusion.
2. Embolization: Part dislodges → carried distally.
3. Dissolution (fibrinolysis): t-PA converts plasminogen → plasmin → degrades fibrin. Newly formed thrombi are susceptible; older thrombi resist lysis.
4. Organization and recanalization: Ingrowth of endothelial cells, smooth muscle, fibroblasts → thrombus becomes vascularized, channels form → flow may be partially restored.

Clinical Consequences

• Coronary artery thrombosis → acute myocardial infarction.
• Cerebral artery thrombosis → ischemic stroke.
• DVT → pulmonary embolism (main life-threatening complication).
• Mural thrombus in left heart → systemic embolism → stroke, limb ischemia, renal/splenic infarction.
• Portal vein thrombosis → portal hypertension.

Recent Advances in Diagnosis and Management

Diagnosis

• D-dimer: Degradation product of cross-linked fibrin; elevated in DVT/PE; highly sensitive (good rule-out test); low specificity.
• Compression Doppler ultrasonography: Gold standard for DVT diagnosis.
• CT pulmonary angiography (CTPA): Gold standard for PE.
• V/Q scan: Used when CTPA contraindicated (renal impairment, allergy to contrast).
• Echocardiography: Detects mural thrombi and right heart strain in massive PE.
• Thromboelastography (TEG) / ROTEM: Point-of-care viscoelastic testing of whole blood coagulation; guides transfusion in surgical settings.
• Genetic testing for inherited thrombophilias (factor V Leiden, prothrombin G20210A).

Management

• Anticoagulation (DOACs): Direct oral anticoagulants (apixaban, rivaroxaban, dabigatran) have largely replaced warfarin for DVT/PE - fixed dosing, no monitoring required, fewer interactions.
• Systemic thrombolysis (t-PA, streptokinase): Reserved for massive PE with hemodynamic instability.
• Catheter-directed thrombolysis (CDT): For submassive PE or iliofemoral DVT to reduce post-thrombotic syndrome.
• Surgical embolectomy: For massive PE when thrombolysis is contraindicated.
• IVC filters: For patients with DVT who cannot be anticoagulated (not first-line; associated with recurrent DVT).
• HIT management: Discontinue heparin; substitute non-heparin anticoagulant (argatroban, fondaparinux).
• Antiphospholipid syndrome: Long-term anticoagulation (warfarin; INR 2-3 or higher in arterial events).

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7. Embolism

Definition

Classification of Emboli

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A. Pulmonary Thromboembolism (PTE)

• Saddle embolus: Large, straddles the bifurcation of main pulmonary artery.
• Smaller emboli: Lodge in segmental/subsegmental arteries.
• Pulmonary infarction: Hemorrhagic, wedge-shaped (apex toward the hilum) infarct - only occurs if bronchial arterial supply is also compromised (e.g., left heart failure).
• Multiple emboli → organization → bridging fibrous webs.
• Chronic recurrent emboli → pulmonary hypertension → cor pulmonale.

• 60-80% are silent (small, no infarct).
• Massive (saddle) embolus → sudden death (acute right heart failure, obstructive shock).
• Moderate embolus + no left heart failure → chest pain, hemoptysis, pleural rub, fever (pulmonary infarction).
• Moderate embolus without infarction → dyspnea, tachycardia, tachypnea.
• Recurrent small emboli → pulmonary hypertension, exertional dyspnea.

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B. Systemic (Arterial) Thromboembolism

• 2/3 from left ventricular infarcts.
• ~25% from dilated fibrillating left atria.
• Remainder from aortic aneurysms, atherosclerotic plaques, valvular vegetations.

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C. Fat Embolism

1. Mechanical: Fat microemboli obstruct pulmonary and cerebral microvasculature.
2. Biochemical: Free fatty acids released from lipid globules cause endothelial injury; trigger platelet aggregation and granulocyte recruitment → ROS, protease, eicosanoid release.

• Triad: Pulmonary insufficiency + neurologic symptoms + petechial rash.
• Pulmonary: Tachypnea, dyspnea, respiratory failure.
• Neurological: Irritability, restlessness, confusion, delirium, coma.
• Petechiae: Over upper body, conjunctiva (in 20-50% of cases) - due to thrombocytopenia; useful diagnostic sign.
• Anemia, thrombocytopenia (platelet adhesion to fat globules).
• Mortality ~10%.
• Diagnosis: Requires frozen sections and fat stains (lipids dissolved during routine processing).

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D. Amniotic Fluid Embolism

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E. Air Embolism

• Large venous gas emboli (>100 mL) can arrest in the heart → "mill-wheel" murmur → acute cor pulmonale.
• Risk from IV lines, laparoscopy, obstetric procedures, penetrating chest injury.

• Scuba divers, deep-sea workers who ascend rapidly.
• At high pressure, N₂ dissolves in blood/tissues. Rapid pressure decrease → N₂ comes out of solution as bubbles.
• Bubbles in joints/muscles → severe pain (the bends).
• Bubbles in lungs → respiratory distress (the chokes).
• Chronic: Caisson disease (aseptic bone necrosis, particularly femoral head).
• Treatment: Hyperbaric chamber (recompression).

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F. Cholesterol (Atheroembolism)

• Cholesterol crystal emboli from ulcerated aortic atherosclerotic plaques; occur spontaneously or post-catheterization/anticoagulation.
• Lodge in small arteries of kidneys, GI tract, lower extremities.
• Characteristic cleft-like spaces in vessel lumens (on histology, where cholesterol crystals dissolved).
• Can cause renal failure, livedo reticularis, blue-toe syndrome.

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8. Shock

Definition

Classification

Pathophysiology of Shock (General)

Stages

1. Nonprogressive (compensated) stage:
   • Reflex compensatory mechanisms activated: baroreceptors → catecholamine release → tachycardia, arteriolar vasoconstriction; ADH release (water conservation); RAAS activation (Na+/water retention).
   • Blood is shunted from skin → vital organs (heart, brain).
   • Clinical: Cold, pale, clammy skin; tachycardia (in septic shock initially: warm flushed skin due to vasodilation).
2. Progressive stage:
   • Perfusion deficit exceeds compensation.
   • Widespread tissue hypoxia → anaerobic glycolysis → lactic acidosis.
   • Acidosis impairs cardiac and smooth muscle contractility.
   • Widespread endothelial injury → ↑ permeability → more fluid loss; DIC may occur.
3. Irreversible stage:
   • Lysosomal enzyme leakage (further cell destruction).
   • Severe myocardial dysfunction.
   • Ischemic gut → intestinal flora enter bloodstream → superimposed bacteremia.
   • Renal failure (ischemic ATN → oliguria, acidosis).
   • Death from multi-organ failure.

Septic Shock (Special Emphasis)

Definition

Pathogenesis of Septic Shock

1. Relative and absolute hypovolemia: From GI losses, sweating, fever; increased venous capacitance + capillary leak → loss of intravascular volume into third spaces.
2. Direct myocardial depression: Early impairment of contractility (even before obvious ↓ EF); caused by TNF-α, IL-1β, overproduction of NO by iNOS, mitochondrial dysfunction. Detectable by global longitudinal strain on echocardiography.
3. Widespread systemic inflammation → multi-organ failure:
   • LPS/microbial components bind TLRs on macrophages, dendritic cells, neutrophils → NFkB activation → release of TNF, IL-1, IL-6, IL-12, IL-18, type I IFN; reactive oxygen species and prostaglandins.
   • Endothelial activation: upregulate adhesion molecules, cytokines, VEGF (↑ permeability).
   • Complement activation: anaphylatoxins (C3a, C5a) → further inflammation.
   • Coagulation activation: microbial products activate factor XII; altered endothelial function → DIC.
   • Thrombin further amplifies inflammation via protease-activated receptors.

Counter-regulatory Immunosuppression

• After the initial hyperinflammatory state, compensatory anti-inflammatory response syndrome (CARS) may develop → impaired immune function → secondary infections.

Morphology of Shock (Organs)

• Kidneys: Acute tubular necrosis (ATN) - proximal tubule cells most vulnerable; pale/swollen kidneys; fibrin thrombi in glomeruli (DIC); → oliguria/anuria.
• Heart: Focal myocardial hemorrhage and necrosis (contraction band necrosis); subendocardial ischemia.
• Adrenals: Cortical lipid depletion (increased steroid synthesis demands); hemorrhage (Waterhouse-Friderichsen in meningococcemia).
• Lungs: Diffuse alveolar damage (DAD) → ARDS ("shock lung") - especially in septic and traumatic shock; edema + hyaline membranes on histology.
• Brain: Ischemic encephalopathy (neurons most sensitive to hypoxia; 3-4 minutes without blood flow).
• GI tract: Superficial mucosal hemorrhages ("stress ulcers"); ischemic colitis.
• Liver: Centrilobular necrosis (ischemia of zone 3 hepatocytes); jaundice.

Clinical Features of Septic Shock

• Warm, flushed skin (initial vasodilation - distinguishes early septic shock from other forms).
• Fever, rigors, tachycardia, tachypnea, hypotension.
• As it progresses: oliguria, confusion, metabolic acidosis, coagulopathy (DIC).
• ARDS, hepatic failure, renal failure → multi-organ dysfunction syndrome (MODS).
• Lab: leukocytosis (or leukopenia in overwhelming sepsis), elevated CRP/procalcitonin, blood cultures positive in ~50%, elevated lactate.

Clinical Consequences and Prognosis

• Hypovolemic shock in young healthy patients: >90% survival with appropriate management.
• Septic or cardiogenic shock: substantially worse outcomes even with state-of-the-art care (septic shock mortality 20-40% in ICU settings).
• Death typically follows MODS (kidneys, lungs, liver, heart).

Management of Septic Shock (Current Approach)

• Source control: Identify and eliminate infection source (drain abscess, remove infected device).
• Antibiotics: Broad-spectrum early (within 1 hour - "hour-1 bundle" of Surviving Sepsis Campaign).
• IV fluid resuscitation: 30 mL/kg crystalloid bolus; reassess with dynamic hemodynamic monitoring.
• Vasopressors: Norepinephrine is first-line (maintains mean arterial pressure ≥65 mmHg).
• Corticosteroids: Hydrocortisone 200-300 mg/day in refractory shock (mixed trial evidence; current guidelines support use in vasopressor-refractory septic shock).
• Anti-inflammatory therapies: Specific antagonists (anti-TNF, anti-IL-1) have not shown consistent benefit in clinical trials; reflects the complexity of sepsis pathogenesis.
• Superantigens (e.g., toxic shock syndrome toxin-1, TSST-1): Polyclonal T-cell activators → massive cytokine release → shock syndrome. Managed with IV immunoglobulin + antibiotics.

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