Adaptations, Necrosis, Apoptosis & Inflammation

HIGH-YIELD STUDY NOTES: Adaptations, Necrosis, Apoptosis & Inflammation

TABLE OF CONTENTS

  • Cellular Adaptations

  • Cell Injury & Death

  • Necrosis (6 Types)

  • Apoptosis

  • Acute Inflammation

  • High-Yield Clinical Correlations

CELLULAR ADAPTATIONS

Overview

  • Cells adapt to environmental stress through reversible changes in size, number, phenotype, metabolic activity, or function.

  • KEY POINT: Remove the stimulus β†’ adaptation reverses (except dysplasia/neoplasia).

The Four Main Types

  1. ATROPHY

    • Definition: Decrease in cell size/number ("Shrinkage")

    • Mechanisms:

      • Decreased protein synthesis.

      • Increased protein degradation (ubiquitin-proteasome pathway).

      • Autophagy.

    • Causes (Remember: DANISH):

      • Disuse (e.g., immobilization, bed rest).

      • Aging (physiologic atrophy of thymus, brain, gonads).

      • Neuropathic (denervation atrophy, e.g., carpal tunnel β†’ thenar muscle wasting).

      • Ischemia (decreased blood supply).

      • Starvation/malnutrition.

      • Hormonal (loss of endocrine stimulation, e.g., postmenopausal uterus).

    • Clinical Examples:

      • Muscle atrophy in a casted limb.

      • Brain atrophy in Alzheimer's disease.

      • Uterine atrophy after menopause.

  2. HYPERTROPHY

    • Definition: Increase in cell size (NOT number) ("Getting bigger")

    • Key Facts:

      • Occurs in cells that cannot divide (permanent tissues).

      • Increased organelles and structural proteins.

      • Can be physiologic or pathologic.

    • Types:

      • PHYSIOLOGIC:

      • Skeletal muscle (exercise, weightlifting).

      • Uterine smooth muscle during pregnancy.

      • Cardiac muscle in athletes (physiologic).

      • PATHOLOGIC:

      • Left ventricular hypertrophy (hypertension, aortic stenosis).

      • Right ventricular hypertrophy (pulmonary hypertension).

    • ⚠ CRITICAL: Pathologic hypertrophy can eventually lead to heart failure if stress persists.

  3. HYPERPLASIA

    • Definition: Increase in cell number ("More cells")

    • Requirements:

      • Only occurs in labile or stable tissues (cells capable of division).

      • Never occurs in permanent tissues (neurons, cardiac myocytes).

    • Types:

      • PHYSIOLOGIC:

      • Hormonal: Breast development during puberty, endometrial proliferation.

      • Compensatory: Liver regeneration after partial hepatectomy.

      • PATHOLOGIC:

      • Endometrial hyperplasia (unopposed estrogen).

      • Prostatic hyperplasia (BPH).

      • Psoriasis (epidermal hyperplasia).

    • πŸ”₯ HIGH YIELD: Hyperplasia does not equal cancer but can increase cancer risk (e.g., endometrial hyperplasia β†’ endometrial carcinoma).

  4. METAPLASIA

    • Definition: Replacement of one differentiated cell type with another ("Cell substitution")

    • Mechanism:

      • Reprogramming of stem cells in response to chronic stress/irritation.

      • Cells become more suited to handle the new environment.

    • Key Examples:

      • BARRETT'S ESOPHAGUS:

      • Normal: Stratified squamous epithelium.

      • Metaplastic: Columnar epithelium (gastric-type) due to chronic acid reflux (GERD).

      • RESPIRATORY TRACT:

      • Normal: Pseudostratified ciliated columnar.

      • Metaplastic: Stratified squamous due to cigarette smoking.

      • BLADDER:

      • Normal: Transitional epithelium.

      • Metaplastic: Squamous due to chronic irritation/stones.

      • CERVIX:

      • Normal: Columnar.

      • Metaplastic: Squamous due to vaginal pH changes.

    • ⚠ DANGER: Metaplasia is reversible if the stimulus is removed, but can progress to dysplasia β†’ cancer if persistent.

  5. DYSPLASIA

    • Definition: Disordered growth and differentiation ("Pre-cancer warning sign")

    • Features:

      • Loss of uniformity of cells.

      • Loss of architectural orientation.

      • Increased mitotic activity (including abnormal mitoses).

      • Pleomorphism (variation in size/shape).

      • Hyperchromatic nuclei (dark staining).

      • Increased nuclear-to-cytoplasmic ratio.

    • Grading:

      • Low-grade β†’ High-grade β†’ Carcinoma in situ β†’ Invasive carcinoma.

    • Classic Example:

      • CERVICAL DYSPLASIA: Caused by HPV (Human Papillomavirus).

      • HPV E6 β†’ inactivates p53.

      • HPV E7 β†’ inactivates Rb.

      • Can be detected by Pap smear and is treatable if caught early.

    • Other Examples:

      • Bronchial dysplasia (smokers).

      • Oral dysplasia (tobacco chewers).

      • Barrett's esophagus β†’ dysplasia β†’ adenocarcinoma.

    • 🎯 KEY DISTINCTION: Dysplasia is reversible in the early stages; high-grade dysplasia is likely to progress to cancer, while carcinoma is irreversible.

CELL INJURY & DEATH

Reversible vs Irreversible Cell Injury
REVERSIBLE INJURY (Early Stage)

  • Morphology:

    • Cellular swelling (hydropic degeneration).

    • Fatty change (in cells with high metabolism - liver).

    • Membrane blebbing.

    • Loss of microvilli.

    • Swelling of ER and mitochondria.

  • Biochemistry:

    • ↓ ATP production.

    • ↓ Na+/K+ ATPase function β†’ Na+ and water enter cell.

    • Glycolysis switches to anaerobic β†’ lactic acid ↑ β†’ pH ↓.

IRREVERSIBLE INJURY ("Point of no return")

  • Indicators:

    • Severe mitochondrial damage (unable to produce ATP).

    • Cell membrane damage (loss of integrity).

    • Lysosomal rupture (enzymes digest the cell).

  • Nuclear changes:

    • Pyknosis = nuclear shrinkage and basophilia.

    • Karyorrhexis = nuclear fragmentation.

    • Karyolysis = nuclear fading/dissolution.

NECROSIS (6 TYPES)

General Features of ALL Necrosis

  • UNCONTROLLED cell death (vs. apoptosis).

  • PATHOLOGIC (always abnormal).

  • Cell swelling β†’ membrane rupture β†’ contents spill out.

  • INFLAMMATORY RESPONSE (releases DAMPs - damage-associated molecular patterns).

  • Enzyme digestion:

    • Autolysis = cell's own enzymes.

    • Heterolysis = enzymes from inflammatory cells.

Types of Necrosis

  1. COAGULATIVE NECROSIS

    • Most common type.

    • Pathophysiology: Architecture PRESERVED for several days because protein denaturation > enzyme degradation.

    • Causes: Ischemia (except brain!). Hypoxic injury to organs.

    • Organs Affected: Heart (myocardial infarction), kidney (renal infarct, acute tubular necrosis), spleen, liver (rare).

    • Gross Appearance: Pale, firm, wedge-shaped (if infarct).

    • Microscopic: Preserved tissue architecture, loss of nuclei, increased eosinophilia (pink on H&E).

    • 🩺 Clinical Example: ST elevation MI β†’ transmural coagulative necrosis.

  2. LIQUEFACTIVE NECROSIS

    • Pathophysiology: Complete digestion of dead cells. Enzyme action > protein denaturation, resulting in a liquid/viscous mass.

    • Two Main Scenarios:

      • A) BRAIN ISCHEMIA (exception to coagulative necrosis!). Brain has high lipid content and low protein, resulting in cystic spaces after liquefaction.

      • B) BACTERIAL/FUNGAL INFECTIONS (any organ) with abundant neutrophils releasing proteolytic enzymes, creating an abscess (pus).

    • Gross Appearance: Creamy yellow pus, liquefied tissue.

    • Microscopic: Loss of tissue structure, inflammatory infiltrate (neutrophils).

    • 🩺 Clinical Examples: Brain abscess, bacterial pneumonia with abscess formation, ischemic stroke β†’ liquefactive necrosis.

  3. CASEOUS NECROSIS

    • Pathophysiology: Combination of coagulative and liquefactive necrosis, characterized by incomplete digestion of cells and granular, amorphous debris.

    • Cause: TUBERCULOSIS (Mycobacterium tuberculosis) and some fungal infections (Histoplasma).

    • Mechanism: Immune response cannot completely eliminate organism; macrophages wall off the area β†’ granuloma formation, leading to central caseous necrosis.

    • Gross Appearance: White, soft, friable, "cheese-like."

    • Microscopic: Amorphous granular pink material, loss of all cellular detail, surrounded by granuloma (epithelioid macrophages, Langhans giant cells, lymphocytes).

    • 🩺 Clinical Example: Pulmonary TB β†’ caseating granulomas β†’ cavitation if ruptured.

  4. FAT NECROSIS

    • Definition: Specialized necrosis of adipose tissue.

    • Two Types:

      • A) ENZYMATIC FAT NECROSIS

      • Location: Pancreas and surrounding tissues.

      • Cause: Acute pancreatitis, where pancreatic lipase is released from trauma, alcohol consumption, or gallstones.

      • Mechanism: Lipase breaks down triglycerides into fatty acids, which bind calcium (saponification) forming chalky white deposits (soap formation).

      • Gross: Chalky white spots on peritoneum/omentum.

      • Microscopic: Outlines of necrotic fat cells, basophilic calcium deposits.

      • B) TRAUMATIC FAT NECROSIS

      • Location: Breast (most common).

      • Cause: Physical trauma.

      • Gross: Firm mass (can mimic cancer!).

      • Microscopic: Foamy macrophages, foreign body giant cells, fat necrosis.

      • 🩺 Clinical Pearl: Fat necrosis in breast can cause calcifications on mammogram β†’ biopsy needed to rule out cancer.

  5. FIBRINOID NECROSIS

    • Definition: β€œFibrin-like” appearance, characterized by immune complexes deposited in blood vessel walls leading to endothelial damage and fibrin leaking into the vessel wall from plasma.

    • Causes: Vasculitis (immune-mediated), malignant hypertension, and Type III hypersensitivity (immune complex disease), autoimmune diseases (SLE, polyarteritis nodosa).

    • Location: Small to medium arteries.

    • Microscopic: Bright pink/red (eosinophilic), smudgy appearance with loss of vessel wall structure and fibrin deposition.

    • 🩺 Clinical Examples: Malignant hypertension leading to acute tubular necrosis, polyarteritis nodosa, Wegener's granulomatosis.

  6. GANGRENOUS NECROSIS

    • Definition: Clinical term, not a histologic pattern, typically associated with ischemia and has two types:

      • A) DRY GANGRENE

      • Histology: Coagulative necrosis.

      • Cause: Ischemia without infection.

      • Location: Extremities (toes, feet, fingers).

      • Appearance: Black, dry, mummified.

      • Examples: Atherosclerosis with arterial occlusion, frostbite, diabetes mellitus (poor circulation).

      • B) WET GANGRENE

      • Histology: Liquefactive necrosis.

      • Cause: Ischemia with bacterial infection.

      • Location: Internal organs or extremities with infection.

      • Appearance: Swollen, black, foul-smelling.

      • Examples: Diabetic foot with superimposed infection, bowel infarction with perforation, gas gangrene (Clostridium perfringens).

    • 🩺 Clinical Pearl: Diabetic patients are at high risk for gangrenous necrosis due to peripheral vascular disease, neuropathy (impaired sensation), and immunosuppression (prone to infection).

COMPARISON: NECROSIS vs APOPTOSIS

  • NECROSIS

    • Nature: Pathologic (accidental).

    • Stimulus: External injury.

    • Cell Size: Swelling.

    • Membrane: Loss of integrity (rupture).

    • Nucleus:

    • Pyknosis β†’ Karyorrhexis β†’ Karyolysis.

    • Contents: Spill into surrounding tissue.

    • Inflammation: YES (always).

    • Energy: No ATP required.

    • Distribution: Groups of cells.

    • Caspases: No.

  • APOPTOSIS

    • Nature: Physiologic (programmed).

    • Stimulus: Internal/external signals.

    • Cell Size: Shrinkage.

    • Membrane: Intact (until late).

    • Nucleus: Fragmentation (neat).

    • Contents: Packaged in apoptotic bodies.

    • Inflammation: NO.

    • Energy: ATP-dependent.

    • Distribution: Single cells.

    • Caspases: YES (essential).

APOPTOSIS

Definition

  • Programmed cell death - ATP-dependent, orderly, genetically controlled process.

Physiologic Roles ("Good Death")

  • Embryonic development (e.g., interdigital web removal β†’ separate fingers).

  • Hormone-dependent involution (endometrium, breast post-lactation).

  • Cell turnover (intestinal epithelium, skin).

  • Immune system regulation (negative selection of self-reactive T cells in thymus).

  • Eliminating damaged/infected cells.

Morphologic Features

  • EARLY:

    • Cell shrinkage.

    • Chromatin condensation (pyknosis).

    • Intact cell membrane.

  • MID:

    • Nuclear fragmentation.

    • Membrane blebbing.

    • Formation of apoptotic bodies.

  • LATE:

    • Apoptotic bodies phagocytosed by macrophages or adjacent cells.

    • NO inflammatory response.

Biochemical Features

  • DNA fragmentation (laddering pattern on gel electrophoresis).

  • Phosphatidylserine externalization (normally on inner membrane) β†’ "eat me" signal.

  • Caspase activation.

  • Mitochondrial changes.

THE TWO PATHWAYS OF APOPTOSIS

  1. INTRINSIC (MITOCHONDRIAL) PATHWAY

    • "Death from within".

    • Triggers:

    1. DNA damage (activation of p53).

    2. Oxidative stress.

    3. Hypoxia.

    4. Growth factor withdrawal.

    5. Radiation.

    6. Chemotherapeutic drugs.

    • Key Steps:

      • Stress signal activates pro-apoptotic Bcl-2 family proteins: BAX and BAK β†’ form pores in mitochondrial membrane.

      • BH3-only proteins (BID, BIM, BAD) β†’ activate BAX/BAK.

      • Mitochondrial Outer Membrane Permeabilization (MOMP) β†’ Loss of mitochondrial membrane potential.

      • Release of cytochrome c into cytoplasm.

      • Apoptosome formation with cytochrome c + Apaf-1 + dATP β†’ apoptosome recruits and activates procaspase-9.

      • Caspase-9 (initiator) activates Caspase-3 (executioner).

      • Execution Phase begins.

    • Key Regulators:

      • ANTI-APOPTOTIC (promote survival): Bcl-2 and Bcl-XL β†’ block BAX/BAK.

      • PRO-APOPTOTIC (promote death): BAX, BAK β†’ form mitochondrial pores.

      • BH3-only proteins (BID, BIM, BAD, PUMA, NOXA).

    • 🎯 Clinical Relevance:

      • Bcl-2 overexpression leads to follicular lymphoma (cells won't die).

      • p53 mutations lead to cancer (damaged cells survive).

      • Chemotherapy targets this intrinsic pathway.

  2. EXTRINSIC (DEATH RECEPTOR) PATHWAY

    • "Death from outside".

    • Triggers:

      • Immune surveillance (cytotoxic T cells, NK cells).

      • Fas ligand (FasL).

      • TNF-Ξ±.

      • TRAIL (TNF-related apoptosis-inducing ligand).

    • Key Steps:

      • Death ligand binds death receptor (Fas-FasL interaction is most studied; TNF-Ξ±-TNFR1; TRAIL-DR4/DR5 which form the Death-Inducing Signaling Complex (DISC)).

      • Receptors trimerize and recruit FADD (Fas-associated death domain adaptor protein).

      • FADD recruits procaspase-8 which becomes activated (initiator caspase).

      • Autocatalytic cleavage occurs. Two Cell Types:

      • Type I cells: Large amount of active caspase-8 β†’ directly activates caspase-3.

      • Type II cells: Small amount of caspase-8 β†’ cleaves BID β†’ tBID β†’ activates intrinsic pathway (amplification).

    • Execution Phase begins.

    • 🎯 Clinical Relevance:

      • Fas-FasL mutations lead to Autoimmune lymphoproliferative syndrome (ALPS).

      • CTLs kill virus-infected cells via this pathway.

      • Perforin/Granzyme pathway (similar mechanism).

  3. EXECUTION PHASE (Final Common Pathway)

    • Once initiator caspases (8 or 9) are activated, executioner caspases are also activated:

      • Caspase-3 (main executioner).

      • Caspase-6.

      • Caspase-7.

    • Cellular Demolition:

      • Nuclear breakdown: CAD (Caspase-Activated DNase) β†’ DNA fragmentation.

      • Lamin degradation β†’ nuclear envelope breakdown.

      • Cytoskeletal degradation: Actin and structural protein cleavage.

      • Cell shrinkage and blebbing.

      • Protein cleavage:

      • PARP (Poly ADP-ribose polymerase) β†’ impairs DNA repair.

      • Fodrin β†’ cytoskeletal disruption.

    • Apoptotic Body Formation:

      • Membrane blebs containing nuclear fragments.

      • Phosphatidylserine exposure β†’ "eat me" signal.

    • Phagocytosis:

      • Macrophages recognize phosphatidylserine and clear apoptotic bodies rapidly with NO inflammation.

REGULATION OF APOPTOSIS

  • INHIBITORS:

    • IAPs (Inhibitors of Apoptosis Proteins): XIAP, survivin.

    • Bind and inhibit caspases-3, -7, -9.

    • Anti-apoptotic Bcl-2 family:

    1. Bcl-2.

    2. Bcl-XL β†’ Block cytochrome c release.

  • PROMOTERS:

    • Smac/DIABLO: Released from mitochondria and inhibit IAPs (disinhibit caspases).

    • AIF (Apoptosis-Inducing Factor): Caspase-independent pathway leading to nuclear DNA cleavage.

    • Endonuclease G: Caspase-independent nuclear DNA cleavage.

ACUTE INFLAMMATION

Definition

  • Rapid, stereotyped response to injury involving vascular and cellular components, typically lasting hours to days.

The THREE Cardinal Roles of Inflammation

  1. Eliminate the initial cause of injury (pathogens, toxins, damaged cells).

  2. Clear out necrotic cells and debris.

  3. Initiate tissue repair.

The FIVE Cardinal Signs of Inflammation (Remember: "PRISH")

  1. Rubor (Redness):

    • Caused by vasodilation β†’ increased blood flow.

  2. Tumor (Swelling):

    • Caused by increased vascular permeability β†’ edema.

  3. Calor (Heat):

    • Increased blood flow brings warmth.

  4. Dolor (Pain):

    • Caused by bradykinin and prostaglandins that stimulate nerves; edema also causes pressure.

  5. Functio Laesa (Loss of Function):

    • Caused by combination of pain and swelling.

VASCULAR EVENTS (The "Plumbing" Changes)
Sequence of Events

  1. TRANSIENT VASOCONSTRICTION (seconds):

    • Brief arteriolar constriction mediated by neurogenic reflex.

  2. VASODILATION (minutes):

    • Involves arterioles β†’ capillaries β†’ venules.

    • Mediated by histamine, NO, and prostaglandins.

    • Result: ↑ Blood flow to area β†’ REDNESS and HEAT, ↑ Capillary hydrostatic pressure.

  3. INCREASED VASCULAR PERMEABILITY ("Leaky vessels")

    • Mechanisms include:

      • A) Endothelial Cell Contraction (Most common).

      • Immediate transient (15-30 minutes), affects venules.

      • Mediators: Histamine, bradykinin, leukotrienes, substance P.

      • Creates intercellular gaps.

      • B) Direct Endothelial Injury.

      • Immediate sustained (until repaired) severe injuries: burns, infections, toxins.

      • Causes: Endothelial necrosis and detachment.

      • Affects all levels: capillaries, venules, arterioles.

      • C) Leukocyte-Mediated Injury.

      • Delayed prolonged (hours) when activated leukocytes release reactive oxygen species (ROS) and proteolytic enzymes.

      • Damages endothelium β†’ gaps form.

      • D) Increased Transcytosis.

      • Mediated by VEGF (vascular endothelial growth factor).

      • Increased pinocytotic vesicles form channels through endothelial cells.

      • E) Leakage from New Blood Vessels.

      • During angiogenesis, immature vessels are leaky.

  4. STASIS (Slowing of blood flow):

    • Fluid leaves vessels β†’ blood becomes more viscous (hemoconcentration).

    • Red blood cells aggregate (rouleaux formation) leading to dramatically slowed blood flow.

    • Importance: Allows leukocytes to marginate!

CELLULAR EVENTS (The "Army" Arrives)
Overview: Leukocyte Journey (Remember: "MR. TAC")

  • Margination

  • Rolling

  • Tight adhesion

  • Across the wall (transmigration)

  • Chemotaxis

Step 1: MARGINATION

  • Slowed blood flow allows leukocytes to move to periphery.

  • Cell Type: Neutrophils first (within minutes to hours).

  • Mediated by SELECTINS:

    • Key Players:

    • P-selectin (endothelial) binds sialyl-Lewis X (leukocyte).

    • E-selectin (endothelial) binds sialyl-Lewis X (leukocyte) synthesized after IL-1 and TNF stimulation (takes 1-2 hours).

    • L-selectin (leukocyte) binds GlycCAM-1 (endothelial).

  • Result: Leukocytes "roll" along endothelium (weak, transient binding).

Step 2: ROLLING

  • Neutrophils line up along endothelium ("pavementing").

  • Mediated by selectins.

Step 3: TIGHT ADHESION (Firm Adhesion)

  • Mediated by INTEGRINS and IMUNOGLOBULIN FAMILY.

  • Key Players:

    • On Leukocytes: LFA-1 (CD11a/CD18 - Ξ²2 integrin), Mac-1 (CD11b/CD18 - Ξ²2 integrin), VLA-4 (Ξ²1 integrin).

    • On Endothelium: ICAM-1 (binds to LFA-1 and Mac-1), VCAM-1 (binds to VLA-4).

  • Activation: Chemokines (IL-8, C5a) activate integrins β†’ change conformation β†’ high affinity binding.

  • Result: Leukocyte stops rolling and firmly adheres.

Step 4: TRANSMIGRATION (Diapedesis)

  • Leukocyte squeezes through endothelial junctions.

  • Mechanism: PECAM-1 (CD31) on both leukocyte and endothelium with homophilic binding (CD31-CD31).

  • Leukocyte extends pseudopods and squeezes between endothelial cells (paracellular) crossing basement membrane (collagenase helps).

  • Location: Primarily postcapillary venules.

Step 5: CHEMOTAXIS

  • Directed migration towards injury (chemoattractants):

    • Remember: "C5a LTB4 Bacterial Chemokines":

    • Bacterial products: N-formyl-methionine peptides (fMLP).

    • Complement components: C5a (most potent), C3a.

    • Lipid mediators: LTB4 (leukotriene B4).

    • Chemokines: IL-8 (CXCL8) for neutrophil chemotaxis, MCP-1 for monocyte chemotaxis.

    • Other: Platelet-activating factor (PAF).

  • Mechanism:

    • Binds G-protein coupled receptors, activates cytoskeletal rearrangement, and forms lamellipodia (leading edge) towards the highest concentration.

TIMELINE OF LEUKOCYTE RECRUITMENT

  1. 0-6 HOURS: NEUTROPHILS (PMNs). First responders. Functions: Phagocytosis, bacterial killing.

  2. 6-24 HOURS: Neutrophils peak. Acute inflammation maximal.

  3. 24-48 HOURS: MONOCYTES begin to transform into macrophages.

  4. 48-96 HOURS: MACROPHAGES predominate. Functions: Phagocytosis, healing begins.

  5. DAYS-WEEKS: LYMPHOCYTES (if chronic). Involved in adaptive immunity.

HIGH YIELD:

  • Neutrophils = acute.

  • Lymphocytes/macrophages = chronic.

LEUKOCYTE ACTIVATION & FUNCTIONS

  1. RECOGNITION: Pattern Recognition Receptors (PRRs) include TLRs (Toll-like receptors) that recognize PAMPs.

    • TLR4 β†’ recognizes LPS (gram-negative bacteria).

    • TLR3 β†’ recognizes viral dsRNA.

    • NOD-like receptors, Mannose receptors, Scavenger receptors.

    • Opsonins (Enhance Recognition): IgG (most important antibody), C3b (complement), Collectins (mannose-binding lectin).

  2. PHAGOCYTOSIS: Steps (Remember: "RACK the bug"):

  • Recognition and Attachment: Opsonins bind pathogen - Fc receptors (bind IgG) and CR1 (bind C3b) on phagocyte.

  • Consumption (Engulfment): Pseudopods extend around particle and form phagosome.

  • Killing:

    • Phagosome fuses with lysosome β†’ phagolysosome.

    • Two mechanisms:

    • A) Oxygen-Dependent Killing (Respiratory Burst):

      • Key Enzyme: Myeloperoxidase (MPO) in neutrophils β†’ creates hypochlorous acid (bleach), the most potent killing mechanism.

    • B) Oxygen-Independent Killing:

      • Lysozyme β†’ breaks down bacterial cell walls.

      • Defensins β†’ pore formation in bacteria.

      • Lactoferrin β†’ iron sequestration (starves bacteria).

      • Major basic protein (eosinophils) β†’ targets parasites.

Clinical Correlations

  • Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase; cannot produce respiratory burst; recurrent catalase-positive infections (Staph aureus, Aspergillus); negative NBT test.

  • Myeloperoxidase Deficiency: Increased susceptibility to Candida, usually mild as backup systems compensate.

  • ChΓ©diak-Higashi Syndrome: Defect in lysosomal trafficking leading to giant lysosomes, recurrent pyogenic infections, partial albinism, peripheral neuropathy.

CHEMICAL MEDIATORS OF INFLAMMATION
Cell-Derived Mediators

  1. VASOACTIVE AMINES:

    • HISTAMINE:

      • Source: Mast cells, basophils, platelets.

      • Actions: Vasodilation (H1 receptors), increased vascular permeability (venules), bronchospasm.

      • Release Triggered By: C3a, C5a (anaphylatoxins), physical injury, IgE binding (type I hypersensitivity).

      • Duration: Minutes (immediate transient response).

    • SEROTONIN (5-HT):

      • Source: Platelets, neuroendocrine cells with actions similar to histamine.

  2. LIPID MEDIATORS: Arachidonic Acid Metabolites:

    • Source: Cell membrane phospholipids, released by Phospholipase A2 (activated by Ca2+ or inflammatory stimuli).

    • Two Pathways:

      • A) CYCLOOXYGENASE (COX) Pathway β†’ PROSTAGLANDINS:

      • Types:

        • COX-1 (constitutive): Present in most tissues; involved in gastric protection, platelet function, renal blood flow.

        • COX-2 (inducible): Induced by inflammatory stimuli such as IL-1 and TNF; major source of inflammatory prostaglandins.

      • Products:

        • PGE2: Vasodilation, increased vascular permeability, pain and fever (hypothalamus).

        • PGD2: Vasodilation, chemotaxis.

        • PGF2Ξ±: Vasoconstriction, bronchoconstriction.

        • PGI2 (Prostacyclin): Vasodilation, inhibits platelet aggregation.

        • TXA2 (Thromboxane A2): Vasoconstriction, platelet aggregation (produced by platelets).

      • Drug Targets:

        • Aspirin: Irreversibly inhibits COX-1 and COX-2.

        • NSAIDs (ibuprofen): Reversibly inhibit COX-1 and COX-2.

        • COX-2 selective (celecoxib): Spares COX-1 (less GI toxicity).

        • Corticosteroids: Inhibit phospholipase A2 (blocking entire pathway).

      • B) LIPOXYGENASE Pathway β†’ LEUKOTRIENES:

      • Source: 5-Lipoxygenase (in leukocytes):

        • LTB4: Potent neutrophil chemotaxis.

        • Cysteinyl leukotrienes (LTC4, LTD4, LTE4): Bronchoconstriction, increased vascular permeability, vasoconstriction.

      • Drug Targets:

        • Zileuton: 5-lipoxygenase inhibitor.

        • Montelukast/Zafirlukast: Leukotriene receptor antagonists (used in asthma).

      • C) LIPOXINS: Anti-inflammatory mediators involved in the resolution of inflammation that inhibit neutrophil chemotaxis and promote macrophage uptake of apoptotic neutrophils.

  3. CYTOKINES:

    • TNF-Ξ± (Tumor Necrosis Factor-alpha):

      • Source: Activated macrophages (main), mast cells, T cells.

      • Actions: Endothelial activation (adhesion molecules), systemic effects (fever, acute phase response), promotes coagulation, causes cachexia (chronic), high levels can cause septic shock.

    • IL-1 (Interleukin-1):

      • Source: Macrophages, endothelial cells.

      • Actions: Similar to TNF-Ξ±; endothelial activation, fever (acts on hypothalamus), induces acute phase proteins in liver.

    • IL-6:

      • Source: Macrophages, endothelial cells.

      • Actions: Hepatic acute phase protein synthesis (CRP, fibrinogen), fever.

    • Chemokines (Chemoattractant Cytokines):

      • IL-8 (CXCL8): Neutrophil recruitment.

      • MCP-1: Monocyte recruitment.

      • Eotaxin: Eosinophil recruitment.

  4. NITRIC OXIDE (NO):

    • Source: Endothelial cells (eNOS), macrophages (iNOS).

    • Actions: Vasodilation (smooth muscle relaxation), inhibits platelet aggregation, antimicrobial (at high concentrations).

  5. REACTIVE OXYGEN SPECIES (ROS):

    • Generated during the respiratory burst.

    • Examples: O2β€’- (superoxide), H2O2 (hydrogen peroxide), β€’OH (hydroxyl radical), HOCl (hypochlorous acid).

    • Functions: Microbial killing, cell signaling, can cause bystander damage by injuring host tissue (oxidizing lipids, proteins, DNA).

Plasma Protein-Derived Mediators

  1. COMPLEMENT SYSTEM:

    • Three Activation Pathways: Lead to C3 convertase and C5 convertase.

    • Products:

      • C3a and C5a (Anaphylatoxins):

      • Cause mast cell degranulation β†’ histamine release, vasodilation, increased vascular permeability.

      • C5a: Neutrophil chemotaxis and activation.

      • C3b: Opsonization (most important opsonin).

      • C5b-9 (Membrane Attack Complex - MAC): Forms pores in bacterial membranes causing cell lysis.

  2. KININ SYSTEM:

    • Factor XII (Hageman Factor) activates β†’ Bradykinin:

      • Increases vascular permeability, causes vasodilation, produces pain (stimulates nerve endings), and contracts smooth muscles (bronchoconstriction).

  3. COAGULATION SYSTEM:

    • Factor XII activates coagulation cascade:

      • Thrombin: Cleaves fibrinogen β†’ fibrin, activates platelets, increases vascular permeability, promotes leukocyte adhesion.

      • Fibrin: Traps bacteria, limiting spread.

  4. ACUTE-PHASE REACTANTS:

    • Proteins synthesized by the liver in response to IL-6:

      • CRP (C-Reactive Protein):

      • Change: ↑↑ (significantly increased).

      • Function: Opsonization, complement activation.

      • Clinical Use: Inflammation marker (↑ in acute inflammation).

      • FIBRINOGEN:

      • Change: ↑ (increased).

      • Function: Coagulation, acute phase.

      • Clinical Use: ↑ ESR (Erythrocyte Sedimentation Rate).

      • FERRITIN:

      • Change: ↑ (increased).

      • Function: Iron storage.

      • Clinical Use: ↑ in inflammation.

      • HAPTOGLOBIN:

      • Change: ↑ (increased).

      • Function: Binds free hemoglobin.

      • Clinical Use: ↓ in hemolysis.

      • ALBUMIN:

      • Change: ↓ (decreased).

      • Function: Negative acute phase reactant.

      • Clinical Use: ↓ in chronic inflammation.

      • TRANSFERRIN:

      • Change: ↓ (decreased).

      • Function: Iron transport.

      • Clinical Use: ↓ in inflammation.

πŸ”₯ HIGH YIELD:

  • ESR ↑ with inflammation (fibrinogen causes RBC aggregation).

  • CRP is more sensitive for acute inflammation than ESR.

  • Both used clinically to monitor inflammatory diseases.

OUTCOMES OF ACUTE INFLAMMATION

  1. RESOLUTION (Best outcome):

    • Complete restoration of normal tissue.

    • Requirements: Minimal tissue damage, short duration, regenerative tissue (labile/stable).

    • Mechanisms: Debris cleared by macrophages, anti-inflammatory mediators (lipoxins, IL-10, TGF-Ξ²), vascular normalization.

  2. HEALING BY REPAIR (Scarring):

    • When tissue cannot regenerate (permanent tissues such as neurons, cardiac myocytes) and extensive damage occurs β†’ fibrosis (scar tissue).

  3. ABSCESS FORMATION:

    • Pus collection walled off by fibrous capsule, commonly associated with bacterial infections.

    • Requires drainage Β± antibiotics.

  4. CHRONIC INFLAMMATION:

    • If stimulus persists, the inflammatory response shifts to lymphocytes and macrophages, leading to tissue destruction and fibrosis.

    • Examples include TB, chronic infections, autoimmune conditions.

HIGH-YIELD CLINICAL CORRELATIONS

🩺 Myocardial Infarction (MI):

  • Cellular Changes:

    • 0-4 hours: Coagulative necrosis begins (reversible injury still possible if reperfusion occurs).

    • 4-12 hours: Coagulative necrosis established.

    • 12-24 hours: Neutrophil infiltration.

    • 1-3 days: Neutrophils maximal.

    • 3-7 days: Macrophages clear debris.

    • 1-3 weeks: Granulation tissue forms (angiogenesis, fibroblasts).

    • Weeks-months: Scar formation (collagen deposition).

  • Complications:

    • Arrhythmias (early).

    • Heart failure.

    • Rupture (4-7 days - when macrophages digest tissue).

    • Ventricular aneurysm (late).

🩺 Stroke (Cerebral Infarction):

  • Note: Brain = liquefactive necrosis (exception!).

  • Cystic cavity forms.

  • Astrocytes (glial cells) form gliosis (brain's version of scar).

🩺 Acute Pancreatitis:

  • Classic triad:

    • Severe epigastric pain radiating to back.

    • ↑ Amylase and lipase levels.

    • Fat necrosis (chalky white spots on CT).

  • Complications:

    • Hypocalcemia (calcium sequestered in saponification).

    • Pseudocyst formation.

    • Hemorrhagic pancreatitis (severe).

🩺 Tuberculosis:

  • Primary TB:

    • Ghon complex = Ghon focus (lung) + hilar lymph nodes caseous necrosis.

  • Secondary TB (Reactivation):

    • Apical location (high O2), cavitation (caseous material drains into bronchus), hemoptysis.

🩺 Acute Appendicitis:

  • Pathophysiology: Obstruction (fecalith) β†’ increased pressure β†’ ischemia β†’ bacterial invasion β†’ neutrophilic infiltration.

  • May progress to:

    • Gangrenous appendicitis.

    • Perforation β†’ peritonitis.

  • Presentation:

    • Periumbilical pain β†’ RLQ (McBurney's point), fever, leukocytosis, rebound tenderness, guarding.

🩺 Apoptosis in Disease:

  • Too Much Apoptosis:

    • Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's).

    • AIDS (CD4+ T cell loss).

    • Ischemic injury.

  • Too Little Apoptosis:

    • Cancer (Bcl-2 overexpression in follicular lymphoma).

    • Autoimmune diseases (failure of negative selection).

QUICK REVIEW TABLES
Cellular Adaptations Summary

  • ATROPHY:

    • Definition: ↓ size/number.

    • Key Example: Muscle wasting in cast.

  • HYPERTROPHY:

    • Definition: ↑ cell size.

    • Key Example: Cardiac hypertrophy (hypertension).

  • **HYPERPLASIA:

    • Definition: ↑ cell number.

    • Key Example: BPH, endometrial hyperplasia.

  • METAPLASIA:

    • Definition: Cell type replacement.

    • Key Example: Barrett's esophagus.

  • DYSPLASIA:

    • Definition: Abnormal growth.

    • Key Example: Cervical dysplasia (HPV).

Necrosis Types Quick Reference

  • COAGULATIVE:

    • Location: Heart, kidney, spleen.

    • Cause: Ischemia.

    • Appearance: Ghost cells, preserved architecture.

  • LIQUEFACTIVE:

    • Location: Brain, bacterial infection.

    • Cause: Ischemia (brain), infection.

    • Appearance: Liquid/pus.

  • CASEOUS:

    • Location: Lung (TB).

    • Cause: Mycobacteria.

    • Appearance: Cheese-like.

  • FAT:

    • Location: Pancreas, breast.

    • Cause: Pancreatitis, trauma.

    • Appearance: Chalky white spots.

  • FIBRINOID:

    • Location: Blood vessels.

    • Cause: Vasculitis, hypertension.

    • Appearance: Pink, fibrin deposition.

  • GANGRENOUS:

    • Location: Extremities.

    • Cause: Ischemia Β± infection.

    • Appearance: Black, dry (dry) or wet (wet).

Apoptosis Pathway Comparison

  • INTRINSIC PATHWAY:

    • Trigger: Internal stress (DNA damage).

    • Key Organelle: Mitochondria.

    • Key Proteins: Bcl-2 family, cytochrome c.

    • Initiator Caspase: Caspase-9.

    • Regulation: Bcl-2 (anti) vs BAX/BAK (pro).

  • EXTRINSIC PATHWAY:

    • Trigger: External signal (Fas, TNF).

    • Key Organelle: Death receptors.

    • Key Proteins: FADD, DISC.

    • Initiator Caspase: Caspase-8.

    • Regulation: c-FLIP (inhibits).

Adhesion Molecules in Leukocyte Recruitment

  • ROLLING STEP:

    • Leukocyte Molecule: Sialyl-Lewis X.

    • Endothelial Molecule: P-selectin, E-selectin.

    • Mediators that Upregulate: Histamine (P-selectin), IL-1/TNF (E-selectin).

  • ADHESION STEP (Part 1):

    • Leukocyte Molecule: LFA-1, Mac-1 (integrins).

    • Endothelial Molecule: ICAM-1.

    • Mediators that Upregulate: IL-1, TNF.

  • ADHESION STEP (Part 2):

    • Leukocyte Molecule: VLA-4.

    • Endothelial Molecule: VCAM-1.

    • Mediators that Upregulate: IL-1, TNF.

  • TRANSMIGRATION STEP:

    • Leukocyte Molecule: CD31 (PECAM-1).

    • Endothelial Molecule: CD31 (PECAM-1).

    • Mediators that Upregulate: Constitutive.

Chemical Mediators Summary

  • HISTAMINE:

    • Source: Mast cells.

    • Main Actions: Vasodilation, permeability (immediate).

  • PGE2:

    • Source: COX pathway.

    • Main Actions: Vasodilation, pain, fever.

  • LTB4:

    • Source: 5-LOX pathway.

    • Main Actions: Neutrophil chemotaxis.

  • C5a:

    • Source: Complement.

    • Main Actions: Chemotaxis, mast cell activation.

  • IL-8:

    • Source: Macrophages.

    • Main Actions: Neutrophil chemotaxis.

  • TNF-Ξ±:

    • Source: Macrophages.

    • Main Actions: Endothelial activation, fever, shock.

  • NO (Nitric Oxide):

    • Source: Endothelium, macrophages.

    • Main Actions: Vasodilation.

STUDY TIPS FOR TBL

  • Before TBL (Tonight):

    • Focus on learning objectives to guide TBL questions.

    • Watch both video playlists on ScholarRx.

    • Review lecture slides from class.

    • Read the "Bricks to Read" articles, especially on acute inflammation.

  • During IRAT (Individual):

    • Read questions carefully (many ask for "EXCEPT" answers).

    • Eliminate obviously wrong answers first.

    • Trust your first instinct unless you're certain it's wrong.

  • During TRAT (Team):

    • Use response cards as directed - no notes or electronics allowed.

    • Discuss rationales, not just answers.

    • Listen to team members - collaborative learning is crucial.

    • If stuck, work backwards from answer choices.

  • During Team Application:

    • Apply concepts; don’t just memorize.

    • Clinical scenarios will test your understanding.

    • Be ready to justify your team's answers.

πŸ”₯ HIGHEST YIELD FACTS TO MEMORIZE

  1. Necrosis = inflammatory.

  2. Apoptosis = no inflammation.

  3. Coagulative necrosis = ischemia (except brain).

  4. Brain = liquefactive necrosis.

  5. Caseous necrosis = TB until proven otherwise.

  6. Fat necrosis + pancreatitis = enzymatic fat necrosis with saponification.

  7. Apoptosis pathways: Intrinsic = mitochondria, cytochrome c, caspase-9.

  8. Extrinsic = death receptors (Fas, TNF), DISC, caspase-8.

  9. Both pathways activate caspase-3.

  10. Bcl-2 family:

    • Anti-apoptotic: Bcl-2, Bcl-XL (promote cell survival).

    • Pro-apoptotic: BAX, BAK (form pores), BH3-only proteins.

  11. Leukocyte recruitment: "Rolling (selectins) β†’ Adhesion (integrins/ICAM) β†’ Transmigration (PECAM)."

  12. Neutrophils = acute (<24 hrs). Lymphocytes/macrophages = chronic.

FINAL CHECKLIST

  • Before you sleep tonight:

    • Read through these notes at least once.

    • Watch the video playlists.

    • Review your lecture notes.

    • Read the "Bricks to Read" articles.

    • Get 7-8 hours of sleep (seriously!).

  • Tomorrow before TBL:

    • Quick 15-minute review of high-yield facts.

    • Eat a good breakfast.

    • Arrive 5 minutes early.

    • Bring your response card.

    • NO NOTES OR ELECTRONICS during TRAT/Team Application.

πŸŽ“ YOU GOT THIS! Remember: TBLs are about application, not just memorization. Focus on understanding the why behind each concept. If you understand the mechanisms, you can figure out the answers even if you don't remember every detail. Good luck tomorrow! You're going to do great! πŸ’ͺ Study smart, not just hard. Review actively, test yourself, and teach these concepts to Honey (your cat) - if you can explain it simply, you understand it well! 🐱