Cell Injury, Death and Adaptation

Introduction
Pathology Study of Disease
Four aspects of disease: 1. etiology 2. pathogenesis 3. morphology 4. clinical significance

Reactions to Adverse Stimuli 1. Cellular Adaptation 2. Reversible Injury 3. Irreversible Injury and Cell Death

Cellular Adaptation occurs when excessive physiologic stresses or pathologic stimuli result in a new but altered steady state preserves the viability of the cell e.g. atrophy, hypertrophy

Reversible Cell Injury

pathologic changes that can be reversed when the stimulus is removed, or if the cause of the injury is mild viability of the cell is still preserved

Irreversible Cell Injury

pathologic changes which are permanent and will cause cell death with certainty

Cell injury implies failure of adaptive mechanisms - the intensity of the adverse stimulus may have exceeded the cell's adaptive capacity.

Causes of Cell Injury Irreversible or Reversible

1. Hypoxia - insufficiency of oxygen leading to disruption of aerobic oxidative metabolism Causes of hypoxia : a. ischaemia cessation blood flow, e.g. tnromboembolus b. inadequate oxygenation, e.g pulmonary disease c. loss of oxygen-carrying capacity of the blood, e.g. anemia

Causes of Cell Injury Irreversible or Reversible 2. 3. 4. 5. Physical Agents Chemical Agents and Drugs Infectious Agents Immunologic Reactions - e.g. hypersensitivity, autoimmunity 6 Genetic Diseases 7. Nutritional Imbalances

Mechanisms of Injury
1. 2. 3. 4. ATP Depletion Oxidative Stress Increase in Cytosolic Calcium Cell Membrane Permeability Defects 5. Mitochondrial Injury

Cellular Points of Attack

1. 2. 3. 4. Membrane Integrity Aerobic Respiratory Mechanisms Protein Synthetic Machinery Genetic Material

Hypoxic-Ischemic Injury
Reversible Ischemic Injury Cause: Ischaemia - deprivation of oxygen and substrates, glucose Mechanism: ATP depletion Point of Attack: 1. Aerobic Respiratory Mechanisms 2. Protein Synthesis Morphology: Cellular and Organellar Swelling

Hypoxic-Ischemic Injury
Irreversible Ischemic Injury Cause: Ischaemia Mechanism: 1. Membrane Permeability Defects 2. Mitochondrial Injury Point of Attack: Membrane Integrity Morphology: Cell and Organelle Rupture

Subcellular Responses to Adverse Stimuli

1. Lysosomal Catabolism a. Heterophagy b. Autophagy 2. Smooth Endoplasmic Reticulum Induction 3. Mitochondrial Changes 4. Cytoskeletal Abnormalities

Factors That Influence the Reaction of a Cell to Injurious Stimuli 1. Type, Duration, Severity of the Injurious Agent 2. Type of Cell SUSCEPTIBILITY OF CELLS TO HYPOXIA Neurons - very sensitive (minutes) Myocytes, Hepatocytes intermediate (minutes to few hours) Fibroblasts, Epidermis, Muscle - low susceptibility (many hours)

MORPHOLOGY OF CELL INJURY

REVERSIBLE CELL INJURY Ultrastructural Findings (Electron Microscopy) 1. Clumping of nuclear chromatin 2. Blebbing of cell membrane 3. Swelling of ER and mitochondria 4. Lysosomal autophagy

MORPHOLOGY OF CELL INJURY

REVERSIBLE CELL INJURY Light Microscopic Features 1. Cellular Swelling a. vacuolar degeneration or hydropic change b. denotes failure of the cell membrane to maintain ion and fluid balance c. the gross specimen may show increased weight, turgor and pallor 2. Fatty Change a. accumulation of fat within the cell b. myocardium, hepatocytes c. grossly, the organ is enlarged, yellow and greasy

MORPHOLOGY OF CELL INJURY

IRREVERSIBLE CELL INJURY (NECROSIS) Necrosis - all morphologic changes that follow cell death in living tissue Ultrastructural Findings 1. Fragmentation of cell membrane 2. Severe vacuolization of mitochondria 3. Rupture of lysosomes with leakage of lysosomal enzymes (autolysis)

MORPHOLOGY OF CELL INJURY

IRREVERSIBLE CELL INJURY Light Microscopic Features 1. Cytoplasmic eosinophilia a. due to loss of basophilia b. denaturation of cytoplasmic RNA 2. Nuclear degeneration a. pyknosis b. karyorrhexis c. karyolysis

Morphology of Cell Death

1. Necrosis pathologic cell death 2. Apoptosis physiologic cell death

Necrosis
TYPES OF NECROSIS 1. Coagulation Necrosis
a. most common pattern associated with ischaemia b. cells become very eosinophilic with loss of cellular detail but preservation of cellular outlines (ghost cells) c. predominant biochemical process is protein denaturation d. myocardial infarction, splenic and renal infarcts

Necrosis
2. Liquefactive Necrosis
a. occurs when autolysis predominates over protein denaturation b. often seen in tissues with high fluid contents; the necrotic area is soft to fluid and may be converted into a cyst containing necrotic debris c. e.g. brain infarcts, abscesses

Necrosis
3. Enzymatic Fat Necrosis
a. necrosis that takes place in tissues with high adipose composition b. due to the action of lipases that break down fat c. shadowy outlines of fat cells with calcium deposition (saponification) d. acute pancreatitis e. traumatic fat necrosis

Necrosis
4. Caseation Necrosis a. tuberculous infections b. gross - soft, friable cheesy material c. microscopic - granulomatous inflammation

Necrosis
5. Gangrenous Necrosis
a. occurs with secondary bacterial infection on ischemic tissues b. two types 1. dry gangrene - bacterial infection superimposed on coagulation necrosis, e.g. diabetic foot 2. wet gangrene - infection superimposed on liquefactive necrosis, e.g. acute appendicitis

Necrosis
6. Fibrinoid Necrosis a. autoimmune diseases e.g. SLE b. perivascular location (vasculitis)

Apoptosis
Programmed cell death (physiologic cell death) E.g. epidermis, endometrial shedding during menses, embryogenesis Morphology: 1. cell shrinkage 2. chromatin condensation and fragmentation 3. lack of inflammation 4. occurs in single or small clusters of cells

Pathologic Calcification
1. Dystrophic Calcification a. necrotic areas b. normal serum calcium levels c. e.g. atherosclerosis, fibrocalcific TB 2. Metastatic Calcification a. viable tissues b. serum calcium levels are very high (hypercalcemia) c. e.g. nephrocalcinosis

Cellular Adaptation
Cells must constantly adapt to the internal and external stimuli they receive in order to escape injury or to survive Altered steady state If the stimulus that incited the adaptation is removed, the cell reverts back to the original steady state, i.e. adaptations are reversible

Types of Cellular Adaptation

1. Physiologic adaptation response of the cell to hormonal or endogenous influences
2. Pathologic adaptation response of the cell to injurious stimuli which enable them to escape injury

Types of Cellular Adaptation

1. Hyperplasia a. increase in the number of cells b. occurs only in cells which are capable of dividing c. epithelium, blood cells, connective tissues d. physiologic or pathologic

Cellular Adaptation - Hyperplasia

Physiologic Hyperplasia a. hormonal hyperplasia, e.g. endometrial proliferation due to estrogen b. compensatory hyperplasia, e.g. hyperplasia of liver cells after hepatectomy Pathologic Hyperplasia a. excessive hormonal stimulation, e.g. endometrial hyperplasia b. may later give rise to neoplastic processes

Types of Cellular Adaptation

2. Hypertrophy a. increase in the size of cells due to an increase in the cellular contents b. cells which are not capable of dividing c. myocytes, skeletal muscle cells d. physiologic or pathologic

Cellular Adaptation - Hypertrophy

Physiologic Hypertrophy a. increased functional demand, e.g weightlifters b. hormonal stimulation, e.g. uterine hypertrophy during pregnancy Pathologic Hypertrophy a. myocardial hypertrophy in hypertension b. heart may lose its capacity to adapt (heart failure)

Types of Cellular Adaptation

3. Atrophy a. shrinkage in the size of the cell due to loss of cell contents b. due to a decrease in functional

demand or a decrease in hormonal stimulation

c. the decrease in cell substance is accomplished by autophagy

Cellular Adaptation - Atrophy

Causes of atrophy: a. decreased workload b. loss of innervation c. diminished blood supply d. inadequate nutrition e. loss of endocrine stimulation f. aging

Types of Cellular Adaptation

4. Metaplasia
a. one adult cell type is replaced by another adult cell type which is more resistant to the injurious stimulus that elicited the process b. Squamous metaplasia of the cervix Glandular metaplasia of the esophagus Osseous metaplasia of soft tissues c. may give rise to neoplasms

Inflammation and Repair

Inflammation
Reaction of vascularized living tissue to local injury Causes of inflammation :injurious stimuli Objective: to contain and isolate injurious agent and achieve healing May also be potentially harmful

Cardinal Signs of Inflammation

1. Rubor - vasodilation and increased blood flow 2. Calor - vasodilation and increased blood flow 3. Dolor - cytokines 4. Tumor - local edema 5. Functio Laesa loss of function

The Inflammatory Response

Two Main Phases in Inflammation 1. Vascular Phase 2. Cellular Phase
Vascular Phase: 1. Changes in Vascular Flow and Caliber 2. Changes in Vessel Wall Permeability

Vascular Phase of Inflammation

1. Changes in Vascular Flow and Caliber
a. initial transient vasoconstriction followed by a more prolonged vasodilation b. vasodilation leads to increased blood flow

2. Increased Vascular Permeability

a. the vascular wall becomes leaky so that both fluid and plasma proteins leaks out b. mechanisms: Direct endothelial injury Endothelial cell retraction

Cellular Phase of Inflammation

Cellular Events 1. Leukocyte Extravasation 2. Chemotaxis 3. Phagocytosis

Cellular Phase - Extravasation

Leukocyte Extravasation
a. margination b. rolling c. adhesion/pavementing d. diapedesis/transmigration

Cellular Phase - Extravasation

emigration of WBC' s: neutrophils followed by lymphocytes bacterial infections neutrophils viral infections - mononuclear cells (lymphocytes and monocytes) allergic reactions - eosinophils

Cellular Phase - Extravasation

Cellular Phase - Chemotaxis

Chemotaxis 1. unidirectional migration of WBC' s to the site of injury 2. chemotactic agents a. bacterial products or cytokines b. lure the cell to the site of injury through a concentration gradient c. receptor-mediated

Cellular Phase -Phagocytosis

Phagocytosis process by which foreign particles, e.g. bacteria, are ingested by the leukocytes a. Attachment b. Engulfment c. Fusion of lysosome d. Killing

Cellular Phase -Phagocytosis

1. Attachment a. Particles coated with opsonins readily attach to the surface of phagocytes. b. Opsonins are plasma proteins that make offending particle tasty to the phagocytes. 2. Engulfment - pseudopods extend around the particle

Cellular Phase -Phagocytosis

3. Fusion of lysosome with the phagocytozed particle phagolysozome
4. Killing a. activation of bactericidal mechanisms within the WBC b. degranulation - the release of bactericidal chemicals stored within granules

Cellular Phase -Phagocytosis

Bactericidal Mechanisms
1. Oxygen-dependent Mechanisms a. respiratory burst b. MPO, H202, HOCL
2. Oxygen-independent Mechanisms lysozymes, lactoferrin

CHEMICAL MEDIATORS OF INFLAMMATION

Inflammation leads to the release of numerous chemical agents that mediate the many effects of inflammation Sources: 1. Damaged tissue 2. Plasma proteins 3. WBC

CHEMICAL MEDIATORS OF INFLAMMATION

1. Vasoactive Amines
a. Histamine and Serotonin b. Source: Platelets, Basophils and Mast Cells c. Effects: Vasodilation Increased Vascular Permeability d. Mechanisms of Release: 1. Physical Agents, e.g. cold, rubbing 2. IgE-mediated 3. Anaphylatoxins 4. Interleukin 1

CHEMICAL MEDIATORS OF INFLAMMATION

2. Complement Components
a. Classic Pathway - antigen-antibody interaction b. Alternate Pathway - endotoxins, polysaccharides, globulins c. C3a, C5a (Anaphylatoxins) - increase vascular permeability d. C5a-chemotactic factor e. C3b - opsonic fragment f. C5b-9 - Membrane Attack Complex

CHEMICAL MEDIATORS OF INFLAMMATION 3. Arachidonic Acid Metabolites

CHEMICAL MEDIATORS OF INFLAMMATION

4. CYTOKINES
a. protein products secreted by macrophages and lymphocytes b. Interleukins IL-1 (TNF) 1. Acute Phase Response a. fever, sleep, anorexia b. acute phase proteins c. neutrophilia 2. Endothelial Effects - adhesion molecules 3. Fibroblast Effects - proliferation and collagen synthesis

CHEMICAL MEDIATORS OF INFLAMMATION

5. COAGULATION PATHWAY PROTEINS 6. LYSOSOMAL ENZYMES 7. NITRIC OXIDE

OUTCOME OF ACUTE INFLAMMATION

1. Resolution and Regeneration 2. Scarring a. replacement by fibrous connective tissue b. tissues that do not regenerate c. abundant fibrin 3. Abscess formation 4. Progression to chronic inflammation

CHRONIC INFLAMMATION
Definition Inflammation of prolonged duration 1) active inflammation, 2) tissue destruction, and 3) attempts at healing are all proceeding simultaneously.

Settings of Chronic Inflammation

1. May follow acute inflammation due to persistence of injurious stimulus or defective healing 2. May follow repeated bouts of acute inflammation 3. Prolonged exposure to nondegradable but potentially toxic substances, e.g. silica 4. Autoimmunity

Histologic Features of Chronic Inflammation

1. Mononuclear cell infiltration lymphocytes, macrophages and plasma cells 2. Tissue Destruction 3. Connective tissue replacement angiogenesis and fibrosis

GRANULOMATOUS INFLAMMATION
Granulomas
nodular collections of modified macrophages called epithelioid cells, rimmed by lymphocytes, plasma cells and multinucleated giant cells multinucleated giant cells - fusion of the epithelioid cells cell-mediated immunity/delayed type hypersensitivity towards insoluble or indigestible particles two types of granulomas: 1. Foreign-body granulomas - inert foreign particles, e.g. suture material 2. Immune granulomas - T-cell mediated reactions to poorly degradable antigens, e.g. fungal antigens

GRANULOMATOUS INFLAMMATION
Examples of Granulomatous Diseases 1. Tuberculosis - granulomas have central areas of caseation necrosis 2. Leprosy - numerous foamy macrophages 3. Fungal infections 4. Parasitic infections - Schistosomiasis; granulomas around the ovum

MORPHOLOGIC PATTERNS OF INFLAMMATION

1. Serous Inflammation - thin plasma fluid or irritation of mesothelial lining cells; e.g. blisters 2. Fibrinous inflammation - plasma proteins such as fibrin; e.g. fibrinous pericarditis in rheumatic heart disease 3. Suppurative inflammation abundant pus; usually associated with pyogenic organisms, e.g. staphylococci 4. Ulcer - excavation of the surface of an organ or tissue due to sloughing (shedding) of necrotic tissues.

MORPHOLOGIC PATTERNS OF INFLAMMATION

TISSUE REPAIR
Two types: 1. Regeneration - replacement of injured cells by the same cell type 2. Fibrosis/Fibroplasia replacement of injured cells by connective tissue

Determinants of Type of Tissue Repair

1. proliferative capacity of the injured cell 2. extent of injury

Determinants of Type of Tissue Repair

Proliferative Capacity 1. Labile cells-continuously dividing cells, e.g. epithelia, blood cells 2. Quiescent or Stable cells - low-level of replication but can be stimulated in response to stimuli, e.g. solid visceral organs, mesenchymal tissues 3. Permanent or Non-dividing cells - e.g. neurons, cardiac muscles, skeletal muscle

Determinants of Type of Tissue Repair

Extent of Injury 1. underlying supporting framework is necessary for organized regeneration 2. when basement membranes are disrupted, the framework collapses

REPAIR BY CONNECTIVE TISSUE REPLACEMENT (FIBROPLASIA) 1. If there is damage to-bothparenchymal and supporting framework (basal lamina) 2. Usually in necrotizing inflammation and chronic inflammation 3. Formation of granulation tissue to replace defect

WOUND HEALING
1. Primary Union/Healing by First Intent 2. Secondary Union/Healing by Second Intent

Primary Union
1. clean, uninfected wound with minimal loss of native tissue 2. deliberate surgical incisions, superficial abrasions

WOUND HEALING
Secondary Union
1. more extensive injuries where there is a large tissue defect to be filled 2. major loss of native tissue 3. more intense inflammation 4. larger amounts of granulation to fill in defect 5. wound contraction 6. ulcers, avulsions, traumatic injuries

WOUND HEALING
WOUND STRENGTH 1. attributed to constant remodeling and deposition of collagen 2. plateus on the third month; achieves 70-80% of original strength

WOUND HEALING

SYSTEMIC FACTORS AFFECTING WOUND HEALING 1. Nutrition - lack of substrates needed for healing 2. Metabolic status 3. Circulatory status - blood supply 4. Hormones-e.g. steroids

LOCAL FACTORS AFFECTING WOUND HEALING

1. Infection - single most important cause 2. Mechanical factors - early motion 3. Foreign bodies 4. Size, location and type of wound

COMPLICATIONS IN WOUND HEALING 1. Deficient scar 2. Excessive scar - e.g. keloid, hypertrophic scar 3. Contractures - deformities of surrounding normal tissues with limitation of motion and movement, e.g. burns

Hemodynamics

HEMODYNAMIC DISORDERS
60% of lean body weight is due to water
2/3 intracellular fluid 1/3 extracellular fluid 5% - plasma/intravascular compartment the rest - interstitial space

1. 2. 3. 4. 5. 6.

Edema Hyperemia and Congestion Hemorrhage Thrombus and Embolism Infarction Shock

EDEMA
increased fluid in the interstitial space
hydrothorax hydropericardium hydroperitoneum/ascites anasarca .

two types of edema

1. inflammatory edema 2. non-inflammatory edema

EDEMA
Inflammatory Edema
increase in vascular permeability due to the action of various cytokines fluid leaks out of the permeable vessels (exudate) protein-rich, with high specific gravity

Non-Inflammatory Edema
hydrodynamic derangements fluid that leaks out is protein-poor with low specific gravity (transudate)

EDEMA

Normal Hydrodynamic Balance 1. Intravascular hydrostatic pressure - higher within the arteriolar side than the venular 2. Plasma oncotic pressure/Colloid osmotic pressure - attributable to proteins within the plasma, e.g. albumin

EDEMA

Mechanisms of Non-inflammatory Edema

1. increased intravascular hydrostatic pressure
a. local increases - e.g. venous thrombosis b. generalized increases - e.g. congestive hear failure (cardiac edema)

2. reduced plasma oncotic pressure hypoproteinemia, e.g. kwashiorkor, liver disease 3. lymphatic obstruction-e.g. surgery, irradiation 4. sodium retention

HYPEREMIA AND CONGESTION

Local increase in the volume of blood within a particular tissue 1. Hyperemia 2. Congestion 1. Hyperemia
a. active process due to arteriolar dilatation b. brings a reddish hue to tissues due to oxygenated blood c. inflammation, heat

HYPEREMIA AND CONGESTION

2. Congestion
a. passive process due to impaired venous outflow b. brings a bluish hue to tissues due to deoxygenated blood (local cyanosis) c. venous thrombosis, congestive heart failure d. congestion and edema often go hand in hand e. prolonged congestion can lead to tissue hypoxia and eventual cell death

HEMORRHAGE
Extravasation of blood because of vascular wall rupture
hematoma petechiae 1-2 mm purpura >3 mm ecchymoses >1 cm hemothorax, hemopericardium, hemoperitoneum, hemarthrosis hypovolemic shock - loss of >20% of total blood volume

Normal Hemostasis
1. Prevent abnormal clotting - maintain blood in a fluid state 2. Prevent hemorrhage - rapid and localized response to vascular injury to stop bleeding Components of Normal Hemostasis 1. vascular wall (endothelium) 2. platelets 3. coagulation proteins - e.g. thrombin, fibrin

THROMBOSIS
Inappropriate activation of the hemostatic pathway in uninjured blood vessels, or excessive clot formation even in minor injuries The blood clot that forms in thrombosis is called a thrombus A thrombus may occlude a vessel leading to infarction

THROMBOSIS
Factors Predisposing to Thrombosis 1. endothelial injury 2. stasis or turbulence of blood flow - e.g. in atherosclerosis 3. blood hypercoagulability - e.g. prolonged immobilization, drugs

THROMBOSIS
Fates of a Thrombus 1. Propagation 2. Embolization 3. Dissolution 4. Organization and Recanalization

Fates of a Thrombus

Thrombus versus a Post-mortem Clot

Thrombus Post-Mortem Clot

Adherent to wall Firm consistency Does not take the shape of vessel Lines of Zahn

Easily detached
Gelatinous red dependent portion; chicken-fat supernatant

Takes the shape of the vessel None

EMBOLISM
Detached mass that is carried by blood to a site distant from its point of origin
99% detached thrombi - thromboembolus Can completely and acutely occlude blood supply to tissues causing infarction

Examples: 1. pulmonary embolism

2. 3. 4. 5. systemic embolism fat embolism air embolism anmiotic fluid embolism

INFARCTION
Area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage Causes: 1. Arterial occlusion due to a thromboembolus - 99%, e.g. MI, stroke 2. Vasospasm 3. Vessel compression 4. Vessel twisting

INFARCTION
Types of Infarcts 1. Red infarcts (hemorrhagic infarcts)
a. venous occlusions b. organs with loose tissue support, e.g. lungs c. organs with dual circulation, e.g. liver

2. White infarcts (anemic infarcts)

a. arterial occlusions b. solid organs, e.g. heart, spleen, kidneys c. endarterial circulation

3. Septic Infarcts

INFARCTION
Factors That Influence Development of Infarcts 1. nature of vascular supply - dual circulations 2. rate of development of occlusion development of collaterals 3. tissue vulnerability to hypoxia - e.g. brain and heart vs. skeletal muscle 4. oxygen content of blood - e.g. anemia

SHOCK
Cardiovascular collapse
systemic hypoperfusion (inadequate blood delivery of 02 and glucose) leads to cellular hypoxia and death manifested as progressively dropping BP (hypotension)

SHOCK
Categories of Shock
1. cardiogenic shock - 'pump failure' 2. hypovolemic shock - massive loss of blood volume 3. septic shock - overwhelming infection results in massive peripheral vasodilation 4. anaphylactic shock - intense allergic reaction leads to massive peripheral vasodilation 5. neurogenic shock - spinal cord injury or anesthetic reaction leads to decreased vascular tone