Chapter 1 - Cellular Injury, Cell Adaptation & Cell Death (Robbins and Cotran Pathologic Basis of Disease )

Cellular Injury, Cell adaptation & Cell death Pathology  Study of structural & functional changes in cells, tissues, & organs  Uses molecular, microbiologic, immunologic & morphologic techniques  Foundation for rational clinical care & therapy  Types of pathology: o GENERAL – reactions of cells to abnormal stimuli o SYSTEMIC – reactions of organs/ tissues to stimuli/ diseases 4 ASPECTS OF DISEASE PROCESS (form the core of pathology)  Etiology or cause o Can be:  Genetic (ex. Trisomy 21)  Acquired (ex. HIV)  Multifactorial (both genetic & acquired)  Ex. Atherosclerosis  Pathogenesis o Time frame (from exposure to developed s/sx) o Sequence of events from the initial stimulus to the clinical manifestations of the disease  Morphology o How the disease produces changes in the cell o Alteration in the structures of the cells  Clinical significance o Refers to the clinical manifestations & prognosis of disease CELLULAR RESPOSES TO STRESS & NOXIOUS STIMULI  Cell is in a state of homeostasis  Physiologic stresses & some pathologic stimuli will bring about cellular ADAPTATIONS such as: o Hyperplasia – both physiologic & pathologic o Hypertrophy – both o Atrophy – both o Metaplasia – always pathologic  Depends upon NATURE & SEVERITY of injurious stimuli o I. Cellular adaptations o II. Cell injury (reduced O2, chemical injury, microbial infection o III. Intracellular accumulations & calcifications o IV. Cellular aging

I. CELLULAR ADAPTATIONS: 1. HYPERPLASIA  Def: Increase in the number of cells  Some cell types are unable to exhibit hyperplasia (nerve, cardiac, skeletal muscle cells)  Is mediated by: o Growth factors, cytokines o Growth promoting genes – proto-oncogenes o Increased DNA synthesis & cell division  PHYSIOLOGIC hyperplasia o Hormonal  Breast development at puberty/preg.  Uterus development at pregnancy  Proliferation of endometrium o Compensatory  After hepatectomy  PATHOLOGIC o Excess hormones  Edometrium (if ↑ estrogen = can lead to atypical hyperplasia – cancerous)  BPH (d/t ↑ adrogens) o Excess growth hormones  Keloid  Papilloma virus  Hyperplasia can be malignant 2. HYPERTROPHY  Def: Increase un cell size d/t synthesis of structural components  Occurs in dividing and non-dividing cells like HEART and SKELETAL muscle cells  Causes of hypertrophy: o Increased functional demand  PHYSIOLOGIC  striated muscles of wt. lifters  PATHOLOGIC  cardiac muscle in ↑BP o Increased endocrine stimulation  Puberty (GH, androgens/testosterone)  Gravid uterus (d/t ↑ estrogen)  Lactating breast (prolactin & estrogen)  Main downstream signaling of G-protein coupled receptor is induced by GROWTH FACTOR & VASOACTIVE agents  Normal ventricular thickness: o Right – 0.3-0.5 o Left – 1.3-1.5  *Mechanisms  *Hypertrophy & Hyperplasia often occur together

3. ATROPHY  Def: Shrinkage in size of cells. Decrease cellular components. Decrease size of organ. Reduce metabolic activity.  Causes of Atrophy o Disuse o Denervation atrophy o Diminished blood supply o Inadequate nutrition o Loss of endocrine stimulation (opposite of hypertrophy) o Aging o Pressure  Mechanisms of Atrophy o ↑ CHON degradation – uses Ubiquitin-Proteasome pathway o ↑  Microscopic characteristics: small shrunken cells with LIPOFUSCIN granules o Lipofuscin – “aging pigment” golden color  Notes: o Senile atrophy – wear & tear pigments 4. METAPLASIA  Def: One differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. Usually in response to IRRITATION  Prone to cancerous transformation (same as hyperplasia)  TYPES: o Columnar to Squamous  Bronchial epith.undergoes bronchial squamous metaplasia in response to tobacco smoking o Squamous to Columnar  AKA: adenocarcinoma  Ex: Barrett’s Esophagus  d/t reflux of gastric content  a benign disease  form of adaptation o Connective tissue metaplasia – formation of cartilage, bone, or adipose tissue (mesenchymal tissues)  Ex: Myositis Ossificans  Example of metaplasia o Columnar  squamous = endocervix o Squamous  columnar = esophagus  Mechanism: Reprogramming of stem cells o The reserve cells (or stem cells) of the irritated tissue  differentiate into a more protective cell

type d/t the influence of growth factors, cytokines, & matrix components

II. CELLULAR INJURY 

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Stages of cell injury o Acute & self-limited  acute reversible injury o Progressive & severe  irreversible injury  cell death necrosis & apoptosis o Mild chronic injury  subcellular alterations in various organelles REVERSIBLE cell injury – functional & morphological changes that are reversible IRREVERSIBLE cell injury – “point of no return” NOTE: Any of the reversible changes can become irreversible when taken to the extreme

HALLMARKS OF REVERSIBLE INJURY  1. Reduced oxidative ATP phosphorylation  2. ATP depletion  3. Cellular swelling (2) MORPHOLOGIC PATTERNS OF CELL DEATH  NECROSIS o Pathogenesis: when damage to membranes is severe, lysosomal enzymes enter the cytoplasm & digest the cell, & cellular contents leaks out.  APOPTOSIS o Nuclear dissolution w/o complete loss of membrane integrity  NOTES o Necrosis – always a pathologic process o Apoptosis – serves many normal function & is not necessarily associated w/ cell injury FEATURES OF NECROSIS & APOPTOSIS Feature NECROSIS Cell size Enlarged Nucleus Karyopyknosis, rrhexis, lysis Plasma Disrupted membrane Cellular Enzymatic digestion contents Inflammation Frequent Physio/Patho Pathologic role

APOPTOSIS Reduced Karyorrhexis – or fragmentation Intact Intact No Physiologic

CAUSES OF CELL INJURY  1. O2 deprivation  2. Physical agents  3. Chem.agents & drugs  4. Nutritional imbalance (anorexia nervosa) (2) MORPHOLOGIC PATTERNS OF REVERSIBLE CELL INJURY  1. Cellular swelling - *1st manifestation o Incapable to maintain ionic & fluid homeostasis o Loss of function of plasma membrane  2. Fatty change o Ex. Liver cirrhosis o There is vacuoles ULTRASTRUCTURAL CHANGES of REVERSIBLE CELL INJURY  1. Plasma membrane alterations o Blebbing, blunting, & distortion of microvilli o Creation of myelin figures o Loosening of intercellular attachments  2. Mitochondrial changes o Swelling o Rarefaction o Appearance of small phospholipid rich amorphous densities  3. Dilatation of ER o With detachment & disaggregation of polysomes  4. Nuclear alterations o With disaggregation of granular & fibrillar elements NECROSIS  Result of denaturation of intracellular proteins & enzymatic digestion of lethally injured cells  Follow cell death  d/t: Degradative action of enzymes  MORPHOLOGIC APPEARANCE o 1. ↑ eosinophilia o 2. Glassy homogeneous appearance o 3. Moth-eaten cytoplasm o 4. Calcification & replacement by myelin figures o 5. Nuclear changes  Karyolysis – nuclear fading/disolution  Karyorrhexis – nuclear fragmentation  Pyknosis – degeneration/shringkage of nuclear chromatin o 6. Morphologic patterns  1. Coagulative necrosis  2. Liquefaction  3. Caseous

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 4. Fat necrosis COAGULATIVE NECROSIS o Denaturation of CHON = is the primary pattern o Basic cellular outline is preserved for a span o *most common form of necrosis o Characterized by hypoxic death of cells on ALL tissues EXCEPT the BRAIN (occurs in liquefaction necrosis) o Microscopic: (-) nucleus but preserved of cell shape o Common: heart, liver & kidney LIQUEFACTION NECROSIS o Hypoxic death of cells w/in the CNS o Digestion of the dead cells o End result is the transformation of the tissue into liquid viscous mass (pus) = *complete dissolution o *gangrenous necrosis (dead tissue)  Is the combination of coagulation + liq.  Common sites:  Lower limbs Testes  Gallbladder GI tract  Dry gangrene: pattern is coagulative n.  Wet gangrene: patter is liquefactive n. o Cellular destruction by hydrolytic enzyme o d/t: autolysis + heterolysis o Common: Abscess, Brain infarcts, pancreatic nec. CASEOUS/CASEATION NECROSIS o Form of coagulative necrosis o Foci of tuberculosis  Usually appears in the apex of the lungs*? o Gross: soft, friable, & “cottage-cheese-like” appearance o (2) types of GIANT CELLS (histiocytes)  Langhans – nucleus are peripherally arranged  Foreign type – nucleus are haphazardly arranged FAT NECROSIS o Caused by the action of activated pancreatic LIPASES (w/c liquefy cell membranes) o TGs –lipases FA + Ca++ = forming saponified fats o Gross: “chalky-white appearance” o Micro: foci of shadowy outlines of necrotic fat cells + basophilic Ca++ deposits FIBRINOID NECROSIS o Additional type o Common in vascular wall o Histologically resembles fibrin o Micro: eosinophilic (pink) homogenous appearance

MECHANISMS OF CELLULAR INJURY  1. ATP depletion (hypoxic & toxic injury) o NORMALLY,  ATP is produced by:  Oxidative phosphorylation of ADP  Anaerobic glycolysis  ATP is required for:  Membrane transport  CHON synthesis  Lipogenesis  Deacylation-reacylation reactions for phospholipid turnover o Effects of ATP depletion to