Cellular Injury, Cell adaptation & Cell death I. CELLULAR ADAPTATIONS: 3.

ATROPHY
 Def: Shrinkage in size of cells. Decrease cellular components.
Pathology 1. HYPERPLASIA Decrease size of organ. Reduce metabolic activity.
 Study of structural & functional changes in cells, tissues, &  Def: Increase in the number of cells  Causes of Atrophy
organs  Some cell types are unable to exhibit hyperplasia (nerve, o Disuse
 Uses molecular, microbiologic, immunologic & morphologic cardiac, skeletal muscle cells) o Denervation atrophy
techniques  Is mediated by: o Diminished blood supply
 Foundation for rational clinical care & therapy o Growth factors, cytokines o Inadequate nutrition
 Types of pathology: o Growth promoting genes – proto-oncogenes o Loss of endocrine stimulation (opposite of
o GENERAL – reactions of cells to abnormal stimuli o Increased DNA synthesis & cell division hypertrophy)
o SYSTEMIC – reactions of organs/ tissues to stimuli/ o Aging
 PHYSIOLOGIC hyperplasia
diseases o Pressure
o Hormonal
 Breast development at puberty/preg.  Mechanisms of Atrophy
4 ASPECTS OF DISEASE PROCESS (form the core of pathology)  Uterus development at pregnancy o ↑ CHON degradation – uses Ubiquitin-Proteasome
 Etiology or cause  Proliferation of endometrium pathway
o Can be: o Compensatory o ↑
 Genetic (ex. Trisomy 21)  After hepatectomy  Microscopic characteristics: small shrunken cells with
 Acquired (ex. HIV)  PATHOLOGIC LIPOFUSCIN granules
 Multifactorial (both genetic & acquired) o Excess hormones o Lipofuscin – “aging pigment” golden color
 Ex. Atherosclerosis  Edometrium (if ↑ estrogen = can lead to  Notes:
 Pathogenesis atypical hyperplasia – cancerous) o Senile atrophy – wear & tear pigments
o Time frame (from exposure to developed s/sx)  BPH (d/t ↑ adrogens)
o Sequence of events from the initial stimulus to the o Excess growth hormones 4. METAPLASIA
clinical manifestations of the disease  Keloid  Def: One differentiated cell type (epithelial or mesenchymal)
 Morphology  Papilloma virus is replaced by another cell type. Usually in response to
o How the disease produces changes in the cell  Hyperplasia can be malignant IRRITATION
o Alteration in the structures of the cells  Prone to cancerous transformation (same as hyperplasia)
 Clinical significance 2. HYPERTROPHY  TYPES:
o Refers to the clinical manifestations & prognosis of  Def: Increase un cell size d/t synthesis of structural o Columnar to Squamous
disease components  Bronchial epith.undergoes bronchial
 Occurs in dividing and non-dividing cells like HEART and squamous metaplasia in response to
CELLULAR RESPOSES TO STRESS & NOXIOUS STIMULI SKELETAL muscle cells tobacco smoking
 Cell is in a state of homeostasis  Causes of hypertrophy: o Squamous to Columnar
 Physiologic stresses & some pathologic stimuli will bring o Increased functional demand  AKA: adenocarcinoma
about cellular ADAPTATIONS such as:  PHYSIOLOGIC  striated muscles of wt.  Ex: Barrett’s Esophagus
o Hyperplasia – both physiologic & pathologic lifters  d/t reflux of gastric content
o Hypertrophy – both  PATHOLOGIC  cardiac muscle in ↑BP  a benign disease
o Atrophy – both o Increased endocrine stimulation  form of adaptation
o Metaplasia – always pathologic  Puberty (GH, androgens/testosterone) o Connective tissue metaplasia – formation of
 Depends upon NATURE & SEVERITY of injurious stimuli  Gravid uterus (d/t ↑ estrogen) cartilage, bone, or adipose tissue (mesenchymal
o I. Cellular adaptations  Lactating breast (prolactin & estrogen) tissues)
o II. Cell injury (reduced O2, chemical injury, microbial  Main downstream signaling of G-protein coupled receptor is  Ex: Myositis Ossificans
infection induced by GROWTH FACTOR & VASOACTIVE agents  Example of metaplasia
o III. Intracellular accumulations & calcifications  Normal ventricular thickness: o Columnar  squamous = endocervix
o IV. Cellular aging o Right – 0.3-0.5 o Squamous  columnar = esophagus
o Left – 1.3-1.5  Mechanism: Reprogramming of stem cells
 *Mechanisms o The reserve cells (or stem cells) of the irritated
 *Hypertrophy & Hyperplasia often occur together tissue  differentiate into a more protective cell
 type d/t the influence of growth factors, cytokines, CAUSES OF CELL INJURY  4. Fat necrosis
& matrix components  1. O2 deprivation  COAGULATIVE NECROSIS
 2. Physical agents o Denaturation of CHON = is the primary pattern
II. CELLULAR INJURY  3. Chem.agents & drugs o Basic cellular outline is preserved for a span
 Stages of cell injury  4. Nutritional imbalance (anorexia nervosa) o *most common form of necrosis
o Acute & self-limited  acute reversible injury o Characterized by hypoxic death of cells on ALL
o Progressive & severe  irreversible injury  cell (2) MORPHOLOGIC PATTERNS OF REVERSIBLE CELL INJURY tissues EXCEPT the BRAIN (occurs in liquefaction
death necrosis & apoptosis  1. Cellular swelling - *1st manifestation necrosis)
o Mild chronic injury  subcellular alterations in o Incapable to maintain ionic & fluid homeostasis o Microscopic: (-) nucleus but preserved of cell shape
various organelles o Loss of function of plasma membrane o Common: heart, liver & kidney
 REVERSIBLE cell injury – functional & morphological changes  2. Fatty change  LIQUEFACTION NECROSIS
that are reversible o Ex. Liver cirrhosis o Hypoxic death of cells w/in the CNS
 IRREVERSIBLE cell injury – “point of no return” o There is vacuoles o Digestion of the dead cells
o End result is the transformation of the tissue into
 NOTE: Any of the reversible changes can become irreversible
when taken to the extreme ULTRASTRUCTURAL CHANGES of REVERSIBLE CELL INJURY liquid viscous mass (pus) = *complete dissolution
 1. Plasma membrane alterations o *gangrenous necrosis (dead tissue)
o Blebbing, blunting, & distortion of microvilli  Is the combination of coagulation + liq.
HALLMARKS OF REVERSIBLE INJURY
o Creation of myelin figures  Common sites:
 1. Reduced oxidative ATP phosphorylation
o Loosening of intercellular attachments  Lower limbs Testes
 2. ATP depletion
 2. Mitochondrial changes  Gallbladder GI tract
 3. Cellular swelling
o Swelling  Dry gangrene: pattern is coagulative n.
o Rarefaction  Wet gangrene: patter is liquefactive n.
(2) MORPHOLOGIC PATTERNS OF CELL DEATH
o Appearance of small phospholipid rich amorphous o Cellular destruction by hydrolytic enzyme
 NECROSIS
densities o d/t: autolysis + heterolysis
o Pathogenesis: when damage to membranes is
 3. Dilatation of ER o Common: Abscess, Brain infarcts, pancreatic nec.
severe, lysosomal enzymes enter the cytoplasm &
o With detachment & disaggregation of polysomes  CASEOUS/CASEATION NECROSIS
digest the cell, & cellular contents leaks out.
 4. Nuclear alterations o Form of coagulative necrosis
 APOPTOSIS
o With disaggregation of granular & fibrillar elements o Foci of tuberculosis
o Nuclear dissolution w/o complete loss of membrane
 Usually appears in the apex of the lungs*?
integrity
NECROSIS o Gross: soft, friable, & “cottage-cheese-like”
 NOTES
 Result of denaturation of intracellular proteins & enzymatic appearance
o Necrosis – always a pathologic process
digestion of lethally injured cells o (2) types of GIANT CELLS (histiocytes)
o Apoptosis – serves many normal function & is not
 Follow cell death  Langhans – nucleus are peripherally
necessarily associated w/ cell injury
 d/t: Degradative action of enzymes arranged
 MORPHOLOGIC APPEARANCE  Foreign type – nucleus are haphazardly
FEATURES OF NECROSIS & APOPTOSIS
o 1. ↑ eosinophilia arranged
Feature NECROSIS APOPTOSIS
o 2. Glassy homogeneous appearance  FAT NECROSIS
Cell size Enlarged Reduced o Caused by the action of activated pancreatic
Nucleus Karyopyknosis, rrhexis, Karyorrhexis – or o 3. Moth-eaten cytoplasm
o 4. Calcification & replacement by myelin figures LIPASES (w/c liquefy cell membranes)
lysis fragmentation o TGs –lipases FA + Ca++ = forming saponified fats
Plasma Disrupted Intact o 5. Nuclear changes
 Karyolysis – nuclear fading/disolution o Gross: “chalky-white appearance”
membrane o Micro: foci of shadowy outlines of necrotic fat cells
Cellular Enzymatic digestion Intact  Karyorrhexis – nuclear fragmentation
 Pyknosis – degeneration/shringkage of + basophilic Ca++ deposits
contents  FIBRINOID NECROSIS
nuclear chromatin
Inflammation Frequent No o Additional type
o 6. Morphologic patterns
Physio/Patho Pathologic Physiologic o Common in vascular wall
 1. Coagulative necrosis
role o Histologically resembles fibrin
 2. Liquefaction
 3. Caseous 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 <5% - 10% of normal lev.
 1. Dec. activity of Na pump (ouabain-
sensitive Na+, K+-ATPase - causing
swelling)
 2. Altered cellular energy metabolism
 3. Failure of Ca++ pump
 4. Structural disruption of CHON synthetic
apparatus
 5. CHON may become misfolded 
“unfolded protein response”
o ↓ Na+ K+ ATPase pump
 Causes: Na+ influx ; K+ efflux
 Further causing:
 Cellular swelling
 Endoplasmic reticulum swelling
 Loss of microvilli
 Membrane blebs
 2. Mitochondrial Damage (all types)
o Dec. oxidative phosphorylation causing formation of
mitochondrial permeability transition (MPT)
channels.
o Thus, there is release of CYTOCHROME C.
 Cytochrome C = trigger for APOPTOSIS
o Mitochondria can be damaged by: *
 ↑ cytosolic Ca++
 Reactive oxygen specie
 Oxygen deprivation
o (2) major consequences of mitochondrial damage
 Formation of high conductance channel
called mitochondrial permeability
transition pore (MPT)
 Cyclophilin D – one of the
structural components of the
mitochondrial permeability
transition pore
 Capable of activating apoptotic pathways
(such as cytochrome C)
 3. Influx of Ca++ and loss of Ca++ homeostasis
2+
o Increased intracellular Ca causes cell injury by
several mechanisms.
 Opening of the mitochondrial
permeability transition pore, w/c leads in
failure for ATP generation
 Activates a number of enzymes:
 phospholipases (cause membrane
damage),
 proteases (break down both
membrane and cytoskeletal
proteins),
 endonucleases (responsible for DNA
and chromatin fragmentation), and
 ATPases (hastening ATP depletion).
 Induction of apoptosis by:
 activation of caspases
 increasing mitochondrial
permeability
 4. Accumulation of O2 derived free radicals (oxidative stress)
o Cell injury induced by free radicals, particularly
reactive oxygen species (chemical and radiation
injury, ischemia-reperfusion injury, cellular aging,
and microbial killing by phagocytes)
o Reactive oxygen species (ROS) are a type of oxygen-
derived free radical.
 are produced normally in cells during
mitochondrial respiration and energy
generation
 excess of these free radicals, leading to a
condition called oxidative stress
(Alzheimer)
 are also produced in large amounts by
leukocytes, particularly neutrophils and
macrophages
o Mechanisms to reduce free radicals
 Antioxidants (A,C,E)
 Binding proteins (transferrin, ferritin,
lactoferrin, and ceruloplasmin)
 Some enzymes
 Catalase
 Superoxide dismutase
 Glutathione peroxidase
o Pathologic effects of free radicals
 Lipid peroxidation in membranes
 Oxidative modification of proteins
 Lesions in DNA
 Free radicals are capable of
causing single- and double-
strand breaks in DNA, cross-
linking of DNA strands, and
formation of adducts
 5. Defects in membrane permeability
o membrane damage is a consistent feature of most
forms of cell injury (except apoptosis)
Mechanisms of Membrane Damage
o In ischemic cells membrane defects may be the
result of ATP depletion and calcium-mediated
activation of phospholipases.
o The plasma membrane can also be damaged
directly by various bacterial toxins, viral proteins,
lytic complement components, and a variety of
physical and chemical agents.
o Several biochemical mechanisms may contribute to
membrane damage:
 Reactive oxygen species
 Decreased phospholipid synthesis
 Increased phospholipid breakdown
 Cytoskeletal abnormalities
Mechanisms of Cell Injury (SUMMARY)
 ATP depletion: failure of energy-dependent functions →
reversible injury → necrosis
 Mitochondrial damage: ATP depletion → failure of energy-
dependent cellular functions → ultimately, necrosis; under
some conditions, leakage of proteins that cause apoptosis
 Influx of calcium: activation of enzymes that damage cellular
components and may also trigger apoptosis
 Accumulation of reactive oxygen species: covalent
modification of cellular proteins, lipids, nucleic acids
 Increased permeability of cellular membranes: may affect
plasma membrane, lysosomal membranes, mitochondrial
membranes; typically culminates in necrosis
 Accumulation of damaged DNA and misfolded proteins:
triggers apoptosis
End of part 1