Cellular Injury, Cell adaptation & Cell death 3.

ATROPHY
I. CELLULAR ADAPTATIONS:
 Def: Shrinkage in size/number of cells. Decrease cellular
Pathology components. Decrease size of organ. Reduce metabolic
1. HYPERPLASIA
 Study of structural & functional changes in cells, tissues, & activity.
 Def: Increase in the number of cells
organs
 Some cell types are unable to exhibit hyperplasia (nerve,  Causes of Atrophy
 Uses molecular, microbiologic, immunologic & morphologic o Disuse
cardiac, skeletal muscle cells)
techniques o Denervation atrophy
 Is mediated by:
 Foundation for rational clinical care & therapy o Diminished blood supply
o Growth factors, cytokines
 Types of pathology: o Inadequate nutrition
o Growth promoting genes – proto-oncogenes
o GENERAL – reactions of cells to abnormal stimuli o Loss of endocrine stimulation (opposite of
o Increased DNA synthesis & cell division
o SYSTEMIC – reactions of organs/ tissues to stimuli/ hypertrophy)
 PHYSIOLOGIC hyperplasia
diseases o Aging
o Hormonal
 Breast development at puberty/preg. o Pressure
4 ASPECTS OF DISEASE PROCESS (form the core of pathology)
 Uterus development at pregnancy  Mechanisms of Atrophy
 Etiology or cause o Ubiquitin-proteosome degradation of the cytoskeleton
 Proliferation of endometrium
o Can be: o Autophagy of cellular components
o Compensatory
 Genetic (ex. Trisomy 21) o Decreased protein synthesis
 After hepatectomy
 Acquired (ex. HIV) o Apoptosis (decrease in number)
 PATHOLOGIC
 Multifactorial (both genetic & acquired)  Microscopic characteristics: small shrunken cells with
o Excess hormones
 Ex. Atherosclerosis LIPOFUSCIN granules
 Endometrium (if ↑ estrogen = can lead
 Pathogenesis o Lipofuscin – “aging pigment” golden color
to atypical hyperplasia – cancerous)
o Time frame (from exposure to developed s/sx)
 BPH (d/t ↑ androgens)
o Sequence of events from the initial stimulus to the 4. METAPLASIA
o Excess growth hormones
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 in cell size d/t synthesis of structural o Columnar to Squamous
disease
components  Bronchial epithelium (pseudostrati.)
 Occurs in dividing and non-dividing cells like HEART and undergoes bronchial squamous
CELLULAR RESPOSES TO STRESS & NOXIOUS STIMULI SKELETAL muscle cells (cardiac hypertrophy) metaplasia in response to tobacco
 Cell is in a state of homeostasis  Causes of hypertrophy: smoking
 Physiologic stresses & some pathologic stimuli will bring o Increased functional demand o Squamous to Columnar
about cellular ADAPTATIONS such as:  PHYSIOLOGIC  striated muscles of  AKA: adenocarcinoma
o Hyperplasia – both physiologic & pathologic wt. lifters  Ex: Barrett’s Esophagus
o Hypertrophy – both  PATHOLOGIC  cardiac muscle in ↑BP  d/t reflux of gastric content
o Atrophy – both o Increased endocrine stimulation  a benign disease
o Metaplasia – always pathologic  Puberty (GH, androgens/testosterone)  form of adaptation
 Depends upon NATURE & SEVERITY of injurious stimuli  Gravid uterus (d/t ↑ estrogen) o Connective tissue metaplasia – formation of
o I. Cellular adaptations  Lactating breast (prolactin & estrogen) cartilage, bone, or adipose tissue (mesenchymal
o II. Cell injury (reduced O2, chemical injury, microbial  Main downstream signaling of G-protein coupled receptor is tissues)
infection) induced by GROWTH FACTOR & VASOACTIVE agents  Ex: Myositis Ossificans (muscle to bone)
o III. Intracellular accumulations & calcifications  Normal ventricular thickness:  Example of metaplasia
o IV. Cellular aging o Right – 0.3-0.5 o Columnar  squamous = endocervix/brochi
o Left – 1.3-1.5 o Squamous  columnar = esophagus
 *Mechanisms  Mechanism: Reprogramming of stem cells
 *Hypertrophy & Hyperplasia often occur together 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 CAUSES OF CELL INJURY  4. Fat necrosis
 Stages of cell injury  1. O2 deprivation  COAGULATIVE NECROSIS
o Acute & self-limited  acute reversible injury  2. Physical agents o Denaturation of CHON = is the primary pattern, so no
o Progressive & severe  irreversible injury   3. Chemical agents & drugs proteolysis even though necrosis has occurred.
cell death (necrosis & apoptosis)  4. Nutritional imbalance (anorexia nervosa) o Basic cellular outline is preserved for a span
o Mild chronic injury  subcellular alterations o *most common form of necrosis
in various organelles (2) MORPHOLOGIC PATTERNS OF REVERSIBLE CELL INJURY o Characterized by hypoxic death of cells on ALL
 REVERSIBLE cell injury – functional & morphological changes  1. Cellular swelling - *1st manifestation tissues EXCEPT the BRAIN (occurs in liquefaction
that are reversible o Incapable to maintain ionic & fluid homeostasis necrosis)
 IRREVERSIBLE cell injury – “point of no return” o Loss of function of plasma membrane o Microscopic: (-) nucleus but preserved of cell shape
 NOTE: Any of the reversible changes can become irreversible  2. Fatty change o Common: heart, liver & kidney
when taken to the extreme o Ex. Liver cirrhosis  LIQUEFACTION NECROSIS
o There are vacuoles o Hypoxic death of cells w/in the CNS
HALLMARKS OF REVERSIBLE INJURY o Digestion of the dead cells
 1. Reduced oxidative ATP phosphorylation ULTRASTRUCTURAL CHANGES of REVERSIBLE CELL INJURY o End result is the transformation of the tissue into
 2. ATP depletion  1. Plasma membrane alterations liquid viscous mass (pus) = *complete dissolution
 3. Cellular swelling vs PM damage in irreversible o Blebbing, blunting, & distortion of microvilli o *gangrenous necrosis (dead tissue)
o Creation of myelin figures (aggregation of  Is the combination of coagulation + liq.
(2) MORPHOLOGIC PATTERNS OF CELL DEATH peroxidized lipids  Common sites:
 NECROSIS o Loosening of intercellular attachments  Lower limbs Testes
o Pathogenesis: when damage to membranes is  2. Mitochondrial changes  Gallbladder GI tract
severe, lysosomal enzymes enter the cytoplasm & o Swelling  Dry gangrene: pattern is coagulative n.
digest the cell, & cellular contents (troponin) o Appearance of small phospholipid rich amorphous  Wet gangrene: patter is liquefactive n.
leaks out. densities o Cellular destruction by hydrolytic enzymes
 APOPTOSIS  3. Dilatation of ER o d/t: autolysis + heterolysis
o Nuclear dissolution w/o complete loss of membrane o With detachment & disaggregation of polysomes o Common: Abscess, Brain infarcts, pancreatic nec.
integrity --> reduced protein synthesis  CASEOUS/CASEATION NECROSIS
 NOTES  4. Nuclear alterations o Combination of coagulative and liquefactive necrosis
o Necrosis – always a pathologic process o Chromatin clumping o Foci of tuberculosis
o Apoptosis – serves many normal function & is not  Usually appears in the apex of the lungs*?
necessarily associated w/ cell injury NECROSIS o Gross: soft, friable, & “cottage-cheese-like”
 Result of denaturation of intracellular proteins & enzymatic appearance (yellow-white)
FEATURES OF NECROSIS & APOPTOSIS digestion of lethally injured cells  FAT NECROSIS
Feature NECROSIS APOPTOSIS  Cell death o Caused by trauma to breast or the action of
Cell size Enlarged Reduced  d/t: Degradative action of enzymes activated pancreatic LIPASES (w/c release
Pyknosis → fatty acids)
Nucleus Karyorrhexis – or  MORPHOLOGIC APPEARANCE in injured cells
karyorrhexis → fragmentation o TGs –lipases FA + Ca2+ = forming saponified fats
o 1. ↑ eosinophilia (stained red by the dye eosin)
karyolysis o Gross: “chalky-white appearance” due to calcium
o 2. Glassy homogeneous appearance
Plasma Disrupted Intact o 3. Moth-eaten cytoplasm o Micro: foci of shadowy outlines of necrotic fat cells
membrane + basophilic Ca++ deposits
o 4. Calcification & replacement by myelin figures
Cellular Enzymatic digestion Intact o 5. Nuclear changes  FIBRINOID NECROSIS
contents o Necrotic damage to blood vessel wall
 Karyolysis – nuclear fading/dissolution
Inflammation Frequent No o Leaking of proteins (including fibrin) into vessel wall
 Karyorrhexis – nuclear fragmentation
Physio/Patho Pathologic Both  Pyknosis – degeneration/shrinkage of results in bright pink staining of the wall
role nuclear chromatin microscopically
o 6. Morphologic patterns o Characteristic of malignant hypertension and vasculitis
 1. Coagulative necrosis
 2. Liquefaction
 3. Caseous
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 species
 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  Oxidative modification of proteins
transition pore  Lesions in DNA
 Capable of activating apoptotic pathways  Free radicals are capable of
(such as cytochrome C) causing single- and double-
 3. Influx of Ca++ and loss of Ca++ homeostasis strand breaks in DNA, cross-
o Increased intracellular Ca2+ causes cell injury by linking of DNA strands, and
several mechanisms. formation of adducts
 Opening of the mitochondrial  Membrane damage
permeability transition pore, w/c leads in  5. Defects in membrane permeability
failure for ATP generation o membrane damage is a consistent feature of most
 Activates a number of enzymes: forms of cell injury (except apoptosis)
 phospholipases (cause Mechanisms of Membrane Damage
membrane damage), o In ischemic cells membrane defects may be the
 proteases (break down both result of ATP depletion and calcium-mediated
membrane and cytoskeletal activation of phospholipases.
proteins),
o The plasma membrane can also be damaged
 endonucleases (responsible for
directly by various bacterial toxins, viral proteins,
DNA and chromatin fragmentation),
lytic complement components, and a variety of
and
 ATPases (hastening ATP depletion). physical and chemical agents.
o Several biochemical mechanisms may contribute to
 Induction of apoptosis by:
 activation of caspases (Ca2+) membrane damage:
 Reactive oxygen species
 increasing mitochondrial
permeability  Decreased phospholipid synthesis
 Increased phospholipid breakdown
 4. Accumulation of O2 derived free radicals (oxidative stress)
o Cell injury induced by free radicals, particularly  Cytoskeletal abnormalities
reactive oxygen species (chemical and radiation
injury, ischemia-reperfusion injury, cellular aging, Mechanisms of Cell Injury (SUMMARY)
 ATP depletion: failure of energy-dependent functions →
and microbial killing by phagocytes)
reversible injury → necrosis
o Reactive oxygen species (ROS) are a type of oxygen-
 Mitochondrial damage: ATP depletion → failure of energy-
derived free radical.
dependent cellular functions → ultimately, necrosis; under
 are produced normally in cells during
some conditions, leakage of proteins that cause apoptosis
mitochondrial respiration and energy
 Influx of calcium: activation of enzymes that damage cellular
generation
components and may also trigger apoptosis
 excess of these free radicals, leading to a
 Accumulation of reactive oxygen species: covalent
condition called oxidative stress
modification of cellular proteins, lipids, nucleic acids
(Alzheimer)
 Increased permeability of cellular membranes: may affect
 are also produced in large amounts by
plasma membrane, lysosomal membranes, mitochondrial
leukocytes, particularly neutrophils and
macrophages membranes; typically culminates in necrosis
o Mechanisms to reduce free radicals  Accumulation of damaged DNA and misfolded proteins:
 Antioxidants (A,C,E) triggers apoptosis
 Binding proteins (transferrin, ferritin,
lactoferrin, and ceruloplasmin)
 Some enzymes
 Catalase
 Superoxide dismutase
 Glutathione peroxidase
o Pathologic effects of free radicals
 Lipid peroxidation in membranes
 PYKNOSIS: Irreversible cell death characterized by
condensation of the nucleus and clumping of chromatin.
 KARYORRHEXIS: Irreversible cell death characterized by
fragmentation of the nucleus.
 KARYOLYSIS: Irreversible cell death characterized by lysing of
nucleus, due to action of DNAse and RNAse.