ADAPTATION, INJURY and DEATH of
CELLS
(Part 1)
Ashley Inman
Tom Davis
8-12-2014
Lecture 2 Learning Objectives
• 1. List examples of hypertrophy, hyperplasia,
atrophy, hypoplasia, metaplasia and dysplasia
• 2. List examples of reversible and irreversible
cell injury
• 3. Diagram abscess, granuloma, renal
infarction and fat necrosis
• 4. List consequences of ATP loss
• 5. List consequences Ca++ increase and
release
Pathology: the Study of Disease
• Etiology or cause: infection, genetic etc. and often
mutifactoral
• Pathogenesis: progression of the disease
• (Molecular and Morphologic Changes)
• Clinical Manifestations: signs and symptoms
Cellular Adaptations
•
•
•
•
•
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Dysplasia
HYPERTROPHY
• Increase in cell size with
subsequent increase in
organ size
Causes of Hypertrophy
1. Increased functional
demand
2. Hormonal stimulation
Hypertrophy of Uterus During Pregnancy
Hypertrophy of Uterus During Pregnancy
No new cells; Cells just bigger
• Hypertrophy can be
physiologic or pathologic
Cardiac Muscle Hypertrophy and Infarction
Results from increased production of cellular proteins
HYPERPLASIA
• Increase in the number of cells in an
organ which may then increase organ
size.
• Physiologic or Pathologic
PHYSIOLOGIC
HYPERPLASIA
1. Hormonal hyperplasiafemale breast at puberty and
in pregnancy
2. Compensatory hyperplasialiver regeneration after
partial resection
Female Breast Tissue after
Puberty
Lactating breast during pregnancy
Causes of Pathologic
Hyperplasia
1. Excess hormoneendometrial hyperplasia
due to estrogens
• Hyperplasia is NOT a neoplastic
process, but it may be fertlie
soil for malignancy
• “Atypical Hyperplasia” in the
endometrium carries an
increased risk for development
of endometrial
adenocarcinoma
Endometrial Hyperplasia
Normal Proliferative Endometrium
Endometrial Hyperplasia
Benign Prostatic Hypertrophy
ATROPHY
• Decrease in the size of a
cell or organ by loss of cell
substance (both size and
number)
Physiologic Atrophy
• Normal development
– Notochord
– Thyroglossal duct
• Uterus following childbirth
Causes of Pathologic Atrophy
1.
2.
3.
4.
5.
6.
Decreased workload
Loss of innervation
Decreased blood supply
Inadequate nutrition
Loss of endocrine stimulation
Pressure
*
*
**Central skeletal muscle bundle is atrophic
Atrophic Brain
Normal Brain
Atrophy results from both…
• Decreased protein synthesis
• Increased protein degradation
Protein degradation is
important in atrophy
A. Lysosomes with hydrolytic
enzymes
B. The ubiquitin-proteasome
pathway
HYPOPLASIA
• Incomplete development
of an organ so that it fails
to reach adult size
Examples of Hypoplasia
Hypoplastic Left Ventricle
Hypoplastic Kidney
METAPLASIA
• A reversible change in
which one ADULT cell type
is replaced by another
ADULT cell type
Metaplasia
• Caused by:
– Chronic irritation (cigarette smoke; calculi in ducts)
– Vitamin A deficiency
• Cervix- squamous epithelium of the endocervix replaces
columnar (dysplasia and squamous CA may develop)
• Barrett esophagus- gastric reflux results in columnar
epithelium replacing squamous epithelium in the esophagus
(dysplasia and adenocarcinoma may occur)
Squamous cells replace columnar cells
Esophagus: glandular epithelium (R) is metaplastic
Hyperplasia and Metaplasia are not
premalignant changes, however they are
“fertile fields” for Dysplasia which is a
premalignant change
DYSPLASIA
• Atypical proliferative
changes due to chronic
irritation or
inflammation;
• Premalignant change
DYSPLASIA IN THE CERVIX
Mild dysplasia
Moderate
dysplasia
Marked
dysplasia
CELL INJURY PRINCIPLES
1. The cellular response to injurious stimuli
depends on the type of injury, its duration
and its severity.
2. The consequences of cell injury depend on
the type, state, and adaptability of the
injured cell
3. Cell injury results from different
biochemical mechanisms acting on several
essential cellular components
1. The cellular response to injurious stimuli depends on the type of
injury, its duration and its severity.
Cellular Changes Secondary to
Injury
REVERSIBLE
• Cellular swelling
• Cell membrane blebs
• Detached ribosomes
• Chromatin clumping
IRREVERSIBLE
• Lysosomes rupture
• Dense bodies in
mitochondria
• Cell membrane
rupture
• Karyolysis,
karyorrhexis,
pyknosis
Myocardial Infarction Markers
• Cardiac specific enzymes and proteins appear
in serum within 2 hours post infarction
• Morphologic (light microscopic) changes in 412 hours
Normal Myocardium
Coagulation Necrosis
at 24-48 hours post MI
A.
Normal kidney
B.
Reversible changes
C. Dying Cell
Normal Kidney Histology
Normal Tubules
Tubules Accumulate Water (cloudy swelling)
2. The consequences of cell injury depend
on the type, state, and adaptability of the
injured cell
Cell Proliferation Varies
• Labile cells – continuously dividing
(epithelium, bone marrow)
• Stable cells – quiescent (in G0
stage; hepatocytes, smooth
muscle, lymphocytes)
• Permanent cells – nondividing
(neurons, skeletal and cardiac
muscle)
Susceptibility of Cells to
Ischemic Necrosis
High
Neurons (3-4 min)
Intermediate Myocardium, hepatocytes, renal
epithelium (30 min-2hr)
Low
Fibroblasts, epidermis, skeletal
muscle (many hours)
3. Cell injury results from different biochemical mechanisms acting
on several essential cellular components
Depletion of ATP
• Na+ pump fails Na+ and water enter and K+
is lost
• Glycolysis depletes glycogen and lowers pH
(loss of enzyme activity)
• Ca++ pump fails- Ca++ into cells (toxic)
• Decreased protein synthesis (ribosomes
detach)
• Unfolded protein response
Mitochondrial Damage
• 3 major consequences:
– Mitochondrial permeability transition (MPT) pore
opens  loss of mitochondrial membrane
potential  decreased oxidative phosphorylation
w/ decreased ATP
– Production of reactive oxygen species
– Leakage of pro-apoptotic proteins
Loss of Ca++ Homeostasis
• Extracellular Ca++ is 15X higher than
cytosolic Ca++
• Loss of ATP increases intracellular Ca++
• Increased Ca++ activates phospholipases,
proteases, endonucleases, and ATPases
• Increased Ca++ also increases
mitochondrial permeability triggering
apoptosis
Free Radical Formation
• Single unpaired electron; highly reactive
• Normal metabolism produces superoxide
anion, hydrogen peroxide and hydroxyl
ion; superoxide is produced in neutrophils
• Reactive oxygen species (ROS) are a type
of free radical
• Excess of ROS within cell leads to
oxidative stress
Pathologic Effects of ROS
• Lipid peroxidation leading to membrane
damage
• Protein damage
• DNA damage
Major Antioxidants
• Antioxidants block the formation of ROS or
inactivate them
• Antioxidant Enzymes: superoxide dismutase,
catalase, glutathione peroxidase
• Vitamins: A, E, ascorbic acid, glutathione
Membrane Permeability Defects
• Plasma membrane
• Mitochondrial membrane
• Lysosomal membrane- release of RNases,
DNases and proteases
CAUSES OF CELL INJURY
•
•
•
•
•
•
•
Oxygen deprivation
Physical agents
Chemical agents and drugs
Infectious agents
Immunologic reactions
Genetic derangements
Nutritional imbalances
Hypoxia and Ischemia
• Hypoxia- deficiency of oxygen; causes:
cardiorespiratory failure, anemia, CO
poisoning
• Ischemia- loss of blood supply (oxygen and
nutrients); more rapidly and severely injures
tissues than does hypoxia alone
NECROSIS vs APOPTOSIS
• Necrosis- death of GROUPS of cells after
injury; usually with inflammation
• Apoptosis- genetically controlled, ATP and
enzyme-dependent death of individual cells;
usually no inflammation
– More details in part 2
NECROSIS
• Morphologic changes in GROUPS of cells that
follow the death of living tissue; cells and
PMNs leak lytic enzymes
• CYTOPLASM: eosinophilia, vacuoles,
calcification, myelin figures
• NUCLEUS: pyknosis, karyorrhexis, karyolysis
Patterns of Necrosis
• Coagulative- hypoxic death (except brain)
• Liquefactive- bacterial infections; *also hypoxic
death in brain tissue (infarction)
• Caseous- tuberculosis
• Fat- enzymatic or traumatic damage to fatty
tissue; eg. Pancreatitis (enzymatic)
• Gangrenous- usually involves lower extremities
and often is a type of coagulative necrosis
• Fibrinoid- immune complexes in arteries
Coagulative Necrosis in Kidney
Brain Abscess with
Liquefactive Necrosis
Abscess/Liquefactive Necrosis
Caseous Necrosis of
Lung
Granulomatous Inflammation with Central Necrosis
Fat Necrosis
Fat Necrosis (L) and Normal Pancreas (R)
Gangrenous Necrosis
Fibrinoid Necrosis
Questions?