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Cell Injury

Mahmud Ghaznawie
Dept of Pathology
Hasanuddin University

Membran plasma

Nukleus

Aparatus golgi

Mitokondria

Lisosom & peroksisom

The rough endoplasmic reticulum

The smooth endoplasmic reticulum

Cytoskeleton

Actin filaments

Mikrotubules

Intermediate
filaments

Normal
cell

Adapted
cell

Injury
Reversibly
injured cell

Cell Injury
Stressed so severely, cant adapt further
Exposed to inherently damaging agents

Irreversibly
Injured cell

* Reversible or irreversible
* Outcome depends on
Type, duration and severity of injury
Type, state, and adaptability of cell

Cellular Adaptation to Stress


Hypertrophy
Hyperplasia
Atrophy
Metaplasia

Cellular Adaptation to Stress


Hypertrophy

Cellular Adaptation to Stress

Physiologic hyperplasia
1.
2.

Hormonal hyperplasia
Compensatory hyperplasia

Pathologic hyperplasia

Excessive hormon stimulation


Papilloma (virus)
Keloid
etc

Cellular Adaptation to Stress


Atrophy

Cellular Adaptation to Stress


Metaplasia

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 3 March 2006 10:56 PM)
2005 Elsevier

Agents of cell injury


1. Oxygen (too much or too little)
2. Physical agents (trauma, temp, pressure, electric shock)
-

3. Chemical agents (CN , Hg, O3, CO, EtOH, drugs, ROS)


4.
5.
6.
7.

Infectious agents (viruses, bacteria, fungi)


Immunologic reactions (anaphylaxis, autoimmune diseases)
Genetic defects (Sickle cell disease, Down synd, Tay-Sachs)
Dietary (vitamins def/xs, malnutrition, xs calories)

Mechanisms of cellular injury


ATP

depletion
Mitochondrial damage
Increased cytosolic Ca
Increased ROS production
Membrane damage

Mechanisms of cellular injury


ATP

depletion
ISCHEMIA

Mechanisms of cellular injury


MITOCHONDRIAL INJURY OR DYSFUNCTION

Mechanisms of cellular injury


Increase

of cytosolic Ca

Mechanisms of cellular injury


A. FREE RADICAL GENERATION

Increased

ROS production

B. CELL INJURY BY FREE RADICALSC. NEUTRALIZATION OF FREE RADICALS NO CELL INJURY

Mechanisms of cellular injury


Membrane

damage

Important targets of injury


Mitochondria (aerobic respiration; apoptotic

signals)
Membranes (cell and subcellular organelles)
Protein

synthesis machinery
Cytoskeleton
Genetic apparatus (DNA)

Agents of cell injury


Oxygen
1. Too much via ROS production
2. Too little via
Hypoxia
decreased O2 content of blood

Ischemia

inadequate blood flow (compromises


delivery of nutrients and removal of
wastes)
NB: ischemia worse than hypoxia

Reactive Oxygen Species (ROS)


Have

unpaired electron (most)


Very-to-Extremely reactive
Non-specific
Self propagating
Referred to as ROS, ROM, free radicals
Usually damaging (2 exceptions)

Major ROS
Superoxide
Hydrogen
Hydroxyl

(O2.-)

peroxide (H2O2)

radical (HO.)
Nitric oxide (NO.)

Sources of ROS
UV

light, ionixing radiation


Mitochondrial ETS
Enzymes (P450, XO, NADPH oxidase)
Reduced metals (Fe, Cu, etc)

NB: Fenton reaction

Effects/Targets of ROS
Membranes

(lipid peroxidation)
Proteins (via SH, TRP and TYR ox, etc)

Cross linking; fragmentation

DNA

damage

Strand breakage, T-T dimers

Cellular defenses against ROS


(Antioxidants)

Enzymatic

SOD, catalase, GPX

Non-enzymatic

Vitamins A, C, E
Glutathione (GSH)
Metal binding proteins (transferrin, ceruloplasmin, etc)
NB: lipid and water soluble species

Example of Cell Injury and


Necrosis
Ischemia-reperfusion

Myocardial infarct
Stroke

injury

Ischemia-reperfusion Injury
ATP
ADP
AMP

Ischemia

Adenosine
Inosine
Hypoxanthin
e

XDH

No Rx (no O2)

Ischemia-reperfusion injury
XDH (xanthine dehydrogenase)

Ca-activated protease

XO (xanthine oxidase)
(produces uric acid + superoxide)

Ischemia-reperfusion Injury
ATP
ADP
AMP
Adenosine
Inosine
Hypoxanthine

Reperfusion
XDH
Ca-activated protease
XO

Uric Acid + Superoxide

O2
Reperfusion

PMNs

Morphology of cell injury

Swelling (via increased water content)


Fatty change (steatosis, TG)
Necrosis (dead cells)
Intracellular deposits (lipid, CHO, protein)
Loss of cellular fine structure (microvilli)
Karyolysis (DNA degradation)
Pyknosis (nuclear shrinkage)
Karyorrhexis (nuclear fragmentation)

Morphology of cell injury

Reversible vs
irreversible cell injury
Reversible injury

Decreased ATP levels


Ion imbalance
Swelling
Decreased pH
Fatty change (liver)

Irreversible injury

Amorphous densities in
mitochondria
Severe membrane
damage
Lysosomal rupture
Extensive DNA damage

Subcellular response to injury


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

Lysosomes (heterophagy; autophagy)


Smooth ER (induction)
Mitochondria ( number, size and shape)
Cytoskeleton ( phagocytosis, locomotion)
Nucleus (karyolysis, karyorrhexis, pyknosis)
Membranes (cellular and subcellullar)

A. Electron micrograph of a normal epithelial cell of the proximal kidney tubule.


Note abundant microvilli (mv) lining the lumen (L).
B. Epithelial cell of the proximal tubule showing reversible ischemic changes.
The microvilli (mv) are lost and have been incorporated in apical cytoplasm;
blebs have formed and are extruded in the lumen (L). Mitochondria are
slightly dilated. (Compare with A.)

Irreversibly
Injured cell

Apoptosis
Dead cell
Necrosis

Chromatin condensation

Cytoplasmic blebs

Chromatin
fragmentation and
cytoplasmic budding

Enzymic digestion
and
leakage of cellular
contents

Phagocytosis of
apoptotic cells and
fragments

Necrosis

Apoptosis

Table 1-2. Features of Necrosis and Apoptosis

Feature

Necrosis

Apoptosis

Cell size

Enlarged

Reduced

Nucleus

Pyknosis/karyorrhexis/karyolysis

Fragmentation

Plasma membrane

Disrupted

Intact

Cellular contents

Enzymatic digestion

Intact

Inflammation

Frequent

Physiologic/pathologic

Pathologic

None
Physiologic

Apoptosis dibahas pada kuliah Prof. Irawan Yusuf

Necrosis
Coagulative
Liquefactive
Caseous
Fat
Gangrenous
Fibrinoid

Coagulative necrosis

Preservation of structure
Firm
Protein denaturation
Hypoxic tissue death
(except brain)

Liquefactive necrosis

Enzymatic digestion

Autolysis + WBC

Liquid, viscous mass

May contain pus

Bacterial infections (via


inflammation)

Hypoxic brain injury

A. Coagulative necrosis
loss of nuclei
clumping of cytoplasm, but
preservation of basic
outlines of glomerular and
tubular architecture

B. Liquefactive necrosis
filled with white cells and cellular
debris
creating a renal abscess that
obliterates the normal architecture

This abscess is an example of localized liquefactive necrosis

Caseous necrosis

Subset of coagulative necrosis


TB
Cheesy, white
Surrounded by inflammatory
cells (granulomatous reaction)
Complete destruction of tissue

Caseous necrosis is just a


combination of
coagulative and
liquefactive necrosis

Caseous necrosis
Confluent cheesy
tan granulomas in
the upper portion
of this lung in a
patient with
tuberculosis

Fat necrosis

Not a specific pattern


Focal areas of fat digestion
Usually via release of lipases from
pancreas
FFA combine with Calcium to produce
soaps
Appear grossly as the soft, chalky white
areas

Fibrinoid necrosis

Intracellular
Accumulations

Lipids (TG and Cholesterol)

Proteins

Pigments

Glycogen (genetic disease)

Normal liver

Fatty change (steatosis)

Mallory bodies

Mallory bodies (the red globular material) composed of


cytoskeletal filaments in liver cells chronically damaged from
alcoholism. These are a type of "intermediate" filament between
the size of actin (thin) and myosin (thick).

Cholesterolosis. Cholesterol-laden macrophages (foam cells) from


a focus of gallbladder cholesterolosis (arrow).

Protein reabsorption droplets in the renal tubular epithelium

Lipofuscin granules in a cardiac myocyte


A. Light microscopy (deposits indicated by arrows)
B. Electron microscopy (note the perinuclear, intralysosomal location)

Hemosiderin granules in liver cells


A. H&E section showing golden-brown, finely
granular pigment
B. Prussian blue reaction, specific for iron.

Calcification

Mahmud Ghaznawie