CELLULAR ADAPTAPTATIONS,

CELL INJURY, AND CELL DEATH

MOESTIKANINGSIH
DEPARTMENT OF PATHOLOGY
MEDICAL FACULTY UNUD
 INTRODUCTION

PATHOLOGY
Pathos : suffering
Logos : study
The study of suffering.
A discipline that bridges clinical practice
and basic science
PATHOLOGY

- STUDY OF THE STRUCTURAL AND FUNCTIONAL

CHANGES IN CELL, TISSUE ,AND ORGAN,THAT
UNDERLINE DISEASE

- BY THE USE OF MOLECULAR,

MICROBIOLOGIC, IMMUNOLOGIC AND MORPHOLOGIC
TECHNIQUES
TO EXPLAIN THE WHYS AND WHEREFORES OF SIGN
AND SYMTOMS
RATIONAL CLINICAL CARE AND THERAPY
4 ASPECTS OF A DISEASE PROCESS
THE CORE OF PATHOLOGY

1. ETIOLOGY
2. PATHOGENESIS
3. MORPHOLOGIC CHANGES
4. FUNCTIONAL DEARANGEMENT AND
CLINICAL MANIFESTATION
RUDOLF VIRCHOW
A FATHER OF MODERN PATHOLOGY
( 19TH CENTURY)

ALL FORM OF ORGAN INJURY START

WITH MOLECULAR MECHANISM AND
STRUCTURAL CHANGES IN CELL.
OVERVIEW OF CELL INJURY
CELLS ARE ACTIVE PARTICIPANTS IN
THEIR ENVIRONMENT
CONSTANTLY ADJUSTING STRUCTURE
AND FUNCTION
TO ACCOMODATE CHANGING
DEMANDS AND EXTRACELLULAR
STRESSES
TO HANDLE NORMAL PHYSIOLOGIC
DEMANDS HOMEOSTASIS
 CELLS IN TISSUE

CELL CELL MATRIX

INTERACTION

NORMAL HOMEOSTASIS
 CELLULAR ADAPTATIONS
1. HYPERPLASIA
- PHYSIOLOGIC H.
- PATHOLOGIC H.
2. HYPERTROPY
- PHYSIOLOGIC
- PATHOLOGIC
MECHANISM OF HYPERTROPHY.(Fig.1-4)
3. ATROPHY
MECHANISM OF ATROPHY
4. METAPLASIA
MECHANISM OF METAPLASIA
 HYPERPLASIA
INCREASE IN NUMBER OF CELLS (ORGAN/TISSUE)
PHYSIOLOGIC HYPERPLASIA
1. HORMONAL HYP.
INCREASES FUNCTIONAL CAPACITY WHEN
NEEDED
(FEMALE BREAST AT PUBERTY ,PREGNANT
UTERUS)
2.COMPENSATORY HYP.
INCREASES TISSUE MASS AFTER
DAMAGE,OR PARTIAL RESECTION
(REGENERATION OF LIVER,AFTER
NEPHRECTOMY)
 MECHANISMS OF HYPERPLASIA.
LOCAL PROD.OF GROWTH F GROWTH
F.RECEPTOR ACTIVATION INTRACELLULAR
SIGNALLING PATHWAY TRANSCRIPTION F.
TURN ON MANY CELLULAR GENES ( GENES
ENCODING G.F.,RECEPTOR FOR G.F.
AND CELLS CYCLE REGULATORS
CELLULER PROLIFERATION.

HORMON ACT AS G.F & TRIGGER TRANSCRIP.F

HYPERPLASIA
PROLIFERATION, FROM REMAIN CELLS/STEM CELLS
 PATHOLOGIC HYP.

-E/ :-EXCESSIVE HORMONAL STIMULATION/

GROWTH F.ACTING ON TARGET
FOR EX.:1.ENDOMETRIAL HYP.(ESTROGEN)
2.BPH (ANDROGEN)
3.WOUND HEALING
(PROLIF. FIBROBLAST & BLOOD V.)
4.VIRAL INFECT.(PAPILLOMA V.)
 HYPERTROPHY
INCREASE IN THE SIZE OF CELLS
INCREASE IN THE SIZE OF THE ORGAN
- Due to synthesis of more structural components, not swelling.

HYPERTROPHY : - PHYSIOLOGIC
- PATHOLOGIC
CAUSED BY :
- INCREASED FUNCTION DEMAND
- SPECIFIC HORMONAL STIMULATION
FOR EXAMPLE : INCREASED WORK LOAD
(-bulging muscles of bodybuilders)
(-chronic hemodynamic over load hypertensive heart)
MECHANISMS OF HYPERTROPHY

- Is based on studies of the heart

- Signal Transduction pathway induction of a number
of genes synthesis a number of numerous cellular
protein (Fig.1-4)

- Genes are induced:

* encoding transcription factors(c-fos,c-jun)
* growth factor(TGF-beta,insulin-like growth factor.1[IGF-
1],fibroblast growth factor)
* vasoactive agents( alfa adrenergic agonists,endothelin-
1,and angiotensin II ).
 ATROPHY
SHRINGKAGE IN THE SIZE OF THE CELL BY LOSS OF CELL
SUBSTANCE

ATROPHY : 1. PHYSIOLOGIC A.
2. PATHOLOGIC A.
AD.1. - During early development (notochord, thyreoglossal duct)
- Uterus post partum
AD.2. Depends on underlying cause
- Disused atrophy
- Denervation atrophy
- Diminished blood supply
- Inadequate nutrition
- Aging (senile atrophy)
- Pressure
MECHANISMS ATROPHY

- Biochemical mechanisms,are incompletely understood

- Are likely to affect the balance ,protein synthesis and degradation

- Lysosme:acid hydrolases(e.g.cathepsins) & enzymes degrade

endocytosed prot.
- Ubiquitin-proteosome pathway degrade many cytosolic & nuclear
proteins degrade within proteosome

- Hormon( glucocorticoids and thyroid horm.) stimulate

proteosome-mediated protein degradation
- Cytokines (TNF) increasing muscle proteolysis
- For.examp.: lipofuscin granules (residual bodies) brown atrophy
 METAPLASIA
REVERSIBLE CHANGE
ONE ADULT CELL TYPE (EPITHELIAL /
MESENCHYMAL) ANOTHER ADULT CELL
TYPE
For Example :
1. Columnar Squamous
2. Squamous Columnar
3. Connective tissue metaplasia
( Cartilage; bone,
myositis ossificans after bone fracture)
MECHANISMS OF METAPLASIA

- Defferentiation of stem cells

- Cytokines,growth factors ,and extracellular matrix components in

environment signal tissue specific & defferentiation genes
For examp.: bone morphogenetic protein(TGF-beta superfamily)
induced chondrogenic/osteogenic expression in stem cell

- Vit A def/excess retinoid acid cell growth,deff. and tissue

patterning (Differentiation pathway of stem cells)
- Cytostatic disruption of DNA methylation pattern transform
mesenchymal cells
fibroblast muscle,cartilage.
 CELL INJURY AND CELL DEATH
REVERSIBLE CELL INJURY
IRREVERSIBLE INJURY AND CELL DEATH
- NECROSIS : 1. Coagulative N.
2. Liquefactive N.
3. Caseous N.
4. Fat N.
- APOPTOSIS
 CAUSES OF CELL INJURY
1. OXYGEN DEPRIVATION
- HYPOXIA
2. PHYSICAL AGENTS
3. CHEMICAL AGENTS AND DRUGS
4. INFECTIOUS AGENTS
5. IMMUNOLOGIC REACTIONS
6. GENETIC DERANGEMENT
7. NUTRITIONAL IMBALANCES
MECHANISMS OF CELL INJURY
COMPLEX.
DEPLETION OF ATP
MITOCHONDRIAL DAMAGE
INFLUX OF INTRACELLULAR CALCIUM AND
LOSS OF CALCIUM HOMEOSTASIS
ACCUMULATION OF OXYGEN-DERIVED
FREE RADICALS (OXIDATIVE STRESS)
DEFECTS IN MEMBRANE PERMEABILITY
 FREE RADICAL-INDUCED CELL
INJURY
- INDUCED BY:
1. ACTIVATED OXYGEN SPECIES (IMPORTANT MECH.)
2. CHEMICAL, RADIATION INJURY, TOXICITY FROM O2 AND
OTHER GASES, CELULAR AGING, MICROBIAL KILLING BY
PHAGOCYTIC CELLS, TUMOR DESTRUCTION BY
MACROPHAGES, AND SO ON (FIG.1-3)

- FREE RADICALS ARE CHEMICAL SPECIES, A SINGLE

UNPAIRED ELECTRON IN AN OUTER ORBITAL, READILY
REACT WITH INORGANIC / ORGANIC CHEMICALS

- INITIATE AUTOCATALYTIC REACTION

FREE RADICALS MAY BE GENERATED
WITHIN CELLS BY :

1. REDOX REACTIONS (PHYSIOLOGIC

REACTION) FIG.1-14
2. ABSORPTION OF RADIANT ENERGY (UV,
X-RAYS)
3. ENZYMATIC METABOLISM OF
EXOGENOUS CHEMICALS (CCL4 CCL3)
4. NITRIC OXIDE (NO), IMPORTANT
CHEMICAL MEDIATOR.
 THREE REACTION CELL
INJURY BY FREE RADICALS
1. LIPID PEROXIDATION OF MEMBRANES
2. DNA FRAGMENTATION
3. CROSS-LINKING OF PROTEINS
FREE RADICALS SULFHYDRYL-
MEDIATED PROTEIN CROSS-LINGKING
DEGRAD./ENZYMATIC ACTIVITY (-),
FREE RADICALS DIRECTLY CAUSE
POLYPEPTIDE FRAGMENTATION
 NEUTRALIZATION OF FREE
RADICALS
1. SPONTANEOUSLY
2. BY MECHANISMS OF:
SUPEROXIDE DISMUTASES (SOD)
GLUTATHIONE(GSH) PEROXIDASE
CATALASE
ENDOGENOUS / EXOGENOUS ANTIOXIDANTS
(VITAMINS E,A,C,BETA CAROTEN)
TRANSFERRIN ,FERRITIN AND
CERULOPLASMIN
 ISCHEMIA-REPERFUSION
INJURY
- CLINICALLY IMPORTANT
* MYOCARDIAL INFARCTION,STROKE
- MECHANISMS:
1. RESTORATION OF BLOOD FLOW CALCIUM
2. DURING REOXIGENATION INCREASED
GENERATION OF FREE RADICALS
3. ROS. PROMOTE THE MITOCHONDRIA
CELL DEATH
4. ISCHEMIC INJURY INFLAMMATION PROD.OF
CYTOKINES INFLAMM. CELLS ROS.
5. COMPLEMENT PATHWAY IMMUNE INJURY
 CHEMICAL INJURY
MECHANISMS
1. ACT DIRECTLY
- MERCURIC CHLORIDE POISONING
MERCURY BINDS TO
SULFHYDRYL GROUPS OF CELL MEMBRANE AND
OTHER PROTEIN
* INCREASED MEMBRANE PERMEABILITY
* INHIBITION OF ATP ASE DEPENDENT TRANSPORT
2. CONVERTED TO REACTIVE TOXIC METABOLITES ACT ON
TARGET CELLS
* CCL4 P-450 OXIDASES CCL3 IN SMOOTH E.R. OF LIVER
AND OTHER ORGAN REACTIVE FREE RADICALS
LIPID PEROXIDATION ,AUTOCATALYTIC REACTION,R.E. AND
RIBOSOME DISSOSIATION , PROTEIN SYNTHESIS ,LIPID
ACCUMULATION ,FATTY LIVER,PROGRESSIVE SWELLING,
MEMBRANE DAMAGE CELL DEATH
 APOPTOSIS
* IS A PATHWAY OF CELL DEATH,
INDUCED BY A TIGHTLY REGULATED PROGRAM
ACTIVATE ENZYMES DEGRADE
NUCLEAR DNA, NUCLEAR & CYTOPLASMIC
PROTEIN

* THE CELLS PLASMA MEMBRANE REMAINS INTACT

* APOPTOTIC CELLS PHAGOCYTOSIS

CAUSES OF APOPTOSIS

* PHYSIOLOGIC CONDITIONS
-THE PROGRAMMED DESTRUCTION OF CELLS
DURING EMBRYOGENESIS
-HORMON DEPENDENT INVOLUTION IN ADULT
-DEATH OF HOST CELLS
-ELIMINATION OF POTENTIALLY HARMFULL SELF-
REACTIVE LYMPHOCYTES
-CELL DEATH INDUCED BY CYTOTOXIC T CELLS

* PATHOLOGIC CONDITIONS
*PATHOLOGIC CONDITIONS

-CELL DEATH PRODUCED BY A VARIETY OF

INJURIOUS STIMULI
-CELL INJURY IN CERTAIN VIRAL DISEASES.
-PATHOLOGIC ATROPHY IN PARENCHYMAL
ORGANS AFTER DUCT OBSTRUCTION.
-CELL DEATH IN TUMOORS
-INCRASED MITHOCHONDRIAL PERMIABILTY
TRIGGER APOPTOSIS
MORPHOLOGIC FEATURES

- CELL SHRINKAGE
- CHROMATIN CONDENSATION
- FORMATION OF CYTOPLASMIC
BLEBS AND APOPTOTIC BODIES
- PHAGOCYTOSIS OF APOPTOTIC
CELLS OR CELL BODIES, USUALLY BY
MACROPHAGES
BIOCHEMICAL FEATURES OF APOPTOSIS

1. PROTEIN CLEAVAGE
- ACTIVATION OF CYSTEINE PROTEASES
CLEAVE MANY VITAL CELLULAR PROTEIN,
LAMINS BREAK UP THE NUCLEAR
SCAFFOLD & CYTOSKELETON (ACTIVE
DNASES).
2. DNA BREAKDOWN
3. PHAGOCYTIC RECOGNITION
MECHANISMS OF APOPTOSIS

1. THE EXTRINSIC (DEATH RECEPTOR-

INITIATED) PATHWAY
2. THE INTRINSIC (MITOCHONDRIAL)
PATHWAY
3. THE EXECUTION PHASE
4. REMOVAL OF DEATH CELLS
SUBCELLULER RESPONSES TO
INJURY
1. LYSOSOMAL CATABOLISM
- HETEROPHAGY
(ENDOCYTOSIS, PHAGOCYTOSIS, PINOCYTOSIS)
FOR EXC. : BACTERIA NEUTROPHILS, NECROTIC
CELLS MACROPHAGES
UNDIGESTED DEBRIS RESIDUAL BODIES (PIGMEN
LIPOFUCIN, TATTOOS)
- AUTOPHAGY
2. INDUCTION (HYPERTROPHY) OF SMOOTH ENDOPLASMIC
RETICULUM
3. MITOCHONDRIAL ALTERATIONS
4. CYTOSKELETAL ABNORMALITIES
- THIN FILAMENTS
- MICROTUBULES
- INTERMEDIATE FILAMENTS
5. INTRACELLULER ACCUMULATIONS
 INTRACELLULER
ACCUMULATIONS
1.LIPIDS
- STEATOSIS (FATTY CHANGES)
- CHOLESTEROL AND CHOLESTEROL ESTERS
2.PROTEINS
- PINOCYTOSIS IN THE PROXIMAL TUBULE
(REVERSIBLE)
- RUSSELL BODIES
- DEFECTS IN PROTEIN FOLDING(FIG.1-39)
3.HYALIN CHANGE
INTRACELLULAR (HYALIN DROPLETS, RUSSEL BODIES,
MALLORY BODIES)
EXTRACELLULAR
4.GLYCOGEN
5.PIGMENTS
 PATHOLOGIC CALCIFICATION

1.DYSTROPHIC CALCIFICATION
-CALCIFICATION IN AREAS OF
NECROSIS (COAGULATIVE,
CASEOUS, LIQUEFACTIVE TYPE, IN
ENZYMATIC NECROSIS OF FAT

2.METASTATIC CALCIFICATION
- IN NORMAL TISSUE, HIPERCALCEMIA
(+)
CAUSES OF HIPERCLACEMIA
1.INCREASED SECRETION OF
PARATHYROID HORMON
2.DESTRUCTION OF BONE TISSUE
(MULTIPLE MYOLOMA, LEUKEMIA,
DIFFUSE SKELETAL METASTASIS)
3.VITAMIN D RELATED DISORDERS
4.RENAL FAILURE
 CELLULAR AGING
PROGRESIVE LOSS OF FUNCTION
CAPACITY
THE RESULT OF PROGRESIVE DECLINE IN
PROLIFERATIVE CAPACITY IN LIFE SPANS
OF CELLS AND THE EFFECTS OF
CONTINUOUS EXPOSURE TO EXOGENOUS
INFLUENCES THAT RESULT IN THE
PROGRESSIVE ACCUMULATION OF
CELLULAR AND MOLECULAR DAMAGE
(Fig.1-43)
July 2005