CELL PATHOLOGY AND AGEING

CELLULAR RESPONSE
Stimuli
1. Altered Physiologic Stimuli CELLUR ADAPTATION
OR Eg : I) Atrophy
Non-Lethal Stimuli ii) Hypertrophy
iii) Hyperplasia
iv) Metaplasia
2. Lethal Stimuli - Transient : Reversible cell injury
Lethal Stimuli - Persistent : Irreversible injury
â
Cell death
â
N ECROSIS
MORPHOLOGICAL CHANGES APOPTOSIS
N ECROPTOSIS
PYROPTOSIS
3. Chronic Injury Stimuli : Intracellular accumulation
Eg : Fats, Glycogen, Proteins
ð Calcification

4. Sublethal Stimuli Persistent : Induce cellular ageing

CELLULAR ADAPTATIONS

- Stimuli Cell Change in their Number, Size, Phenotype, functions

- Removal Comeback to N State

: CELLULAR ADAPTATIONS ARE REVERSIBLE
- These are both Physiologic & Pathologic
ò ò
Pregnant Uterus Barrett's Esophagus

HYPER TROPHY

- Definition : Size of cell ñ but Number of cell Same

- Mechanism : ñ In synthesis of cellular protein
- Is also both : Physiological & Pathological
ò ò
Eg : Pregnant uterus Eg : Cardiac Enlargement
(both hypertrophy d/t Valvular defect
& hyperplasia

HYPERPLASIA

- def : No of cell Increased But size of cell remains same

- Mechanism : I) ñ Growth Factor : Most important mechanism
Cell
N
ñ Nu Transcription Factor
ñ Cell proliferation
ii) ñ Tissue stem cells
ò
ñ no of cells
Both Physiologic & Pathological
ò ò
s Pregnant uterus ñ Estrogen on the endometrium
s Pregnant Breast ò
s Compensatory Hyperplasia Endometrial Hyperplasia
Liver Regeneration
After Liver Resection
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 Dr. Devesh Mishra’s Pathology Notes

ATROPHY

- def : Size & no. of cell are decreased

- Mechanisms : i) ò Protein synthesis
ii) Ubiquitin Proteasome iii) Autophagy
Degradation pathway ò ò
Self Eating

INTRACELLULAR PROTEIN
DEGRADATION PATHWAY
Ubiquitin - Ligase Activation
ò
Ubiquitin
+
Target Protein
ò These are taken into

Activate proteasome Double membrane bound

(organelle) Autophagosome
ò (Contain Ubi +Tar. Pro)
degradation of ò
Ubiquitin + Tar. protein Combine with Lysosome
ò ò
ATROPHY Degradation of Protein
- Both Physiologic & Pathological
ò ò
during fetal development Denervation atrophy
ò Muscle
loss of notochord & Muscle
Thyroglossal duct Nerve Atrophy
Supply Trauma

- Endometrial Adenocarcinoma a/w BOTH HYPER PLASIA & ATROPHY

ò a/w ò a/w
Type 1 Endometrial Type-2 Endo
Adenocarcinoma Adenocarcinoma
ò ò
Good Prognosis Poor prognosis
ò
Both are precancerous lesion

M ETAPLASIA

- def : 1 mature cell replaced by another type of mature cell

- Mechanism : CYTOKIN E/GF
ò
- Alteration of tissue-stem cell Reprogramming
- Both Physiologic & Pathologic
ò
In cervix (during / menustruation)
Squamous metaplasia EPITH ELIAL CONN ECTIVE TISSUE
at squamo colournhar junction MESENCHYMAL METAPLASIA
Eg : Myositis ossificans
Trauma Muscle Injury

Bone within Muscle

s MCType : s BARRETT'SEOSOPHAGUS
- MCC : Gastro esophageal Reflux
ò
Disease (GERD)
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 Dr. Devesh Mishra’s Pathology Notes

Smoking Muscle in
GERD o on ofi o Vacules
stress
stress Tissuecell
Tissuestem stem cell OOOGERB Moon Goblet cell
ppm Reprograming
Reprogramming 000 Squamous cell Coloumnar
Columnar CELL Squamous
Squomous cell cell 2 cell

Squamous Metaplasia of Resp. Tract Colourmnar Metaplasia

(MC Type of Metaplasia)
# d/t Vitamin A Deficiency
Vitamin A excess
# Risk of Barret’s Esophages :
# Metaplasia Dysplasia
d/t to the presence of Goblet Cell
aka INTESTINAL M ETAPLASIA
(Hall mark of barret’s Esophage.)
Stain for GOBLET CELL :
Alcial Blue Stain : pH-2.5
for intestinal Goblet : pH - alkaline
Adenocorcinoma of Esophagus
Carcinoma

Exception : Apocrine metaplasia of breast tissue have no risk of malignancy

CELL INJURY

- MCC of cell injury : ISCHAEMIA

ò
HYPOXIA OXI DATIVE STRESS
on mitochondria
ò
# Free radicals production
FREE RADICALS aka = Oxidants

= Reactive oxygen species (ROS)

- FR are normally produced d/t incomplete oxidation within mitochondria
- Def : Any chemical species with unpaired e- outer orbit
- Mechanism of action : by oxidative damage
Damage of
i) Cell membrane
ii) Cytoplasmic Proteins organelle
iii) Nu. membrane
iv) Nu. chromatin
DNA damage
FREE RADICAL (Oxidant) Anti Oxidant

i) OH : MOST REACTIVE i) Vitamins A/C / E

ii) H2O2 ii) Proteins : Transferrin Ceruloplasmin
iii) 02 iii) Enzymes : Catalase Glutathione
iv) ONOO SOD (Superoxide dismutase)
# 1. Catalase PEROXISOMAL
2. Glutathione : MOST POTENT ANTIOXI DANT ENXYM ES
3. SOD
Responsible for Brain protection from FR damage
Multation inSOD gene : Amyotrophic Lateral Sclerosis
(Motor neuron disease)
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 Dr. Devesh Mishra’s Pathology Notes

*** HYPOXIA
N EURONS : Survival time
3-4 Min
Most - Susceptible CARDIAC : 20-40Min
( ~ 30Min)
FIBROBLAST : Hrs to days
Types of cell injury

Transient Stimuli Persistent Stimuli

Reversible injury Irreversible Injury

REVERSIBLE INJURY

Ischaemia ( O2)

Oxidative phosphorylation in mitochondria

ATP production
( 5 lot ofNormal)
5
N 1. First sign : Cell Swelling
Injury
Nats Except for Apoptosis
in Nat
ATP H2O
KT 7 Kt First sign : Cell Shrinkage
2. Vacuolar Degeneration / HydropicDegeneration
d/t intracellular water accumulation
Aka Cloudy Swelling
Eg : Acute Tubular necrosis of kidney
3. Organelle changes : EM Examination
0
omg
O y
i
OJO i
i
L 1h20

Ribosomes Er Swelling
ii) Ribosomal Detachment
iii) Mitochondria

Absence of Cristal
Absence
Cristal
Cristal Mito chondrial swelling
Cell inj Puca
cellinj
Yoo o Small amorphous
N Densities

2+ 2+
# M. Important Factor for cell injury : Ca (Cytosolic Ca )
iv)
Na+/H2O PLtcazt
Na 41420
Ca2+ WHORL LIKE
Ca c cast WHORL
v MYELIN-FIGURES
Mild9 AM Made up of PL+Ca2+
I seen in both reversble & irreversible
Reversible Irreversible
ò injury (MC)
cytosolic Ca2+ (Mild ñ)
ò +
Phospholipase
ò
PL (on cell membrane)
# Nucleus - Damage
Eosino philic (Pink/red)
Bascophilic
of granulomy / fibrillany chromatin

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 Dr. Devesh Mishra’s Pathology Notes

In Reversible injury
1. Dis aggregation of granular/fibrillary Nu. chromatin

REVERSIBLE INJURY
- Because of Persistent lethal stimuli
ò
ñ Cytosolic Ca2+
ò + / Activates
ò
Phospholipase Proteases Endo nuclease
ò ò ò
Cell membrane damage damage of cytoskeleton protein Nu - damage
ò ò ò
i) Myelin figures (max) Loss of cell architecture DNA chromatin)
ii) EM : Large, flocculent, amorphous I) Pyknosis SEQUENTIAL
densities in mitochondria ii) Karyo-rrherix DAMAGE
iii) Karyo - lysis
I) PYKNOSIS : Clumping / Condensation
of chromotin
+
Shrinkage of Nucleus
ii) Karyo rrhexis : Nuclearfragmentation

Fragmented Nuclei
E
iii) Karyo lysis : Chromatin Lysis dissolution
Decreased basophilia
Thrown out

Irreversible Injury - Cell death

ò
Morphological Changes

Necrosis Apoptosis Necroptosis Pyroptosis

N ECROSIS
- 2 Patterns of Necrosis
i. COAGULATIVE N ECROSIS ii. LIQUEFACTIVE N ECROSIS
ð Mc pattern of necrosis ð d/t ñ Lysosomal permeability
ð Denaturation of Protein ò
ò Enzymes leak out
Tissue architecture : Preserved ò
Eg : Ischaemic infarction of solid to Enzymes leak out
organs Eg : Heart (Mc) ò
Kidney Enzymatic damage of cell
Liver (HYDROLYTIC DAMAGE)
ð Tissue architecture Lost
# EXCEPT IN BRAIN : Eg : i) Ischaemic infarction of Brain
Ischaemic infarction Brain
: there is no stromal support
of absence of collagen also
brain is rich in Liquefactive
enzymes
ii) Infections
SPECIAL TYPES
1. GANGREN E
- MC site l : LOWER LI MB
a Dry gangrene b Wetgangrene

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 Dr. Devesh Mishra’s Pathology Notes

* Tissue architecture is presevered * Bacterial Contamination

: Eg of Coagulative necrosis Toxin Enzyme release
* Type of Lique factive necrosis

2 CASEOUS N ECROSIS
- It's called like this : of cheesy appearance Gross

Yellowish-White debris
- Seen in TB : Cheesy d/t presence of MYCOLIC ACI D
- On microscopic examination : Coagulative Liquefactive Necrosis
&
Amorphous Granular Pink structure
Considered as Variant of coagulative Necrosis

3 FAT N ECROSIS
It may be due to
a) Enzymes b) Trauma
Acute pancreatitis Eg Breast inj
ò
Lipase released
ò
Act on Lipids
ò
Release FA
Combine with Ca2+
Called Saponification
: GROSS : Chalky white appearance
appearance
M/E MIE : Eccentric
2EccentricNu Nu
Normal AAnucleated M
I 08 Fat
Fat cell Fat cell (GHOST CELL)
Pink Cytop
Ba Ba
Amorphous Basophilic deposits
S/O Calcium deposits

80
d

5 FIBRINOLD N ECROSIS
- Presence of Fibrin + Immune Complex [Ag + Ab]
- Pathology : Vessel Wall Damage
ò
Coagulation Pathway Fibrin Formation

- Seen in i. Vasculitis : Polyarteritis Nodosa

Blood
ii. Malignant HTN
- M/E

- Blood vessel
vessel
L

Pink, amorphous homogenous

Pink
ò
FIBRINOI D N ECROSIS

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 Dr. Devesh Mishra’s Pathology Notes

N ECROSIS APOPTOSIS
* ñ Lysosomal permeability * d/t ñ Mitochondrial Permeability
ò ò permeability
Enzymes
k Intact Cell membrane intact
ò No Leacking
Cell Membrane damage ò
ò NO INFLAM MATION
IC Content leak outside & Acts
as chemoattractant
ò
INFLAM MATION
* Alwaysp Pthological * Apoptosis Both physiological &
Pathological
pathological

APOPTOSIS
- Falling - off the cells from the tissue (literal meaning)
- Programmed cell death Is seen in I. Apoptosis
II. Necroptosis
III. Pyroptosis
IV. Neutrophilic Extra Cellular Trap (N ET)
- Energy depend. process >> Programmed Cell Death
(active process)
- Apoptosis is PHYSIOLOGICAL (MC) PATHOLOGICAL
ò ò
Eg : 1. Organogenesis /Embryogenesis Eg 1. Chemotherapy or Radio
2. Neo Vascularisation therapy (Apoptosis + Necrosis)
3. Killing of inflammatory cells 2 Glucorticoid induce
after completing their function apoptosis ( Prevent autoimmune)
4. Elimination of auto-reactive 3. Graft V/s Host disease
cell (To prevent Auto immunity 4 Councilman bodies in
Viral Hepatitis : There are
Apoptic bodies
5. Misfolding of Protein
- MORPHOLOGY : a. Cell Shrinkage
b. MOST CHARACH ERISTIC FEATURE : Chromatin Condensation
c. 2nd MOST : Cell Membrane intact
d. NO INFLAM MATION
INFLAMMATION
e. e Hyper Eosinophilic Cytoplasm (Not Specific)
By By chromatin Condensation
chromatin condensation
f. N cell 7 Phosphatidyl - Serine Receptor
Apo Induction (Lipid Receptor)
EAT-M E SIGNAL
EAT
Flipped Receptors
ANNE
ANN EXIN -V: MARKER OF
APOPTOSIS
g. “Bleb”
g b
Detach
J aetach
Mitochondria
Mitochondria
Apoptotic Bodies
Membrane bound structure
with organelle they may &
may not have nuclear
h Eg
remenents
remenents
re Eg : Councilman Bodies
J ups
Scanger R END OUTCOM E
= Phagocytosis
Phago cytic Cell

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 Dr. Devesh Mishra’s Pathology Notes

- BIO CH EMISTRY : Pro Caspase (Pro-C)

ò Activation
Caspase Endo Nuclease Activation
t
Chromatin Condensation
Function : Nu DNA Damage As specific Fragments
INTER NUCLEOSOMAL DNA DAMAGE
Size of fragments : 180-200 Base pairs
Can be Observed Agarose Gel Electrophoresis

Stepladderseen in
Apoptosis Charachteristic
Seen in
ii Necrosis
Necrosis

M ECHANISM OF APOPTOSIS
in
in unnummmm rumrunner
i 2events y
V y
INITIATION EXECUTIONAL
Pathways 7
t
C , 6,3 Activation
v Ga 3
k
INTRINSIC iPATHWAY EXTRINSIC PATHWAY Endonuclease
t t t
C9 C 8 (In lowerAnimal) Chromatin condensation
C10 (In Humans) (= Apoptosis)
INTRINSIC PATHWAY
Aka Mitochondrial Pathway PROTO ONCOGENE
as mitochondria is the
v
M. Important Organelle a PROAPOPTOTIC b ANTI APOPTIC
Endonuclease
It’s a Major Pathway BAX Bch 2
C BAK BCL XL
BCLXs MCL 1
STRESS/INJ. ISTI MULI
STIMULI BHzonly proteins family Apoptosis
concell surface
BH3proteins STRESSSENSORS
501 v v
BAX MaBCL v
Ma Cyt
BAkq.dz Bim PUMA
i y
mmietaf.it
ufyr
SMANDIABLO CYTOSOLIC
o
I CytC
Bad
Bid
NOXA

lap 0 t
Cinhibitorotapo
Apaf I
khmHTpoptosome 5M InhibitsIAP
2 µzo
Theyare
They areproapoptic
v v
pro C9 C9

EXTRINSIC PATHWAY
Aka Death Receptor mediated pathway

i) TNF - Receptor : MOST WELL- DEFIN ED

CD CD
ii) FAS / CDD5
Death R Death
+ D-Ligand (Eg : TNFR + TNF2)

WELL AdapterProtein
C 8/10
pro C8 10
TNFRTTNFL
Press in * N Cell
FLIP Viruses (HIV)
Anti aptotis - apoptotic in Ext. Patyway
# FLIP : Anti-apoptotic protein present in : Normal cell
: Virus (HIV)
- Apoptosis at extrinsic pathway by inhibiting the formation of C8/10

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 Dr. Devesh Mishra’s Pathology Notes

# Hallmark of Apoptosis Activation : Caspase Activation

Hallmark of neuronal apoptosis activation : AIF (Apoptosis Inducing Factor)

No caspaces
Clinicopathological Co-relation
ð Misfolding of proteins ññ Mis folded protein Feature of neurological disorders
I. Alzheimer ds
Caspase II. Parkinsons ds
ò III. Hunligton ds
Apoptosis

N ECROPTOSIS
- Programmed Cell Death Without Caspase Activation
- Necrosis + Apoptosis
ò
- Morphology Programmed Cell death
Mechanism :
TNFR + TNF
ò Recruits
RIP-1 + RIP-3 (Receptor Interacting Protein)

without caspase
Mitochondrial Stress C-8
ò ò
FR Production Apoptosis (Extrinsic
I) Cell Swelling
II) CM damage MORPHOLOGY OF NECROSIS
III) Inflammation = N ECROPTOSIS
Considered as variants of Necrosis
N ECROPTOSIS is both Physiologic & Pathological
ò ò
Eg : Mammalian Bone I) Neurological disorder
growth plate formation II) Pancreatitis

PYROPTOSIS
- Pyrogen induced Apoptosis

IL-1
- Variant of necrosis
Mechanism : Bacterial Ag (Eg : Flagellin)
Flagellin
t

proc 11 C11 Ag
K Nod like R NLR
i
ii t t
damage INFLAMMOSOME
x
proc I CI
1L-1,yIL-
I. Cell Swelling
II. Cm Damage
III Inflammation

Chronic Injurious Stimuli

Leads to
Intracellular accumulations

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 Dr. Devesh Mishra’s Pathology Notes

I, N substances ii. Abnormal substances iii. Calcification

Coal / Silica
Lipid (Mc) Pigments
Glycogen I. Lipofuschin
Proteins II. Hemosiderin
III. Melanin
LIPI D : Mc intracellular accumulation
Aka STEATOSIS (ñLipid deposit in cell)
It can be Triglycerides (TG) : MC Lipid Accumulation
Cholesterol
C Esteraces Alcoholic / INAFLD/Hepatitis/viral
Phospholipid

Clear Vacoules : SPECIAL STAIN Best stain in frozen / Crosection

fl
i. Vacoules
Oil-Red-O-stain : Lipid will be Red
ii. Sudan Black-B : Lipid will be black
µ

BE
GLYCOGEN : SPECIAL STAIN
i. PAS +ve GLYCOGEN IN RED COLOUR
ii. Best’s carmine Stain

PROTEINS : ñ Protein Synthesis

ò
Mis folding of proteins
ò
Response : UPR (Unfolding Pr. Response)

Stress on ER Autoplay Caspases

ò (Programmed cell death) ò
Synthesis of chaperons ñ prt. Misf IC Apoptosis
(Req. for proper folding Protein Degradation
of proteins) Ubiquitin + Protein (Target)
ò
Taken in to Autophagosome &
combine with Lycosome
ò
Degradation of proteins
# Failure of Unfolding Protein Response
ò
Misfolding Protein Disorder
# Autophagy / Ubiquitin Proteasome Degradation Pathway
is a/w i. Atrophy
ii. Inflamation (TB)
Atgs - 5 gene controls : N Phagocyle function of macrophage
ò
Deletion
ò
ñTB
iii. Concers (Dsyregulated)

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 Dr. Devesh Mishra’s Pathology Notes

IV. Mitochondrial Inheritance

PIGM ENT ACCUMULATION

N. Pigment Abnormal Pigment

i. Lipo fuschin i. Lipofuschin
ii. Hemosiderin ii. Hemosiderin
iii. Melanin iii. Melanin
PIGM ENTS

BROWN BLACK

LIPOFUSCHIN H EMOSIDERIN Melanin * In : Skin (Normal

* Oil-Red-O * PEARL’S PRUSSIAN : Melanoma)
* Sudan Black B Blue Stain * Special Stain : Fontana Masson
LIPO FUSCHIN : Aka Ageing Pigments
FR Damage CM Brown Perinuclear pigment

Made up of Phospholipid + Proteins (Dominants)

Seen in : * Cancer Cachexia
* Severe Malnutrition
* Ageing
It’s aka TELL- TALE SIGN OF FR-INJURY aka WEAR & TEAR Pigment

CALCIFICATION
Seen in ñalkaline pH of tissue
Starts in mitochondria
except for Kidney

Starts in Basement Memb.

Pathological Calcification

DYSTROPHIC M ETASTATIC
*Tissue - Damage * Normal tissue
* Ca2+Level : Normal * High Ca2+
Eg : I. TB Lymph Node * MCC
o
II. Rheumatic Heart Disease 1 HYPER PARATHYROI DISN
Volve Damage ò
III. Mancke berg Medial Calcific Sclerosis MCC : Parathyoird Adenoma
IV. Psammoma Bodle * Other Causes
Seen in : Menhgoma I. Rena Failure ‘(2 Hyper Para.
Mestholioma II.) Excessive Vit A&D Synthesis
Repillary RCC Thyroid * MC Site : Lung (Alveoli)
Gastric Mucosa Systemic Artery
Least common : Parathyroid
# M/E : Basophilic Amorphous Material (H&E)
Confirmation
MC & BEST : I) Von-Kassa Stain : Black
II) Alizanh - Red : Red Colour

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 Dr. Devesh Mishra’s Pathology Notes

AGEING
1. Progressive accumulation of sublethal inj. stimuli
ò
FR production : Most Widely Accepted Hypothess
ò
Ageing
2. Increased collagen deposition or Increase cross-linking of collagen
ò
Ageing
Most effective method to prolong life spon : Colorie - Restriction
I.) ò FR Injury Induction
II) ñ Proper pr. Folding SIRUTUIN
III) ò Apoptosis Induce
IV) ñInsulin Sensitivity ðñ Glucose Metatolism M.O.A
V) ò Overall Metabolism
Small Amount
of Red- Wine

Changes in ageing : I. Cell Damage

II. Mito Chondrial Damage
III. Glucose Metabolism
IV. DNA Damage
V. Telomere Shorting
TELOM ERE : Short stretches of DNA @ the end of chromesome
Function : I. Ensure complete replication of chromosome
II. Prevent fusion & degradation of chromosome
Progressive cell division
ò
Telomere shorteing
ò
Fusion / degradation of Choromosome
ò
Ageing
WERN ER SYN DROM E v/s WERM ER SYN DROM E
* Pre mature ageing * M EN-I Endorine
d/t Defect in DNA Helicase disorder
ò
Required for repair & Replication
Defective

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