Cell injury/Cell Damage/Jejas sel

Patologi Klinik
Tim dosen
 DEFINITION
 Cell damage (also known as cell injury) is a variety
of changes of stress that a cell suffers due to
external as well as internal environmental
changes. Amongst other causes, this can be due to
physical, chemical, infectious, biological, nutritional
or immunological factors.
KONSEP DASAR
 ETIOLOGI

https://www.lecturio.com/concepts/cell-injury-and-death/
Etiologi injury
Respon sel
Stimulus stress---injury
 Peningkatan kebutuhan cell
 Hipoksia
 Iskemia
 Inflamasi (exp. Infection)
 Trophic stimulation (exp growth hormone)
 Decreased nutrient
Hypoxic cell
 Kondisi akibat :
 kekurangan oksigen
 Kekurangan hemoglobin
 Iskemia (https://www.youtube.com/watch?
v=7FR1TsKLoDI)
Sel normal vs adaptasi vs reversibel injury
vs sel mati
Adaptasi sel
 Injury terjadi jika mekanisme adaptif tidak mampu
menjaga homeostasis sel tetap normal.
 Jenis mekanisme adaptif sel:
 Perubahan UKURAN sel (hipertrofi)
 Perubahan JUMLAH sel (hiperplasia; atrofi)
 Perubahan DIFERENSIASI sel (metaplasia)
 Metaplasia??
ATROPI
Atrofi dan Atrofi dan
penurunan fungsi malnutrisi Atrofi dan iskhemi
Hypertrophy dan increase fungsional
demand
 PATOGENESIS

https://www.lecturio.com/concepts/cell-injury-and-death/
Mekanisme sel injury
Mekanisme sel injury (1)
Mitokondria
• Major site of synthesis of adenosine triphosphate or ATP 
• ATP: 
• Energy required in synthetic and degradative processes
• Sources:
• From oxidative phosphorylation of adenosine diphosphate 
• From the glycolytic pathway (anaerobic)
 Mitochondria are the cell’s suppliers of life-sustaining energy in
the form of ATP, but they are also critical players in cell injury and
death.
Mekanisme
 ATP depletion and decreased ATP synthesis are frequently
associated with both hypoxic and chemical (toxic) injury.
Mekanisme sel injury (2)
 Calcium homeostasis
• Intracellular calcium (Ca²⁺):
normally low (sequestered in the
mitochondria and ER)
• Common injurious stimuli: 
• Oxygen deprivation/ischemia
• Toxins 
 Influx of calcium and loss of
calcium homeostasis
>> The accumulation of Ca2+ in
mitochondria results in opening
of the mitochondrial permeability
transition pore and failure of ATP
generation.
Mekanisme sel injury (3)
 DNA damage
• Common injurious stimuli: Radiation, Chemotherapeutic drugs, ROS (Reactive Oxigen Species)
• May be part of aging 
 Consequences of damaged DNA
• Triggers p53 pathway: arrests cell cycle phase, activating repair mechanisms
• Apoptosis occurs:
• If repairs cannot correct the damage 
• To protect the tissue involved (cell dies rather than persists with an abnormal DNA, which has
potential for malignant transformation)
Mekanisme cell injury (4)
• Normal membrane: made of lipids, with phospholipids as the most abundant form
• Common injurious stimuli: 
• Bacterial infection (toxins)
• Viral proteins
• Complement-mediated lysis
• Physical/chemical agents 
• Ischemia
• Other mechanisms overlap and cause membrane damage:
• Oxygen free radicals → lipid peroxidation → phospholipid loss
• Mitochondrial damage → reduced ATP → decreased phospholipid synthesis
• Calcium-dependent phospholipases → phospholipid breakdown → loss of membrane
• Calcium-dependent proteases → cytoskeletal filament damage → increased cellular
swelling and rupture 
 Consequences of membrane damage
• ↑ Permeability of plasma membrane → influx of fluids and ions + loss of cell osmotic
balance
• Injury to lysosomal membranes → lysosomal enzymes disrupt cytoplasmic organelles
Mekanisme Injury Cell (5)
 Endoplasmic reticulum
• Site of protein synthesis and folding, lipid synthesis, and free calcium storage
• Chaperones: control protein folding 
• Misfolded proteins: usually processed for proteolysis
• Unfolded protein response: 
• Signal transduction pathways that sense misfolded proteins
• ↑ Chaperones, ↓ protein translation, and ↑ degradation of misfolded proteins
• Injurious stimuli: 
• Genetic abnormalities/mutations
• Ischemia/hypoxia 
• Viral infections
 Consequences of ER stress
• ER stress: Protein folding demand exceeds protein folding capacity.
• Unrepaired proteins accumulate → apoptosis
• Diseases and their associated misfolded proteins:
• Cystic fibrosis: cystic fibrosis transmembrane conductance regulator (CFTR)
• α1- antitrypsin deficiency: α1- antitrypsin
• Alzheimer’s disease: Aβ peptide
• Familial hypercholesterolemia: LDL receptor
• Creutzfeldt-Jacob disease: prion
 Free radicals
• Molecular species with single unpaired
electron in the outer orbit
• Highly reactive: attack adjacent molecules
(proteins, carbohydrates, nucleic acids)
• ROS: an oxygen-derived free radical
• Principal free radicals:
• Superoxide anion (O2–)
• Hydrogen peroxide (H₂O₂)
• Hydroxyl radical (•OH): most reactive ROS
• Peroxynitrite (ONOO⁻)
• Injurious stimuli:  •
• Ischemia-reperfusion injury
• Chemical and radiation injury
• Aging
• Phagocytosis of microbes
 Consequences of oxidative
stress
• Membrane damage by lipid
peroxidation:
• ROS attack unsaturated fatty
acids of the membrane.
• Lipid hydroperoxides are
produced → ↓ function of
membranes
DNA damage or fragmentation 
• Oxidative modification of
proteins: ↑ protein cross-linking
leads to ↑ degradation and ↓
activity
PROGNOSIS CELL INJURY
Tipe injury
Irreversibe
Reversibel
l

Bersifat
Nekrosis
non letal

Apoptosis
Faktor yang mempengaruhi injury sel

Agen:
>> nature of the Sel:
injury; its >> type; state,
duration; and its and adaptability
severity

Respon
sel
Irreversible injury :
Apoptosis
necrosis
Nekrosis vs apoptosis
Necrosis
 Necrosis : local death of cells while the individual is a life
followed by morphological changes in the surrounding
living tissue
 Cytoplasm change
 Nucleus change
 Tipe necrosis
 Coagulative necrosis (infarction of heart)
 Liquifactive necrosis (abscess)
 Caseous necrosis (TB)
 Fat necrosis (adipose tissue)
 Fibrinoid necrosis (rheumatoid)
 PROCESS OF NECROSIS

• Uncontrolled cell death after irreversible injury:

• Cell membrane is disrupted; lysosomal enzymes enter and
digest the cell.
• Cellular contents are released and circulate into the
extracellular space. 
• Circulating contents elicit an inflammatory reaction and
recruit leukocytes to the site of necrosis.
• Clinical correlation (tests for tissue-specific injury
represent circulating intracellular contents):
• Troponin: from damaged cardiac muscle cells
• Alkaline phosphatase: from bile duct epithelium
• Transaminases: from hepatocytes
 CELLULAR CHANGES

• Cytoplasmic changes: 
• Eosinophilic cytoplasm: due to denatured cytoplasmic proteins (which
bind to eosin dye) 
• Vacuolated cytoplasm: Enzymes digest organelles, leaving “moth-eaten”
appearance.
• Myelin figures: large whorled phospholipid precipitates (from the
damaged membrane), which are phagocytosed or degraded to fatty acids
• Nuclear changes (1 of 3 patterns):
• Karyolysis: reduced basophilia due to DNA loss (effect of DNAse)
• Pyknosis: nuclear shrinkage and increased basophilia (condensation of
chromatin into a dense basophilic mass)
• Karyorrhexis: fragmentation of the nucleus
Necrosis
 Patterns of Necrosis
Coagulative necrosis:myocardial and renal infarction
• Cell and tissue architecture maintained for several days
• Denatures enzymes, so initial proteolysis is blocked.
• leukocyte enzymes break down the dead cells.
• Often in ischemia or hypoxic injury
• Liquefactive necrosis:
• Tissue is digested and dissolved into a viscous liquid.
• Seen in bacterial and fungal infections, which stimulate
leukocytes and the release of hydrolytic enzymes
• Caseous necrosis/cheese like: tuberculosis and
some fungal infections
• Fragmented cells and debris surrounded by an
inflammatory border: granuloma
• Fat necrosis: acute pancreatitis, fat necrosis of the breast
• Change in adipose tissue due to trauma or enzymatic
release
• Release of pancreatic lipases into the pancreatic
parenchyma and the peritoneum → destruction of
adipocytes  digestion and phagocytosis
• Liberated fatty acids combine with calcium, producing
chalky-white areas (fat saponification).
Fibrinoid necrosis
• Microscopic change
• Deposition of immune complexes in the walls
of vessels
• Fibrinoid: fibrin combined with immune
complexes deposited in the vessel walls
(homogeneously pink in hematoxylin and
eosin stains)
Gangrenous necrosis
• Not a pattern of necrosis; a clinical description
used when a limb becomes necrotic due to
ischemia 
• Indicates coagulative necrosis of multiple
layers of tissue (dry gangrene)
• With superimposed bacterial infection,
liquefaction necrosis occurs due to enzymes
from bacteria and leukocytes (wet gangrene).
Dystrophic calcification:
• Necrotic cells: eliminated by enzymatic
• Inadequately reabsorbed necrotic cells become
a nidus of calcium and mineral deposition.
Apoptosis
*menjaga homeostasis*
programmed cell death

 Apoptosis is a actively regulated form of cell death.

 It has a role in biological processes, including
embryogenesis, normal homeostasis and aging.
 It is an important component of many diseases, including
cancer and immune-mediated processes.
 Programmed cell death (apoptosis)
• Activated enzymes degrade DNA and proteins in cells that
are destined to die
• Features:
• ↓ Cell size, eosinophilic cytoplasm
• Chromatin condensation (chromatin aggregates peripherally)
• Cytoplasmic blebs and apoptotic bodies
• Phagocytosis of apoptotic cells by macrophages
 Apoptosis in different conditions
Jenis apoptosis
Physiological apoptosis
 Destruction of cells during
embryonic development
 Balance between cell
death/proliferation in normal
tissues
 Regulation of cellular
populations in hormonally
sensitive tissues
• Involution of tissues with
hormone withdrawal:
• Endometrial shedding in
menstrual cycle
• Lactating breast regression
(weaning)
Pathological apoptosis
 Cell death after DNA damage
caused by radiation, cancer
treatment drugs
 Cell death caused by cytotoxic T
cells; death of B and T lymphocytes
 Removal of self-reactive lymphocytes
(may cause autoimmune disease)
 Cell death caused by many viruses
 Cell death in tumors, in growing
tumor but particularly during tumor
regression
 Cell death in reperfusion injury
 Ductal obstruction (e.g., kidney, parotid
gland): Atrophy occurs by apoptosis. 
Mekanisme Apoptosis
 Caspases: Cystein aspartic acid
proteases
 Exist in inactive form, requiring
enzymatic cleavage to be activated
 Active caspases: a marker for cells
undergoing apoptosis
 Phases of apoptosis:
 Initiation: activation of caspases
→ cascade of other caspases
 Intrinsic pathway
 Extrinsic pathway
 Execution: terminal caspases →
cellular fragmentation
 Mekanisme Apoptosis
 Intrinsic pathway (initiation):
 In viable cells, growth factors and survival signals
reduce mitochondrial leakage of cytochrome c by
producing anti-apoptotic proteins (principal
members): BCL2, BCL-XL, MCL-1
Extrinsic pathway (initiation):
• Death receptor-initiated pathway
• Plasma membrane death receptors initiate this pathway.
• Death receptors: 
• Members of tumor necrosis factor (TNF) family with

 In damaged cells, loss of survival signals, DNA a cytoplasmic death domain (delivers the apoptotic

damage, protein misfolding:  signals)
• Best known death receptors: 
 Allow cytochrome c leakage from the • Type 1 TNF receptor (TNFR1)
mitochondria by producing pro-apoptotic • Fas (CD95)
proteins (main members): BAX, BAK  • Events:
 Activate apoptosis initiators (BH3-only • FasL (Fas ligand on T cells and cytotoxic T
proteins): BAD, BIM, BID, Puma, Noxa lymphocytes) binds to Fas → a signal for apoptosis is
 Events: given to the cell.
• 3 or more Fas molecules combine to form the protein,
 Increased permeability of the mitochondrial Fas-associated death domain (FADD).
outer membrane → release of cytochrome c into • FADD binds pro-caspase-8.
the cytoplasm  • Caspase-8 (or caspase-10) is activated → stimulates
 Cytochrome c initiates apoptosis. executioner caspases 
 In the cytoplasm, cytochrome c binds with
apoptosis-activating factor-1 (APAF-1), forming
a structure, apoptosome.
 Apoptosome leads to self-cleavage and
activation of caspase-9, the initiator caspase.
 Activated caspase-9 → cascade of executioner
caspases 
Execution phase:
• Both pathways converge in the execution phase.
• Events:
• Starts with sequential activation of executioner caspases.
• Inhibitor of deoxyribonuclease (DNase) is cleaved → active DNase →
nuclear proteolysis and fragmentation
• Cytoskeleton proteins break down.
• Cell fragments → cytoplasmic blebs form → become apoptotic bodies
• Apoptotic bodies are eaten by phagocytes.
• Efferocytosis: 
• Apoptotic cell phagocytosis
• Rapid clearance with reduced production of pro-inflammatory cytokines
→ limited inflammatory reactions even with substantial apoptosis
Intracellular accumulation
Intracellular accumulations of a variety of materials
can occur in response to cellular injury
 Lipid
 Protein
 Hyaline changes
 Glycogen
 Pigment