This is a lecture note presented by our beloved lecturer at Bayero University Kano. I hope it might help my fellow bio-medical students.

1. CELL INJURY AND CELL DEATH

2. OUTLINES
INTRODUCTION
CAUSES OF CELL INJURY
MECHANISM
MORPHOLOGIG FEATURES
NECROSIS VS APOTOSIS

3. INTRODUCTION
Cells actively control the composition of their immediate
environment and intracellular milieu within a narrow range of
physiological parameters (“homeostasis”)
If the limits of adaptive response to a stimulus are exceeded, or in
certain instances when adaptation is not possible, a sequence of
events follows termed cellular injury
Cellular injury is reversible up to a certain point, but if the stimulus
persists or is severe enough from the beginning, the cell reaches a
point of no return & suffers irreversible cell injury and cell death

4. Causes of cell injury
Oxygen deprivation – hypoxia
Physical agents
Chemical agents & drugs
Infectious agents
Immunologic reactions
Genetic derangements
Nutritional imbalances

5. Mechanisms of Cell Injury: General Principles
Cell response to injury is not an all-or-nothing phenomenon
Response to a given stimulus depends on the type, status, and
genetic make-up of the injured cell
Cells are complex interconnected systems, and single local
injuries can result in multiple secondary and tertiary effects
Cell function is lost far before biochemical and subsequently
morphological manifestations of injury become detectable

6. General Biochemical Mechanisms
1. Loss of energy (ATP depletion, O2depletion)
2. Mitochondrial damage (“permeability transition”)
3. Loss of calcium homeostasis
4. Defects in plasma membrane permeability
5. Generation of reactive oxygen species (O2•, H2O2, OH•) and other free
radicals

7. Free Radicals
Free radicals are chemical species with a single unpaired electron in
an outer orbital
Free radicals are chemically unstable and therefore readily react with
other molecules, resulting in chemical damage
Free radicals initiate autocatalytic reactions; molecules that react
with free radicals are in turn converted to free radicals

8. Intracellular Sources of Free Radicals
Normal redoxreactions generate free radicals
 Nitric oxide (NO) can act as a free radical
 Ionizing radiation (UV, X-rays) can hydrolyze water into hydroxyl
(OH•) and hydrogen (H•) free radicals
 Metabolism of exogenous chemicals such as CCl4can generate free
radicals
 Free radical generation is a “physiological” antimicrobial reaction

9. Neutralization of Free Radicals
1 Spontaneous decay
2.Superoxidedismutase(SOD):
2O2•+ 2H →O2+ H2O2
3.Glutathione (GSH):
2OH•+ 2GSH →2H2O + GSSG
4.Catalase:
2H2O2→O2+ H2O
5.Endogenous and exogenous antioxidants (Vitamins E, A, C and β-carotene)

10. Free Radical-Induced Injury
If not adequately neutralized, free radicals can damage cells by three
basic mechanisms:
1.Lipid peroxidation of membranes:double bonds in polyunsaturated
membrane lipids are vulnerable to attack by oxygen free radicals
2.DNA fragmentation:Free radicals react with thymine in nuclear and
mitochondrial DNA to produce single strand breaks
3.Protein cross-linking:Free radicals promote sulfhydryl-mediated
protein cross-linking, resulting in increased degradation or loss of
activity

11. Chemical Injury
Direct damage such as binding of mercuric chloride to
sulfhydrylgroups of proteins
Generation of toxic metabolites such as conversion of CCl4 to
CCl3•free radicals in the SER of the liver

12. Morphologic features of Reversible cell injury
• Cell swelling
• Formation of blebs on the cell membranes
• Aggregation of intra membranous particles
• E R swelling
• Mitochondrial swelling
• Dispersion of ribosomes
• Formation of small densities
• Clumping of nuclei chromatin

13. Morphologic features of Irreversible cell injury
• Rupture of lysosomes and autolysis
• Formation of myelin figures
• Lysis of E R
• Defects in cell membranes
• Formation of large densities
• Mitochondrial swelling
• Nuclei pyknosis, karyolysis or karyorrhexis

14. NECROSIS VS APOPTOSIS
Two morphologic features of cell death exist.
Necrosis– Pathological
Apoptosis– Both physiologic and pathologic

15. NECROSIS
• Necrosis refers to a spectrum of morphologic changes that follow cell
death in living tissue,
• Largely resulting from the progressive degradative action of enzymes
on the locally injured cell.
• It’s the result of 2 essentially concurrent processes:
• (1) Enzymatic digestion of the cell
• (2) Denaturation of proteins.

16. Morphology Of Necrosis:
i. Increased eosinophilia - ↓RNA, ↑eosin binding
ii. Glassy homogenous appearance due to loss of glycogen
iii. Vacuolated appearance
iv. Finally calcification-basophilic granules, dystrophic calcification
(lithopaedion)

17. Nuclear Changes
• break down of DNA-3 patterns of changes
• a. Karyolysis –fading out of basophilia
• b. Pyknosis – nuclear shrinkage & basophilia
• c. Karyorrhexis – pyknotic nucleus fragments

18. Types of necrosis
1. Coagulative necrosis or structured necrosis:-
• Preservation of the basic outline of the coagulated cell.
• Firm texture;
• Predominantly denaturation of proteins including both structural
and enzymatic protein
• – Usually followe hypoxia → fragmentation and phagocytosis by
macrophages and proteolysis e.g.

19. Coagulative necrosis heart

20. 2. Liquefactive necrosis or colliquative)
• Characteristic of focal bacterial
• (suppuration or caseous necrosis) or occasionally fungal infections
due to attraction of inflammatory cells,
• Also xristic of hypoxic death to brain cells → complete cell digestion
→ liquid viscous mass or pus.
• Colliquative necrosis –necrosis with softening usually seen in brain
infarcts.

21. Liquefactive necrosis – lung abscess

22. Liquefactive necrosis – liver abscess

23. 3. Gangrene
• Gangrenous necrosis is coagulative necrosis modified either by
exposure to air “Dry gangrene”or
• bacterial infection → wet gangrene (All true gangrene is wet)
4. Caseous necrosis:-
• Encountered most in tuberculosis infection
• Micro- amorphous granular debris + fragmented coagulated cells
enclosed within a granulomatous reaction –
• Tissue architecture is completely obliterated.

24. 5. Fat necrosis:-
• Pancreas and peritoneal cavity damage in acute pancreatitis;
• Released activated lipases act on triglyceride esters → FA + Ca ---
chalky white areas (fat saponification)

25. APOPTOSIS
• Initially recognized in 1972 as a distinctive form of cell death named
after the greek word for “falling off”
• (= programmed cell death or “cell suicide).
• It is a form of cell death designed to eliminate unwanted host cells
through:
• activation of a coordinated internally programmed series of events
effected by a dedicated set of gene products.
• It’s a coordinated and internally programmed cell death

26. APOPTOSIS VS NECROSIS`
Defintion Programmed and coordinated cell
death
Cell death by hydrolytic enzymes
Causative agents Physiologic & pathologic process Hypoxia, toxins
Morphology -No inflammatory reactions
-Death of single cell
-Cell shrinkage
-Cytoplasmic blebs on membrane
-Apoptotic bodies
-Chromatin condensation
-Phagocytosis of apoptotic bodies by
macrophages
-Inflammatory reaction always present
-Death of many cells
-Cell swelling initially
-Membrane distruption
-Damaged organelles
-Nuclear distruption
- Phagocytosis of cell debris by
macrophages
Molecular changes -Lysosomes and other organelles
intact
-Genetic activation by proto-
oncogenes and cytotoxic T cell-
mediated cell target killing
-Lysosomal break down with liberation
of hydrolytic enzymes
-Celll death by ATP depletion,
mebrane damage and free radical
injury

27. Apoptosis in Physiologic situations
1. Embryogenesis, Implantation, Organogenesis.
Organised cell destruction of tissues during development
2. Developmental involution and metamorphosis
Involution of thymus in early age
3. Hormone dependent involution in the adult eg Regression of the
lactating breast after weaning, endometrial shedding
4. normal cell destruction followed by replacement proliferation such
as in intestinal epithelium.

28. Apoptosis in Pathologic situations
1. Cell death as a result of injurious stimuli e.g. radiation &
anticancer drugs
2. Pathologic atrophy in parenchymal organs after duct
obstruction e.g salivary gland/ kidneys, prostatic atropy after
castration.
3. Cell death by cytotoxic T-cells in rejection reactions
4. Cell injury in certain viral diseases e.g. Viral hepatitis –
councilman bodies
5. in degenerative diseases of CNS eg Alzheimers/ parkinsons
diseases
6. cell death by injurious agents involved in causation of necrosis.

29. Mechanism of Apoptosis
• The process involve two phases;
• INITIATION PHASE
• EXECUTION PHASE
INITIATION PHASE ;
1- Intrinsic (Mitochondrial) Pathway
Leads to activation of caspase 8
2-Extrinsic (Death Receptor) Pathway
Leads to activation of caspases 9 and 10
EXECUTION PHASE
Leads to activation of caspase 3 and 6

30. APOPTOTIC MOLECULES
1-Proapototic proteins;
Bax, Bak
2- Anti apoptotic protein;
Bcl-2, Bcl-x and Mcl-1
3- Sensors of cell damage;
Bim, Bid and Bad