CELLULAR INJURY,

NECROSIS AND
APOPTOSIS (PATH 303):
General Pathology I
300 LEVEL MEDICAL RADIOGRAPHY
TIME: 10.00-12.00
DATE: 10TH FEB. 2022
VENUE: BLUE SEAT, CLINICAL SKILL CENTRE, NEW COLLEGE BUILDING, ABUTH SHIKA, ZARIA
PROF. A. H RAFINDADI
ASSISTED BY DR. RIMAMSKEP IFUSUMU
FORMAT

 INTRODUCTION
 CAUSES OF CELL INJURY
 REVERSIBLE CELL INJURY
 NECROSIS
 PATTERNS OF TISSUE NECROSIS
 MECHANISMS OF CELL INJURY
 ISCHEMIA-REPERFUSION INJURY
 APOPTOSIS
 CAUSES OF APOPTOSIS
 MORPHOLOGIC AND BIOCHEMICAL CHANGES IN APOPTOSIS
 MECHANISMS OF APOPTOSIS
INTRODUCTION

 Pathology is the study of structural, biochemical and functional changes in cells, tissues
and organs that underlie disease.
 Traditionally, the study of pathology is divided in to General and Systemic pathology.
 The four (4)aspect of disease process that form the core of pathology are causation
(etiology), biochemical and molecular mechanisms (pathogenesis), the associated
structural (morphologic changes) and functional alterations in cells and organs and the
resulting clinical consequences (clinical manifestations)
INTRODUCTION- 2

 If the limit of adaptive responses are exceeded or if cells are exposed to damaging insults,
deprived of critical nutrients, or compromised by mutations, that affect essential cellular
functions, a sequence of events follows that is termed cell injury.
INTRODUCTION- 3

Copied from Robblns and Cotran text of Pathology 10th edition

CAUSES OF CELL INJURY

 Oxygen Deprivation
 Physical Agents
 Chemical Agents and Drugs
 Infectious Agents
 Immunologic Reactions
 Genetic Abnormalities
 Nutritional Imbalances
REVERSIBLE CELL INJURY
(MORPHOLOGY)

 Cellular Swelling

 Fatty Change
ULTRASTRUCTURAL CHANGES OF
REVERSIBLE CELL INJURY

 Plasma membrane alterations, such as blebbing, blunting, and loss of 

microvilli
  Mitochondrial changes, including swelling and the appearance of small 
amorphous densities

  Dilation of the ER, with detachment of polysomes; intracytoplasmic 
myelin figures may be present
  Nuclear alterations, with disaggregation of granular and  fibrillar elements
NECROSIS

 Necrosis can be defined as the morphologic evidence of cell death following an injurious
stimuli.
 It is characterized by denaturation of intracellular proteins, and enzymatic digestion of
lethally injured cells.
NECROSIS- 2 (MORPHOLOGY )

 Increase eosinophilia
 Myelin figures
 Karyolysis
 Pyknosis
 Karyorrhexis
PATTERNS OF NECROSIS

 Coagulative Necrosis
 Liquefactive Necrosis
 Gangrenous Necrosis
 Caseous Necrosis
 Fibrinoid Necrosis
 Fat Necrosis
COAGULATIVE NECROSIS (WEDGE
INFARCT)

Copied from Robblns and Cotran text of Pathology 10th edition

MICROGRAPH (NORMAL/ INFARCTED
AREA)

Copied from Robblns and Cotran text of Pathology 10th edition

LIQUEFACTIVE NECROSIS

Copied from Robblns and Cotran text of Pathology 10th edition

CASEOUS NECROSIS
FIBRINOID NECROSIS
FAT NECROSIS
MECHANISMS OF CELL INJURY

 The cellular response to injurious stimuli depends on the nature of the injury, its duration,
and its severity
 The consequences of cell injury depend on the type, state, and adaptability of the injured
cell
 Cell injury results from different biochemical mechanisms acting on several essential
cellular components
MECHANISMS OF CELL INJURY- 2

Copied from Robblns and Cotran text of Pathology 10th edition

MECHANISMS OF CELL INJURY- 3

Copied from Robblns and Cotran text of Pathology 10th edition

MECHANISMS OF CELL INJURY- 4

Copied from Robblns and Cotran text of Pathology 10th edition

ISCHEMIA-REPERFUSION INJURY

 Restoration of blood flow to ischemic tissues can promote recovery of cells if they are
reversibly injured, but can also paradoxically exacerbate the injury and cause cell death.
 Oxidative Stress
 Intracellular Calcium Overload
 Inflammation
 Activation of the Complement System
APOPTOSIS

 Apoptosis is a pathway of cell death that is induced by a tightly regulated suicide program
in which cells destined to die activate intrinsic enzymes that degrade the cells’ own
nuclear DNA and nuclear and cytoplasmic proteins.
 Apoptosis is sometimes referred to as programmed cell death
CAUSES OF APOPTOSIS (PHYSIOLOGIC)

 The destruction of cells during embryogenesis

 Involution of hormone­dependent tissues upon hormone withdrawal.
 Cell loss in proliferating cell populations
 Elimination of potentially harmful self-reactive lymphocytes
 Death of host cells that have served their useful purpose, such as neutrophils in an acute
inflammatory response, and lymphocytes at the end of an immune response
CAUSES OF APOPTOSIS (PATHOLOGIC)

 DNA Damage
 Accumulation of Misfolded Proteins
 Cell death in certain infections
 Pathologic atrophy in parenchymal organs after duct obstruction
MORPHOLOGIC AND BIOCHEMICAL
CHANGES IN APOPTOSIS

 Cell shrinkage
 Chromatin condensation
 Formation of cytoplasmic blebs and apoptotic bodies
 Phagocytosis of apoptotic cells or cell bodies
MECHANISMS OF APOPTOSIS- 1

 Apoptosis results from the activation of enzymes called caspases (so named because they
are proteases containing a cysteine in their active site and cleave proteins after aspartic
residues).
 Like many proteases, caspases exist as inactive proenzymes and must undergo enzymatic
cleavage to become active.
 The process of apoptosis is divided into an initiation phase, during which some caspases
become catalytically active and an execution phase, during which the terminal caspases
trigger cellular fragmentation
 Regulation of these enzymes depends on a finely tuned balance between the activity of
pro-apoptotic and anti-apoptotic proteins.
MECHANISMS OF APOPTOSIS- 2

 Two distinct pathways converge on caspase activation:

-the mitochondrial pathway and

-the death receptor pathway

THE MITOCHONDRIAL (INTRINSIC)
PATHWAY- 1
THE MITOCHONDRIAL (INTRINSIC)
PATHWAY- 2

 The mitochondrial pathway is responsible for apoptosis in most physiologic and

pathologic situations.
 It results from increased permeability of the mitochondrial outer membrane with
consequent release of death-inducing (pro-apoptotic) molecules from the mitochondrial
intermembrane space into the cytoplasm.
 Anti­apoptotic. BCL2, BCL-XL, and MCL1 are the principal members of this group; they
possess four BH domains (called BH1-4). These proteins reside in the outer mitochondrial
membranes as well as the cytosol and ER membranes. They keep the mitochondrial outer
membrane impermeable thereby preventing the efflux of cytochrome c into the cytosol
THE MITOCHONDRIAL (INTRINSIC)
PATHWAY- 3

 Pro­apoptotic. BAX and BAK are the two prototypic members promote mitochondrial
outer membrane permeability allowing leakage of cytochrome c from the
intermembranous space.
 Sensors. Members of this group, including BAD, BIM, BID, Puma, and Noxa, act as
sensors of cellular stress and damage, and regulate the balance between the other two
groups, thus acting as arbiters of apoptosis
 Once released into the cytosol, cytochrome c binds to a protein called APAF-1 (apoptosis-
activating factor-1), that has been called the apoptosome. This complex is able to bind
caspase-9, the critical initiator caspase of the mitochondrial pathway.
THE DEATH RECEPTOR
(EXTRINSIC)PATHWAY

 This pathway is initiated by engagement of plasma membrane death receptors on a variety

of cells. Death receptors are members of the TNF receptor family
 Binding of FasL to Fas triggers cascade of events that culminate to activation of Caspase
8 or 10 and executioner caspases
THE EXECUTIONAL PHASE OF
APOPTOSIS

 The two initiating pathways converge to a cascade of caspase activation, which mediates
the final phase of apoptosis.
 The executional caspases (caspase -3 and -6) acts on many cellular component.
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