2. cellular injury and necrosis
TRANSCRIPT
-
7/30/2019 2. Cellular Injury and Necrosis
1/68
CELLULAR INJURY
AND NECROSIS
Dr. Thuaibah Hashim
-
7/30/2019 2. Cellular Injury and Necrosis
2/68
-
7/30/2019 2. Cellular Injury and Necrosis
3/68
CAUSES OF INJURY
1. Oxygen deprivation
2. Physical agents
3. Chemical agents and drugs
4. Infectious agents
5. Immunologic reactions6. Nutritional imbalances
7. Genetic derangements
Acquired
-
7/30/2019 2. Cellular Injury and Necrosis
4/68
1. Oxygen deprivation
HYPOXIA
Oxygen deficiency, affects oxidative respiration
common cause of injury and cell death.
eg. respiratory failure
eg. anaemia, CO poisoning
ISCHAEMIA = shortage of blood supply
often due to blockage of artery or veins. Hypoxia + deficiency of metabolic substrate
**Ischaemic tissues are more rapidly and severely
injured than hypoxic tissues.
-
7/30/2019 2. Cellular Injury and Necrosis
5/68
2. Physical Agents
Mechanical trauma
Extreme temperatures (burns & cold)
Sudden change in atmospheric pressures
Radiation
Electrical shock
-
7/30/2019 2. Cellular Injury and Necrosis
6/68
3. Chemicals & Drugs
The list of chemicals that may produce cell injury defiescompilation.
Caustic agents: Acids & AlkaliAlcohol & narcotic drugs
Therapeutic drugs
Insecticides, Pesticides
Herbicides
Environmental and air pollutants
Simple chemicals eg. glucose and salt in hypertonicconcentrations may cause cell injury directly or by derangingelectrolyte homeostasis.
Even O2, in high concentrations, is severely toxic.
-
7/30/2019 2. Cellular Injury and Necrosis
7/68
4. Infectious agents
Viruses (cytopathic effects)
Bacteria
Fungi
ParasitesWorms etc
-
7/30/2019 2. Cellular Injury and Necrosis
8/68
5. Immunological Reactions
Bodys defense mechanism, may in fact, cause cellinjury.
eg. anaphylactic reactions (hypersensitivity)
eg. autoimmune diseases
-
7/30/2019 2. Cellular Injury and Necrosis
9/68
6. Nutritional imbalances
Deficiencies:
Common protein-calorie malnutrition,
severe degree leads to death of tissues-individuals.
Specific vitamin deficiencies.
Excesses: Excess of lipids predispose to
atherosclerosis.
-
7/30/2019 2. Cellular Injury and Necrosis
10/68
7. Genetic Defects
eg. Chromosomal abnormalityDowns syndrome
eg. Single amino acid substitution in Hb Ssicklecell anaemia.
eg. Enzyme abnormality gene defects -- inborn
errors of metabolism (Production of substanceswhich are toxic to cells)
-
7/30/2019 2. Cellular Injury and Necrosis
11/68
EFFECTS OF INJURIES ON
CELLS/TISSUESTYPES OF INJURIES EFFECTS ON CELLS
1. SUBLETHALINJURY
(Removal of injurious
agents allows recovery to
normal state)
2. LETHAL INJURY
(No possible recovery)
REVERSIBLE DAMAGE1.1 Hydropic degeneration
1.2 Fatty Change
IRREVERSIBLEDAMAGE
2.1 Apoptosis
2.2 Necrosis
-
7/30/2019 2. Cellular Injury and Necrosis
12/68
Mechanisms of cell injury
The biochemical mechanisms responsible for cellinjury are complex.
With most stimuli, multiple mechanisms contributeto injury, and in the case of many injuriousstimuli,the actual biochemical locus of injuryremains unknown.
Basic principles: Depends on type of injury, its duration and severity. Depends on type of injured cells, its status and
adaptability.(eg. Cardiac muscle withstands hypoxia 20-30 mins, Striated muscle withstands hypoxia 2-3 hrs)
-
7/30/2019 2. Cellular Injury and Necrosis
13/68
MECHANISM OF INJURY
Interdependance of cellular organelles
Damage of one component leads to secondarydamage of other components.
Cell death occurs when threshold of accumulateddamage is passed
Cell response ranges from recoverable damage toinstant death
Primary targets of damaging stimuli:1. Cell membrane 2. Mitochondria
3. Cytoskeleton 4. Protein synthesis
5. Cellular DNA
-
7/30/2019 2. Cellular Injury and Necrosis
14/68
Pathogenesis of
ischaemic/hypoxic injuriesDecreased generation of cellular ATP.
Plasma membrane energy-dependent Na pump fails Naaccumulate intracellular cell swelling, dilated ER.
Anaerobic glycolysis lactic acidosisactivity ofcellular enzymes.
Failure of calcium pump.
Disruption of protein synthetic apparatus.
Damage to mitochondrial and lysosomal membranes.
Proteins may become misfolded unfolded proteinresponse leading to cell injury.
-
7/30/2019 2. Cellular Injury and Necrosis
15/68
Ischaemia-Reperfusion injury
Depending upon the duration of ischaemia, restoration of
blood flow may result in 3 different consequences:
1. Short duration, reversible injurycell restored to
normal.
2. Longer durationreperfusion paradoxically deteriorates
the already injured cell = Ischaemia-Reperfusion injury
due to increased generation of oxygen free radicals or
reactive oxygen species (superoxide, H2O2, OH-).
3. Irreversible injury during ischaemia itselfno role of
reperfusion.
-
7/30/2019 2. Cellular Injury and Necrosis
16/68
Pathogenesis of chemical injury
Direct cytotoxic effects.
Combine with components of cell.
eg. mercury binds to cell membrane protein
permeability.
Conversion to reactive metabolites
Metabolic activation to yield ultimate toxin.
Target cells may not be the same cells that metabolisethe chemicals
Eg. CCl4 converted to CCl3.causing toxic livernecrosis.
-
7/30/2019 2. Cellular Injury and Necrosis
17/68
Pathogenesis of physical injury
Ionizing radiation can hydrolyze water into
H+ and OH- free radicals.
OH- radical produce injury by:
Lipid peroxidation
Protein oxidation
DNA damage
-
7/30/2019 2. Cellular Injury and Necrosis
18/68
Morphology of Sublethal Injury
The term degeneration denote morphology
of reversible injury.
Cellular change:HYDROPIC DEGENERATION.
(a.k.a CLOUDY SWELLING,
VACUOLAR DEGENERATION)
-
7/30/2019 2. Cellular Injury and Necrosis
19/68
Hydropic degeneration
Commonest and earliest form of cell injury
Results from impaired regulation of cellular
volume esp sodium.
Plasma membrane
Sodium pump
Supply of ATP
-
7/30/2019 2. Cellular Injury and Necrosis
20/68
Hydropic degeneration
Gross:
Enlarged organs eg kidney, liver
Cut surface bulges outwards, slightly opaque. (hencethe term cloudy swelling)
Microscopic:
Cells swollen
Microvasculature is compressed
Small clear intracytoplasmic vacuoles (represents
distended cisternae of ER.)
-
7/30/2019 2. Cellular Injury and Necrosis
21/68
Hydropic degeneration
Ultrastructural changes (refer diagram)
Dilated ER
Detachment of polysomes from surface of RERMitochondrial swelling
Blebs on plasma membrane, distortion ofmicrovilli, loosening intercellular attachment,
myelin figures.Nuclear alteration: disaggregation of granular
and fibrillar elements.
-
7/30/2019 2. Cellular Injury and Necrosis
22/68
-
7/30/2019 2. Cellular Injury and Necrosis
23/68
Intracellular Accumulations
Substances in abnormal amounts due to deranged cellmetabolism. Mild degree causes reversible injury.
Normal constituents eg. lipid, carbo, protein Abnormal substances
Exogenous (eg product of infectious agents)
Endogenous (eg inborn error of metabolism, storage
diseases. ) Pigments
Exogenous (eg coal dust)
Endogenous (eg melanin, hemosiderin)
-
7/30/2019 2. Cellular Injury and Necrosis
24/68
Process ofintracellular
accumulations
-
7/30/2019 2. Cellular Injury and Necrosis
25/68
FATTY DEGENERATION
Fatty change due to hypoxia, toxic substances ormetabolites, infection.
Occurs occasionally in all organs but is most common inthe liver (central role in fat metabolism)
Injured cells are not able to metabolise lipids & hencetriglycerides accumulate in cytoplasm
Gross appearance: Fatty livers are enlarged, yellow, greasy
Microscopically, cells become enlarged, sometimes
nucleus displaced to the side giving crescent shapeappearance. Cytoplasm contain varying amounts of lipid(clear area due to lipid being removed during processing) -microvesicular / macrovesicular.
Fatty cyst, lipogranuloma.
-
7/30/2019 2. Cellular Injury and Necrosis
26/68
-
7/30/2019 2. Cellular Injury and Necrosis
27/68
QuickTimdecomp
are needed to se
-
7/30/2019 2. Cellular Injury and Necrosis
28/68
Photomicrograph of normal liver : Liver cell plates & acinar/lobulararran ement :central vein & ortal tracts with sinusoids
-
7/30/2019 2. Cellular Injury and Necrosis
29/68
Photomicrograph of normal liver(hi her ma nification)
-
7/30/2019 2. Cellular Injury and Necrosis
30/68
Photomicrograph of liver with fatty change due to chronic venous
congestion, changes predominantly around central vein
-
7/30/2019 2. Cellular Injury and Necrosis
31/68
Fatty change in liver (high power)
-
7/30/2019 2. Cellular Injury and Necrosis
32/68
Cholesterol and cholesterol esters
Accumulation of cholesterol is seen in severalpathologic processes:
Atherosclerosis
Cholesterol accumulates in smooth muscle
cells and macrophages in walls of arteries Xanthomas
Cholesterol accumulates in macrophages andmesenchymal cells in soft tisue due tohyperlipidemia
Foamy (lipid-laden) macrophages
Found in inflammation and necrosis due tophagocytosis of membrane lipids of injuredcells by macrophages
-
7/30/2019 2. Cellular Injury and Necrosis
33/68
Proteins
Excess of proteins may cause morphologically
visible accumulations within cells appearing as
rounded eosinophilic droplets or masses in the
cytoplasm
Occurs due to excessive synthesis, absorption or
defects in cellular transport
Example:
Prolonged proteinuria causing reabsorption of protein
and formation of protein droplets in proximal
convoluted tubules
-
7/30/2019 2. Cellular Injury and Necrosis
34/68
Morphology of
excess proteinaccumulations
-
7/30/2019 2. Cellular Injury and Necrosis
35/68
Glycogen
Excessive intra-cellular glycogen deposits
are seen in abnormalities of glycogen and
glucose metabolism:Eg: Glycogen storage diseases
-
7/30/2019 2. Cellular Injury and Necrosis
36/68
Pigments Exogenous pigments:
Anthracosis (accumulation of carbon in macrophages oflungs and lymph nodes)
Tattooing (injected pigment)
Endogenous pigments: Lipofuscin
The wear and tear pigment
Microscopically seen as yellow-brown, fine, intra-cytoplasmicgranules
Usually associated with old age / atrophy (brown atrophy)
Melanin
Derived from melanocytes Microscopically seen as a brown-black pigment
Hemosiderin Derived from hemoglobin
Often seen in hemorrhage, rupture of vessels, vascular
congestion
-
7/30/2019 2. Cellular Injury and Necrosis
37/68
Lipofuscin
Lipofuscin deposits in cardiac fibres (brown
atrophy of the heart) in old age
l i
-
7/30/2019 2. Cellular Injury and Necrosis
38/68
Melanin
Melanin pigment in a nevus (mole)
-
7/30/2019 2. Cellular Injury and Necrosis
39/68
Hemosiderin deposits
-
7/30/2019 2. Cellular Injury and Necrosis
40/68
Morphology of Lethal Injury
Necrosis
Apoptosis
-
7/30/2019 2. Cellular Injury and Necrosis
41/68
NECROSIS
Spectrum of morphologic changes that follow celldeath in living tissue
Largely resulting from progressive degradativeaction of enzymes on the lethally injured cells.
Autolysis: enzymes derived from ownlysosomes
Heterolysis: enzymes from immigrantleukocytes.
Also results from denaturation of proteins
-
7/30/2019 2. Cellular Injury and Necrosis
42/68
Morphology of cell necrosis
Cytoplasm:
increased eosinophilia due to
1. Loss of normal basophilia imparted by RNA
2. increased eosin binding to denatured proteins Vacuolated and moth eaten when cytoplasmic
organelles have been digested
Nucleus:
karyolysis Pyknosis
Karyorrhexis
Ultimately: nucleus disappear, dead cells replaced by myelinfigures or calcified, phagocytosed by other cells.
-
7/30/2019 2. Cellular Injury and Necrosis
43/68
PATTERNS OF NECROSIS (mass of cells)
COAGULATIVE NECROSIS
protein denaturation
LIQUEFACTIVE NECROSIS enzyme digestion
CASEOUS NECROSIS
FIBRINOID NECROSIS
FAT NECROSIS
-
7/30/2019 2. Cellular Injury and Necrosis
44/68
Coagulative necrosis
refers to preservation of basic outline of thecoagulated cell for a span of at least some
days. is due to denaturation of not only structural
proteins, but also enzymes, thus blockingproteolysis of the cell.
is characteristic of ischaemic death of cellsin all tissues except brain.
-
7/30/2019 2. Cellular Injury and Necrosis
45/68
Dead (necrotic) Myocardium.
Cardiac cells appear more
eosinophilic, loss of nuclei, cellular
outlines maintained
Collection of neutrophils
(normally not present) as part
of acute inflammatory process,
reaction to dead tissue
Myocardial infarction: coagulative necrosis
-
7/30/2019 2. Cellular Injury and Necrosis
46/68
Liquefactive necrosis
1. Dead tissue becomes liquefied due to digestion of
tissue by enzymes released by dead cells eg abscess
(collection of neutrophils, release of enzymes
destruction of cells & liquefied)
2. Dead tissue becomes liquefied ?due to high content
of water eg Infarction of cerebral tissue
Characteristic of bacterial infections bcos they stimulate
accumulation of inflammatory cells.
.
-
7/30/2019 2. Cellular Injury and Necrosis
47/68
Microscopic appearance of necrotic/infarcted brain with dead
neuronal cells becoming disintegrated (n), and intercellular
spaces accumulating fluid (f). Finally becomes pale acellular area
Liquefactive necrosis in brain after an infarction
n
n
f
f
-
7/30/2019 2. Cellular Injury and Necrosis
48/68
Liquefactive necrosisSubcutaneous abscess with collections of pus
Kidney: coagulative necrosis
-
7/30/2019 2. Cellular Injury and Necrosis
49/68
Kidney: coagulative necrosis
Kidney: Liquefactive necrosis
-
7/30/2019 2. Cellular Injury and Necrosis
50/68
Kidney: Liquefactive necrosis
-
7/30/2019 2. Cellular Injury and Necrosis
51/68
Caseous necrosis
Combine features of coagulative and
liquefactive necrosis.
Cheesy white gross appearance.
Microscopic: Structureless, eosinophilic
granular debris.
Typically seen in tuberculosis.
-
7/30/2019 2. Cellular Injury and Necrosis
52/68
Caseous necrosis
Gross appearance of lung:
Caseation necrosis of lymph node : Friable
fragmented whitish area of necrosis in hilar
lymph node
Microscopic appearance of lungwith caseous/caseation necrosis (c)
appearing as eosinophilic & amorphous
surrounded by viable epithelioid cells,
multinucleated (Langhans) giant
cells (m) & scanty lymphocytes.
c
mm
C ti i
-
7/30/2019 2. Cellular Injury and Necrosis
53/68
Caseation necrosis
Cm
l
l
e
e
Microscopic appearance of lung (a high magnification) with caseous necrosis appearing as
eosinophilic & acellular area (c) surrounded by viable epithelioid cells (e), multinucleated
(Langhans) giant cells (m) & scanty lymphocytes (l)
-
7/30/2019 2. Cellular Injury and Necrosis
54/68
Fat necrosis
1. ENZYMATIC FAT NECROSISOccurs in the abdomen (peritoneal cavity).Fat tissue lysed by enzymes (pancreatic lipase), released fatty
acids combine with calcium to produce grossly visible chalkywhite areas.
Histo: shadowy outline of necrotic fat cells, with basophiliccalcium deposits, surrounded by inflammatory reaction.
eg fat saponification following Acute Pancreatitis
2. TRAUMATIC FAT NECROSIS
Injury to fatty tissue causes necrosis.
Necrosis of fat cells associated with calcification, may mimiccancer.
eg Traumatic fat necrosis in breast
-
7/30/2019 2. Cellular Injury and Necrosis
55/68
Enzymatic fat necrosis
in pancreas andadjacent fatty tissue in
acute pancreatitis
Microscopic appearances of pancreas
(low power) showing residual
pancreatic acini (a) and a area of
necrosis (n) in picture 1. In picture 2necrosis is extensive and
haemorrhagic (n) and viable fat is
present (f)
a
a
n
n
PICTURE 1
PICTURE 2
n
n
f f
Traumatic fat necrosis in the breast
-
7/30/2019 2. Cellular Injury and Necrosis
56/68
Microscopic appearance of breast tissue (high power) with traumatic fat
necrosis. The area of necrosis is not obvious now but it demonstrates collections
of foamy macrophages (f) which have engulfed necrotic fat to remove it from
the area in the breast
Traumatic fat necrosis in the breast
f
f
s
-
7/30/2019 2. Cellular Injury and Necrosis
57/68
Fibrinoid necrosis
Deposition of fibrin-like material which has
the staining properties of fibrin.
Encountered in various examples ofimmunologic tissue injury, arterioles in
malignant hypertension, peptic ulcer etc.
Histo: Brightly eosinophilic hyaline-likedeposit.
Fibrinoid necrosis
-
7/30/2019 2. Cellular Injury and Necrosis
58/68
Fibrinoid necrosis
f
Microscopic appearance of kidney with fibrinoid necrosis of
arteriolar wall in Malignant (accelerated) hypertension,
appearing as eosinophilic acellular area
-
7/30/2019 2. Cellular Injury and Necrosis
59/68
Pathologic calcification
Abnormal deposition of calcium salts in
soft tissues
2 types:Dystrophic calcification
Serum calcium isnormal
Metastatic calcification Serum calcium israised(hypercalcemia)
-
7/30/2019 2. Cellular Injury and Necrosis
60/68
Dystrophic calcification
Localizedcalcium deposition in non-viableor dying tissues in the presence ofnormal
serum calcium. Occurs in arteries in atherosclerosis,damaged heart valves and areas of necrosis.
Calcium can be intracellular, extracellularor both.
Calcification may be visualised onradiographs.
Dystrophic calcification
-
7/30/2019 2. Cellular Injury and Necrosis
61/68
Dystrophic calcification
Metastatic calcification
-
7/30/2019 2. Cellular Injury and Necrosis
62/68
Metastatic calcification
Generalizedcalcium deposition throughout the
body due to increase in serum calcium(hypercalcemia)
4 principal causes:
Increased secretion of parathyroid hormone
(hyperparathyroidism) Eg: Parathyroid tumours or ectopic secretion by other
malignant tumours (eg small cell carcinoma of the lung)
Destruction of bone tissue
Eg: Bone tumours (primary and secondary) Vitamin D related causes
Eg: Vitamin D intoxication
Renal failure
Causing secondary hyperparathyroidism
-
7/30/2019 2. Cellular Injury and Necrosis
63/68
Apoptosis
Cell death through activation of an internal suicide
program.
Purpose: Eliminate unwanted cells selectively withminimal disturbance to surrounding cells and host.
Protein cleavage by caspases.
Protein cross-linking by transglutaminase
Internucleosomal cleavage of DNA
Plasma membrane alteration eg flipping of
phosphatidylserine to outer layer recognition of cells
by phagocytes.
Necrosis vs Apoptosis
-
7/30/2019 2. Cellular Injury and Necrosis
64/68
Necrosis vs Apoptosis
Feature Necrosis Apoptosis
-
7/30/2019 2. Cellular Injury and Necrosis
65/68
p p
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis karyorrhexis karyolysis
Fragmentation into
nucleosome size fragments
Plasma
membrane
Disrupted Intact; altered structure, especially
orientation of lipids
Cellular
contents
Enzymatic digestion;
may leak out of cell
Intact; may be released in
apoptotic bodies
Adjacent
inflammation
Frequent No
Physiologic
or pathologic
role
Invariably pathologic
(culmination of
irreversible cell injury)
Often physiologic, means of
eliminating unwanted cells; may
be pathologic after some forms of
cell injury, especially DNA
damage
STRESS
-
7/30/2019 2. Cellular Injury and Necrosis
66/68
Increased
functionaldemand
Reversible
cell injury
ADAPTATION
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
Dysplasia
NORMAL CELL
Irreversible
cell injury
NECROSIS
MildSevere
Persistent
Relief of stress
-
7/30/2019 2. Cellular Injury and Necrosis
67/68
Learning Objectives
List the causes of cell injury and explaintheir mechanisms.
Define sublethal and lethal injuries.Describe their morphological changes.
Describe the patterns of necrosis withclinical examples.
Describe intracellular accumulations andpathologic calcification.
-
7/30/2019 2. Cellular Injury and Necrosis
68/68