cell injury and inflammation pathology Flashcards

1
Q

What is apoptosis?

A

● Programmed cell death
● A process that removes degraded or unneeded cells, prevents excess growth
● Tightly controlled
● Cells activate degradation enzymes, chromatin is condensed, the cell contents
are degraded within cytoplasmic blebs forming apoptotic bodies, and the cell
shrinks
● Cell membrane remains intact
● Not an inflammatory process

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2
Q

List some important stimuli for apoptosis

A

Physiological
● Developmental atrophy (embryogenesis)
● Loss of growth stimulation (such as endometrial cells during menstruation)
● Cell death induced by cytotoxic T cells
● Elimination of potentially harmful self reactive lymphocytes

Pathological
● Excessive DNA damage (p53 build up)
● Unfolded protein build up
● Cell death secondary to radiation or cytotoxic injury
● Cells displaying harmful characteristics
● Viral infections such as hepatitis

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3
Q

Describe the cellular changes in necrosis

A

● Irreversible injury
● Swollen cells
● Myelin figures
● Nucleus may fade, shrink and fragment
● Organelle and cell membrane disruption with release of contents
● Adjacent or surrounding inflammation

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4
Q

What are the patterns of tissue necrosis?

A

● Coagulative - architecture of tissue preserved
● Liquefactive - digestion of tissue into a viscous liquid mass
● Fibrinoid - a microscopic feature of antigen/antibody complexes in vessel walls
● Caseous - friable white (such as in TB)
● Gangrenous - typically a type of coagulable necrosis applied to a limb, may have
superimposed liquefactive necrosis
● Fat necrosis - focal area of fat destruction

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5
Q

What is atrophy?

A

Decrease in the size of an organ or tissue resulting from a decrease in cell size and
number. Can be physiological or pathological.

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6
Q

What are the causes of atrophy?

A

● Decreased workload (such as immobilisation of a limb in plaster)
● Denervation
● Diminished blood supply (such as arterial occlusion)
● Inadequate nutrition (such as marasmus)
● Loss of endocrine stimulation
● Ageing
● Pressure

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7
Q

What are the mechanisms underlying atrophy?

A

● Decreased protein synthesis
● Increased protein degradation
● May be accompanied by increased autophagy, where a cell consumes its own
components for energy and nutrients

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8
Q

Please describe the 2 different forms of pathological calcification and give an
example of each.

A

● Dystrophic calcification
○ Normal serum calcium
○ Occurs in necrotic or damages/dying tissue
○ Examples: atherosclerosis, calcific aortic stenosis, tuberculous nodes

● Metastatic calcification
○ Abnormally raised calcium
○ Occurs in normal tissues
○ Examples: nephrocalcinosis, pulmonary calcinosis, gastric mucosal
calcification

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9
Q

What are the different causes of hypercalcaemia?

A

● Increased parathyroid hormone (PTH) secretion + bone resorption, seen in
hyperparathyroidism
● Destruction of bone tissue - skeletal mets, myeloma, Paget’s disease
● Vitamin D related disorders - sarcoidosis, hypervitaminosis D
● Renal failure causing secondary hyperparathyroidism and phosphate retention

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10
Q

What is hyperplasia?

A

The increase in the number of cells in an organ or tissue. Usually associated with
increase mass

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11
Q

What are the different types of hyperplasia? Please give some examples.

A

● Physiologic:
○ Hormonal i.e. breast tissue development during puberty and pregnancy
○ Compensatory: post partial hepatectomy, skeletal muscle with increased
workload

● Pathological:
○ Excess hormones i.e. Benign prostatic hyperplasia or dysfunctional
uterine bleeding
○ Viral infection i.e. papillomavirus

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12
Q

What is hypertrophy?

A

Increased size of a tissue due to increased cell size. Arises from increased synthesis of
cell structural components

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13
Q

What are the types of hypertrophy?

A

May be physiological or pathological depending on either increased functional demand
or specific hormonal stimulation.
Cell hypertrophy can occur in dividing or non dividing cells

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14
Q

Give some examples of each type of hypertrophy

A

Physiological - skeletal muscles with exercise, the uterus during pregnancy, breast
tissue during lactation

Pathological - heart in chronic hypertension

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15
Q

What is metaplasia?

A

Replacement of one normal cell type with another normal cell type. May be adaptive or
pathological. Can be reversible.

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16
Q

Metaplasia examples

A

Columnar to squamous due to chronic respiratory irritation i.e. smoking
Squamous to columnar i.e. in Barretts oesophagus
Connective tissue change in myositis ossificans - muscle to bone or cartilage

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17
Q

What are the potential outcomes of metaplasia?

A

● Malignant transformation
● Reversibility/resolution
● Ongoing change

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18
Q

What is the mechanism underlying metaplasia?

A

● Reprogramming of epithelial stem cells or undifferentiated mesenchymal cells
● Involves signals from cytokines, growth factors, cellular matrix components,
genes and DNA methylation

19
Q

What is steatosis?

Which organs are commonly involved?

A

Abnormal accumulation of triglycerides within parenchymal cells

Liver, kidneys, muscle

20
Q

What are the causes of hepatic steatosis?

A

● Alcohol excess
● Toxins
● Protein malnutrition
● Obesity
● Anoxia
● Starvation

21
Q

Describe the sequence of events that occur in reversible ischaemic cellular injury

A

● ATP depletion due to decreased oxidative phosphorylation
● Failure of the sodium/potassium pump, leading to K efflux and Na influx
● Cell swelling, leads to
● Calcium influx
● Detachment of ribosomes from the ER
● Cytoskeleton changes: loss of microvilli, bleb formation, myelin figures from
degenerating cell membrane
● Mitochondrial swelling

22
Q

List the morphological changes of irreversible cell injury

A

● Severe mitochondrial swelling
● Extensive damage to plasma membrane
● DNA/protein damage and leakage of proteins such as AST/ALT or troponin
● Lysosomal swelling and rupture
● Necrosis or apoptosis

23
Q

Describe reperfusion injury

A

Further cell death in ischaemic tissues following restoration of blood flow. Occurs during
MI and stroke with reperfusion therapy, as well as in ischaemic bowel due to collateral
blood supply.
4 major mechanisms

● Reactive oxygen species
○ Generated from the incomplete reduction of O2 by damaged mitochondria
in affected tissue, PLUS action of oxidases from damaged cells and
incoming leukocytes.

● Inflammation
○ Via cells and cytokines.
○ Damaged cells release adhesion molecules that attract neutrophils.
○ This inflammation causes additional injury.

● Complement Activation
○ IgM deposits in ischaemic tissues and when reperfusion occurs,
complement proteins bind, causing inflammation

● Mitochondrial permeability transition pore
○ Pore in mitochondria that opens after reperfusion.
○ Stimulated by oxidative stress via ROS
○ Decreases mitochondrial function
○ Uncoupling of oxidative phosphorylation
○ Matrix swelling
○ Prevents recovery of ATP generation
○ Pivotal point in cell death

24
Q

What is a free radical?

A

Chemical species with a single unpaired electron in outer orbit e.g. reactive oxygen
species: super oxide, hydrogen peroxide, hydroxyls

25
Q

What are the pathological effects of free radicals?

A

● Overall cause necrosis or apoptosis and can stimulate production of degrading
enzymes.

● Directly cause:
○ Lipid peroxidation (plasma membrane or organelle damage)
○ Oxidation of proteins (affecting the protein structure i.e. enzymes)
○ DNA lesions (breaks in DNA or cross linkages)

26
Q

Please describe the major components of acute inflammation

A

● Small vessel dilatation - leading to increased blood flow
● Increased vascular permeability - enabling plasma proteins and leukocytes to
leave the circulation
● Leukocyte emigration - from the microcirculation towards the focus of injury, and
activation to eliminate the offending agent

27
Q

What are the mechanisms responsible for increased vascular permeability?

A

● Contraction of endothelial cells - resulting in increased inter-endothelial spaces
(most common)
● Direct endothelial injury - resulting in endothelial cell necrosis and detachment
(such as in burns, as a result of toxins or by direct action of neutrophils)
● Transcytosis - increased transport of fluids and proteins through the endothelial
cell itself.

28
Q

What are the different types of acute inflammation?

A

● Serous: thin fluid from plasma or mesothelial lining cells e.g. burns, effusions
● Fibrinous: more severe injuries and greater vascular permeability allows larger
molecules, such as fibrin, to pass into the space.
● Suppurative/purulent: large amounts of pus or purulent exudates from
neutrophils, necrotic cells and oedema. Depends on organism type and location.
● Ulcerative: local defect in an organ or tissue

29
Q

What are the outcomes of acute inflammation?

A

● Complete resolution with or without scarring
● Abscess formation
● Fibrosis
● Chronic inflammation

30
Q

Leukocytes in inflammation

A

● What leukocytes are involved in acute inflammation?
● Neutrophils in first 6-24 hours - may last longer in pseudomonas infections
● Monocytes at 24-48 hours
● Lymphocytes in viral
● Eosinophils in hypersensitivity reactions

31
Q

How are leukocytes delivered to the site of injury?

A

This is a multistep process, mediated and controlled by adhesion molecules and
chemokines.

● Margination - occurs when leukocytes adopt a peripheral position along the
vessel wall. Rolling (transient adherence mediated by selectins), activation and
attachment (mediated by integrins) to the epithelium.
● Transmigration or diapedesis - occurs when leukocytes cross the endothelium.
Migration occurs through the interendothelial spaces, typically in the post
capillary venules.
● Chemotaxis - leukocytes move towards the site of injury along a chemical
gradient.

32
Q

What are the mediators that aid chemotaxis?

A

Common chemo-attractants include

● Exogenous - mostly bacterial products/proteins/peptides
● Endogenous - cytokines (IL-8) complement (C5a) arachidonic acid metabolites
(leukotriene B4)
● They all bind to specific receptors and promote polymerisation of actin

33
Q

What stimuli cause production of mediators of inflammation?

A

Substances released from necrotic cells, microbial products, cell injury, mechanical
irritation

34
Q

What are the chemical mediators of acute inflammation and what are their
actions?

A

● Histamine: vasodilation, increased vascular permeability, endothelial activation
● Prostaglandins: vasodilation, increased vascular permeability
● Leukotrienes: increased vascular permeability, chemotaxis, WBC adhesion and
activation
● Platelet activating factor: vasodilation, increased vascular permeability,
chemotaxis, WBC adhesion, degranulation
● Complement: WBC chemotaxis, activation and vasodilation
● Cytokines (TNF, IL-1): endothelial activation, fever, pain, hypotension, decreased
vascular resistance
● Chemokines : chemotaxis, WBC activation
● Kinins: vascular permeability, vasodilation, paion, smooth muscle contraction

35
Q

What are the characteristics of chronic inflammation?

A

● Inflammation for a prolonged period of time
● Characterised by macrophages, lymphocytes and plasma cells
● Simultaneous active inflammation/tissue destruction and attempts at repair by
connective tissue fibrosis

36
Q

What cell types are present in chronic inflammation?

A

● Macrophages
● Lymphocytes
● Eosinophils
● Plasma cells
● Mast cells
● Multinucleate giant cells

37
Q

What processes mediate the persistent accumulation of macrophages seen in
chronic inflammation?

A

● Continued recruitment of monocytes - due to continued expression of adhesion
molecules and chemotactic factors
● Local proliferation of macrophages
● Immobilisation of macrophages at the site of injury (via migration inhibition factor)

38
Q

What products are released by activated macrophages in chronic inflammation?

A

● Products associated with tissue injury
○ Toxic O2 metabolites
○ Proteases
○ Neutrophil chemotactic factors
○ Coagulation factors
○ AA metabolites
○ Nitric oxide

● Products associated with fibrosis
○ Growth factors (PDGF, FGF, TGF)
○ Fibrogenic cytokines
○ Angiogenesis factors
○ Remodelling collagenases

39
Q

What clinical conditions cause chronic inflammation?

A

● Persistent infection i.e. tuberculosis, abscess, syphilis, empyema, osteomyelitis
● Prolonged exposure to an agent i.e. exogenous foreign body, persistent trauma,
silica leading to silicosis or lipid accumulation leading to atherosclerosis
● Autoimmune i.e. rheumatoid arthritis, inflammatory bowel disease, multiple
sclerosis, SLE.

40
Q

What is the complement system?

A

● A plasma protein system involved in immunity against microbes.
● Complement proteins numbered C1- C9 are present in plasma in inactive forms

41
Q

What are the pathways by which complement activation occurs?

A

● There are 3 pathways
● Classical pathway: involving antigen-antibody complex
● Alternate pathway: triggered by microbial surface molecules e.g. endotoxin. No
antibody involvement
● Lectin pathway: plasma mannose binding lectin binds to carbohydrate on
microbe
● All pathways result in cleavage and activartion of C3 (the most important and
abundant complement component)

42
Q

What are the most important complement components?

A

C3 and C5

43
Q

How do activated complement products mediate acute inflammation?

A

● Vascular effects - increased permeability, vasodilation via C3a and C5a mediated
histamine release from mast cells
● Leukocyte adhesion chemotaxis and activation via C5a
● Phagocytosis vis C3b which acts as an opsonin on the microbe and leads to
phagocytosis
● Cell lysis by the membrane attack complex (MAC) composed multiple C9
molecules