Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.
-
Upload
dawson-golightly -
Category
Documents
-
view
215 -
download
0
Transcript of Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.
![Page 1: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/1.jpg)
Leicester Warwick Medical School
CELL INJURY
Dr Gerald Saldanha
Dept of Pathology
![Page 2: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/2.jpg)
2
Introduction
This presentation will……
• be a guide to cell injury and cell death
• outline causes and pathogenesis of cell injury/death
• describe the morphological changes of cell injury/death
• Describe the process of apoptosis
![Page 3: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/3.jpg)
3
Introduction
General considerations……
• Adapt or die!
• Reaction patterns in a given cell/tissue is often limited
• Degree of injury is a function of type, duration and severity of insult
![Page 4: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/4.jpg)
4
Types of insult - hypoxia
• Ischaemia– Local e.g. embolus– Systemic e.g. cardiac failure
• Hypoxaemia– Oxygen problems e.g. altitude– Haemoglobin problems e.g. anaemia
• Oxidative phosphorylation– E.g. cyanide poisoning
![Page 5: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/5.jpg)
5
Types of insult - chemical
• Many of the common poisons (arsenic, cyanide, mercury) interfere with cellular metabolism. If ATP levels drop below critical levels, affected cells will die.
• The list of pharmaceuticals that may have toxic effects on cells is enormous. Some act directly, but most have their effect through breakdown metabolites. Metabolism of alcohol (a type of drug) to acetaldehyde is one example.
![Page 6: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/6.jpg)
6
Types of insult - infections
• Fungi, Rickettsiae, Bacteria and Viruses– E.g. viruses can take over protein
translation machinery and subvert it entirely to the production of new virions.
![Page 7: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/7.jpg)
7
Types of insult - Physical
• Direct Physical Effects - Exposure of tissue to extreme heat or cold results
in direct injury that is often irreversible, resulting in a pattern of coagulative necrosis (see later).
- Sudden changes in pressure can cause cellular disruption (e.g. a hammer blow to the thumb).
- Electrical currents can cause direct breakdown of cellular membranes that may be irreversible.
![Page 8: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/8.jpg)
8
Types of insult –immune
• Inflammatory mediators such as interferons and interleukins
– can alter both gene expression and cellular metabolism. The effects are designed to help cells combat an infectious process, but the resulting stress to the cells can be highly injurious and sometimes deadly.
• Activation of complement – can result in direct attack on a cell's surface membrane.
• Cytotoxic T-cells and NK cells – can mediate a direct attack on a target cell's and initiate
the self-destruct cascade within a target cell.
![Page 9: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/9.jpg)
9
Types of insult - nutrition
• Dietary insufficiency – of protein, vitamins and/or minerals can
lead to injury at the cellular level due to interference in normal metabolic pathways.
• Dietary excess– can likewise lead to cellular and tissue
alterations that are detrimental e.g. fat is the biggest offender, or excess ingestion of "health supplements"
![Page 10: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/10.jpg)
10
Causes of cell injury - summary
• Hypoxia
• Chemical
• Physical
• Infection
• Immune
• Nutritional deficiency (or excess!)
![Page 11: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/11.jpg)
11
Principle structural targets for cell damage
• Cell membranes– Plasma membrane– Organelle membranes
• DNA• Proteins
– Structural– Enzymes
• Mitochondria– oxidative phosphorylation
![Page 12: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/12.jpg)
12
Pathogenesis of cell injury - hypoxia
• Reversible– Loss of ATP
• Failure of Na/K pump
– Anaerobic metabolism
• Increased lactic acid and phosphate
– Reduced protein synthesis
![Page 13: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/13.jpg)
13
Pathogenesis of cell injury - hypoxia
• Irreversible– Massive intra-
cytoplasmic calcium accumulation
– Enzyme activation
![Page 14: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/14.jpg)
14
Pathogenesis of cell injury - general
• Reduced ATP synthesis/mitochondrial damage
• Loss of calcium homeostasis
• Disrupted membrane permeability
• Free radicals
![Page 15: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/15.jpg)
15
Free radicals
• Highly reactive, unstable chemicals
• Associated with cell injury– Chemicals/drugs, reperfusion injury,
inflammation, irradiation, oxygen toxicity, carcinogenesis
![Page 16: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/16.jpg)
16
Free radicals• Free radical generation occurs by….
– Absorption of irradiation• E.g. OH•, and H•
– Endogenous normal metabolic reactions• E.g. O2
-•, and H2O2
– Transition metals• E.g. Fe+++
– nitrous oxide• an important paracrine-type mediator that helps regulate
vascular pressure
– Toxins • e.g. carbon tetrachloride
![Page 17: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/17.jpg)
17
Free radicals
• Free radicals are removed by….– Spontaneous decay– Anti-oxidants
• E.g. Vitamin E, vitamin A, ascorbic acid, glutathione
– Storage proteins• E.g. transferrin, ferritin, ceruloplasmin
– Enzymes• Catalase, SOD, glutathione peroxidase
![Page 18: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/18.jpg)
18
Free radicals
• Injure cells by…..– Membrane lipid peroxidation
• Autocatalytic chain reaction
– Interaction with proteins• Protein fragmentation and protein-protein
cross-linkage
– DNA damage• Single strand breaks (genomic and
mitochondrial)
![Page 19: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/19.jpg)
19
General protective mechanisms
• Heat shock response genes– comprise a large group of genes – expression is up-regulated in the face of cell stressors
and – serve to protect proteins from stress-related damage – "clean up" damaged proteins from the cell.
• Many tissues and organs can survive significant injury if they are "pre-stressed" – Ways to exploit this phenomenon to improve organ
transplantation and tissue repairs are being tested in clinical trials.
![Page 20: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/20.jpg)
20
Cell injury - morphology
• Reversible
• Irreversible
![Page 21: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/21.jpg)
21
Cell injury - morphology
• Light microscopy
– Cytoplasmic changes
– Nuclear changes
![Page 22: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/22.jpg)
22
Cell injury - morphology
• Abnormal accumulations– Lipid
– Protein
![Page 23: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/23.jpg)
23
Necrosis• Definition
– Death of groups of contiguous cells in tissue or organ
• Patterns– Coagulative– Liquefactive– Caseous– Fat necrosis– (gangrene)– (Infarct)
• Red/haemorrhagic• White
![Page 24: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/24.jpg)
24
Coagulative necrosis• Cells have died but the basic shape and
architecture of the tissue endures• Most common manifestation of ischaemic
necrosis in tissues. • Affected tissue maintains solid
consistency. • In most cases the necrotic cells are
ultimately removed by inflammatory cells. • The dead cells may be replaced by
regeneration from neighboring cells, or by scar (fibrosis).
![Page 25: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/25.jpg)
25
Coagulative necrosis
NecrosisNormal
![Page 26: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/26.jpg)
26
Coagulative necrosis
![Page 27: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/27.jpg)
27
Liquefactive necrosis
• Complete dissolution of necrotic tissue.
• Most commonly due to massive infiltration by neutrophils (abscess formation). – Release of reactive oxygen species
and proteases
• Liquefaction is also characteristic of ischaemic necrosis in the brain.
![Page 28: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/28.jpg)
28
Liquefactive necrosis
![Page 29: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/29.jpg)
29
Caseous necrosis
• Accumulation of amorphous (no structure) debris within an area of necrosis.
• Tissue architecture is abolished and viable cells are no longer recognizable.
• Characteristically associated with the granulomatous inflammation of tuberculosis. Also seen in some fungal infections.
![Page 30: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/30.jpg)
30
Caseous necrosis
![Page 31: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/31.jpg)
31
Caseous necrosis
![Page 32: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/32.jpg)
32
Fat necrosis• Results from the action of lipases released into
adipose tissue. – pancreatitis, trauma.
• Free fatty acids accumulate and precipitate as calcium soaps (saponification). – These precipitates are grossly visible as pale
yellow/white nodules
• Microscopically, the digested fat loses its cellular outlines. There is often local inflammation
![Page 33: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/33.jpg)
33
Fat necrosis
![Page 34: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/34.jpg)
34
Gangrene ("gangrenous necrosis")
• Not a separate kind of necrosis at all, but a term for necrosis that is advanced and visible grossly. – If there's mostly coagulation necrosis, (i.e., the typical
blackening, desiccating foot which dried up before the bacteria could overgrow), we call it dry gangrene.
– If there's mostly liquefactive necrosis (i.e., the typical foul-smelling, oozing foot infected with several different kinds of bacteria), or if it's in a wet body cavity, we call it wet gangrene.
![Page 35: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/35.jpg)
35
Gangrenous necrosis
![Page 36: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/36.jpg)
36
Infarction
• An area of ischaemic necrosis in a tissue or organ– White
• Arterial occlusion in most solid tissues
– Red/haemorrhagic• Venous occlusion• Loose tissues• Dual blood supply• Previously congested
![Page 37: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/37.jpg)
37
White infarct
![Page 38: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/38.jpg)
38
Red infarct
![Page 39: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/39.jpg)
39
Apoptosis - basics
• is a distinct reaction pattern which represents programmed single-cell suicide.
• Cells actually expend energy in order to die. • Derived from Greek "falling off" (as for
autumn leaves) • Apoptosis is "the physiological way for a cell
to die", seen in a variety of normal situations.
![Page 40: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/40.jpg)
40
Apoptosis - morphology• Necrosis:
– pathological response to cellular injury. – Chromatin clumps, mitochondria swell and
rupture, membrane lyses, cell contents spill, inflammatory response triggered
• Apoptosis– DNA cleaved at specific sites - 200 bp
fragments. – Cytoplasm shrinks without membrane rupture – Blebbing of plasma and nuclear membranes – Cell contents in membrane bounded bodies,
no inflammation
![Page 41: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/41.jpg)
41
Apoptosis - normal
A stain for apoptotic cells in the developing paw of a foetal mouse.
![Page 42: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/42.jpg)
42
Apoptosis -pathological
Graft-versus-host disease in colonic mucosa
![Page 43: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/43.jpg)
43
Apoptosis - triggers
• Withdrawal of growth stimuli– E.g. growth factors
• Death signals– E.g. TNF and Fas
• DNA damage– p53 plays an important role
![Page 44: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/44.jpg)
44
Apoptosis - mechanisms
• Extrinsic factors – E.g. by
members of the TNF family
• Intrinsic mechanisms – E.g. hormone
withdrawal
![Page 45: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/45.jpg)
45
Summary
• This talk has covered….– Causes of cell injury– Cellular targets– Pathogenesis– Morphology of cell injury– Patterns of necrosis– Apoptosis
![Page 46: Leicester Warwick Medical School CELL INJURY Dr Gerald Saldanha Dept of Pathology.](https://reader035.fdocuments.us/reader035/viewer/2022062620/551ba220550346167e8b5ad0/html5/thumbnails/46.jpg)
46
Final thought…
Our lives are filled with joys and strife,
And what is death but part of life?
Will come the day that we must die,
And leave behind those learning why.