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1

What are the main causes of cell injury?

Hypoxia Chemical Physical Infection Immune Nutritional deficiency/excess

2

What are causes of hypoxia?

Ischaemia: local (e.g. embolus) or systemic (e.g. cardiac failure) Hypoxaemia: a state of chronic/lowered O2, usually less accute than ischaemia. Caused by oxygen problems (e.g. altitude) or haemoglobin problems (e.g. anaemia - blood cells cannot caputre and carry normal levels of O2) Oxidative phosphorylation: e.g. cyanide poisoning which can lead to rapid cell death

3

What is Ischaemia? What is its effect?

A blockage in blood supply that leads to hypoxia due to an insufficiency of O2. This leads to a decrease in the production of ATP, limits metabolite substrates and allows for the accumulation of wastes. The effect of ischaemia is related to balance between reversible and irreversible injury and is largely dependent on the length of time the cell/tissue/organ is exposed to the stress. If the injury persists then the damage increases. If mitochondria are irreversibly damaged then there is no cellular energy: this irreversible damage means the cell CANNOT recover and will lead to cell death.

4

Is recovery possible after ischaemia?

There is a window of opportunity for rescue. This varies between cell and tissue types and is largely dependent on time. Reperfusion is the restoration of blood flow: cells can recover if O2 and substrates are provided. However there is the 'REFLOW PARADOX' in which sometimes damage is INCREASED as the blood begins to flow again. This is known as reperfusion injury, aka Ischaemic-Reperfusion Injury

5

What are types of chemical insults to the cell?

Many of the common poisons (arsenic, cyanide, heavy metals) interfere with cellular metabolism. If ATP levels drop below critical levels, cells will die. The number of pharmaceuticals that may have toxic effects on cells is enormous. Some act directly, but most exert their effect via metabolites. Metabolism of alcohol (a type of drug) to acetaldehyde is one example.

6

What are types of infectious insults to the cell?

Fungi, Rickettsiae, Bacteria and Viruses: e.g. viruses can take over protein translation machinery and subvert it entirely to the production of new virions. Can also promote abnormal apoptosis.

7

What are types of physical insults to the cell?

Direct physical effects can include: - exposure of tissue to extreme heat or cold resulting in direct injury that is often irreversible and a pattern of coagulative necrosis - 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.

8

What are some immune insults to the cell?

Major inflammatory mediators such as cytokines can alter both gene expression and cellular metabolism. The effects are designed to help cells combat an infectious process, by 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 and initiate the self-destruct cascade within a target cell. Abnormally triggered, they can cause abnormal cell death.

9

What are some insults to the cell caused by 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"

10

What are Free Radicals?

FRs are highly reactive, unstable chemicals. They are associated with cell injury and are formed by a number of things including chemicals/drugs, reperfusion injury, inflammation, irradiation, oxygen toxicity and carcinogenesis. They interfere with normal molecules and cause things such as DNA damage.

11

How are FRs formed?

Generation occurs by: - absorption of irradiation e.g. OHº, and Hº - endogenous normal metabolic reactions e.g. O2-º and H2O2 - Transition metals e.g. Fe+++, Cu, Mg etc - Nitrous oxide (NO): an important paracrine-type mediator that helps regulate vascular pressure - Toxins e.g. acetaldehyde

12

How are FRs removed?

- Spontaneous decay: don't usually hang around for a long time after formation - Anti-oxidants e.g. Vitamin E, Vitamin A, ascorbic acid, glutathione - Storage proteins can scavenge FRs e.g. transferrin, ferritin, ceruloplasmin - Enzymes - mop up FRs e.g. catalase (breaks down H2O2), SOD, glutathione peroxidase

13

How do FRs injure cells?

- Membrane lipid peroxidation: autocatalytic chain reaction - Interaction with proteins: protein fragmentation and protein-protein cross linkage - DNA damage: single strand breaks (genomic and mitochondrial)

14

What are principle structural targets for cell damage?

- Cell membranes (plasma and organelle) - DNA - Proteins (structural and enzymes) - Mitochondria (oxidative phosphorylation); they are the energy factory of the cell and very sensitve to imbalances

15

What are the general features of pathogenesis of cell injury?

- Reduced ATP synthesis/mitochondrial damage - loss of calcium homeostasis - disrupted membrane permeability - free radicals

16

What are some general protective mechanisms?

Heat shock response genes: - comprise a large group of genes - expression is upregulated in the face of cell stressors - 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" = ADAPT - ways to exploit this phenomenon to improve organ transplantation and tissue repairs are being tested in clinical trials

17

What are key factors/indicators of reversible vs irreversible cell injury?

TIME is a critical factor, in conjuction with severity of the injury itself.

18

What are some examples of reversible cell injury?

Reversible injuries can include a loss of ATP due to e.g. failure of a Na/K pump, anaerobic metabolism and increased lactic acid and phosphate, reduced protein synthesis.

19

What are some examples of irreversible cell injury?

Massive intra-cytoplasmic calcium accumulation. Enzyme activation.

20

What are some morphological changes in reversible cell injury/necrosis?

In comparison to normal cells: - early reversible ischemic injury can show things such as surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. - Necrosis of epithelial cells can show loss of nuclei, fragmentation of cells, and leakage of contents

21

What are some features of necrosis vs apoptosis?

Cell size: enlarged/swelling vs reduced/shrinkage Nucleus: pyknosis > karyorrhexis > karyolysis vs fragmentation into nucleosome-size fragments Plasma membrane: disrupted vs intact; altered structure, especially orientation of lipids Cellular contents: enzymatic digestion; may leak out of cells vs intact; may be released in apoptotic bodies Adjacent inflammation: frequent vs none Physiologic or pathologic role: invariably pathologic (culmination of irreversible cell injury) vs often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage

22

What is necrosis?

Death of groups of contiguous cells in tissue or organ. The main patterns of necrosis are coagulative, liquefactive, caseous, fat necrosis, gangrene, infarct (red/haemorrgaic, white)

23

What is coagulative necrosis?

-Cells have died but the basic shape and architecture of the tissue remains -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 or replaced by scar (fibrosis)

24

What is caseous necrosis?

- Accumulation of amorphous (no structure) debris within an area of necrosis - TIssue architecture is abolished and viable cells are no longer recognisable - Characteristically associated with the granulomatous inflammation of tuberculosis. Also seen in some fungal infections.

25

What is 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

26

What is 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

27

What is apoptosis?

- A distinct reaction pattern which represents programmed cell-autonomous suicide - Cells actually expend energy in order to die - Apoptosis is "the physiological way for a cell to die", seen in a variety of normal situations - Triggered by: withdrawal of growth stimuli e.g. growth factors, death singals e.g. TNF and Fas, DNA damage - p53 plays an important role - Apoptosis is normal and very controlled, the most obvious examples occur in embryonic development

28

What is the morphology of apoptosis?

- DNA cleaved at specific sites - 200bp fragments - Cytoplasm shrinks without membrane rupture - Blebbing of plasma and nuclear membranes - Cell contents in membrane bounded bodies, no inflammation

29

What are the mechanisms of apoptosis?

There are two main mechanisms for apoptosis: - The mitochondrial/intrinsic pathway - The death receptor/extrinsic pathway