1
Q
Describe the 4 categories of hypoxia
A
- Hypoxaemic -> low pO2
- Anaemic -> reduced ability of Hb to carry O2
- Ischaemic -> interruption to blood supply
- Histiocytic/cytotoxic -> inability to utilise oxygen
2
Q
What are the 4 target areas of cellular injury?
A
- Cell membrane
- Nucleus
- Proteins
- Mitochondria
3
Q
Describe the consequences of hypoxia on a cellular level and how it leads to cell death
A
- Decreased oxidative phosphorylation = decreased ATP = decreased NaKATPase = imbalance of electrolytes = oncosis
- Anaerobic metabolism produces lactic acid = lower pH = enzymes begin to denature and ribosomes fall of rER causing decreased protein synthesis
- Increased cytosolic Ca from mitochondria, endoplasmic reticulum and increased pm permeability = activation of cellular enzymes such as phospholipase and endonuclease = cell death
4
Q
What is a free radical and why are they so dangerous?
Name 3 in the body
A
- Molecule with single unpaired electron
- highly reactive, often producing more free radicals and result in damage to DNA and other cellular components -> apoptosis
- OH-, O2*, H2O2
5
Q
How does the body defend against free radicals?
A
- Enzymes such as superoxide dismutase and catalase
- Free radical scavengers such as vitamins ACE
- Reducing molecules such as glutathione
6
Q
What is ischaemic reperfusion injury?
A
-When blood vessels undergo ischaemia they continue to produce vasodilator metabolites such as adenosine/H+ which causes a high bloodflow to return. The returning flow can damage cells as it contains a high amount of free radicals, neutrophils and complement
7
Q
Decribe the nuclear changes which occur in necrosis
A
- Pyknosis -> chromosome clumping
- Karryohexis -> chromosome lysis
- Karyolysis -> disintegration
8
Q
Describe the main differences morphologically between apoptosis and necrosis
A
- Apoptosis -> single cell death with shrinkage and organised degradation and disintergration of cells forming budding apoptotic bodies -> cell membrane preserved
- Necrosis -> cell death with swelling -> loss of integrity of pm causing blebbing and release of proteolytic enzymes
9
Q
Describe the 4 types of necrosis and when they are seen
A
- Coagulative -> proteins coagulate and clump and outline preserved, associated with ischaemia
- Liquefactive -> proteins autolysed and dissolved, associated with abscesses and bacterial infections and tissues with little support
- Caseous -> TB
- Fat -> acute pancreatitis or direct trauma to fatty tissue
10
Q
Describe the different types of gangrene
A
- Dry -> Necrosis which has been modified by the air
- Wet -> necrosis which has been modified by bacteria (septecaemia)
- Gas -> tissue infected with anaerobic bacteria producing bubbles under the skin
11
Q
What is infaction and describe its types and when they occur
A
- Ischaemic necrosis
- White -> solid organs as limits haemorrahage from adjacent capillaries, occulsion of end arteries
- Red -> dual blood supply with one vessel not being sufficient to maintain perfusion, loose tissue with poor stromal support as adjacent capillaries burst
12
Q
In which two ways is apoptosis initiated?
A
- Intrinsic by leakage of Cytochrome C
- Extrinsic by binding of death ligand
13
Q
List 3 abnormal accumulations which can occur in cells and a disease associated with it
A
- Fat -> steatosis in fatty liver disease
- a1-antitrypsin produced in liver -> misfolded proteins accumulate -> liver failure
- Carbon -> coal worker’s pneumoconiosis
- Haemosiderin -> Hereditary haemochromotosis (increased intestinal absorption of iron which gets deposited in liver, skin, pancreas and heart - bronze diabetes)
- bilirubin -> jaundice
14
Q
What are the two types of pathological calcification and their causes?
A
- Dystrophic -> local deposition due to local disease
- Metastatic -> systemic deposition, often due to hyperpatathyroidism
15
Q
Define acute inflammation and name its 4 cardinal signs
A
- Response of living tissue to injury which is immediate, innate and stereotyped with a short duration
- rubor -> redness
- tumor -> swelling
- calor -> heat
- dolor -> pain
16
Q
Describe the changes in vessels which occurs in acute inflammation
A
- Transient vasoconstriction
- Vasodilatation of arterioles/capillaries causing increased blood flow (rubor and calor)
- Increased vascular permeability resulting i exudation of fluid into tissues and vascular stasis (tumor)
17
Q
Describe the role of histamine in acute inflammation
A
-Early responder as it is presynthesised and stored. released from mast cells, basophils and platelets in response to many stimuli to cause vascular dilatation, increase in vascular permeability and pain
18
Q
What causes exudation of fluid in inflammation?
A
- Increased vascular permeability
- Vasodilation -> increased bf -> increased hydrostatic pressure
- Increased oncotic pressure of interstitium
19
Q
Give 3 generic causes of exudative oedema
A
- Infection
- Inflammation
- Malignancy
20
Q
What is the primary wbc involved in acute inflammation? Describe its infiltration into tissues
A
- Neutrophil
1) Margination (stasis causes neutrophils to line up along endothelium)
2) Rolling
3) Adhesion (ICAMs, Integrins)
4) Extravasation
21
Q
What are the 2 killing mechanisms used by neutrophils and what immunodeficiency is associated with one of them?
A
- O2 independant -> Lysozyme and hydrolases
- O2 dependant -> produces superoxide and H2O2 -> most efficient mechanism -> inability to do this produces Chronic Granulomatous Disease
22
Q
What is the purpose of exudation of fluid in acute inflammation?
A
- Deliver plasma proteins to site of injury -> Igs, inflam mediators
- Dilute toxins
- Increases lymphatic drainage -> increase delivery of microorganisms to lymph nodes
23
Q
What is the acute phase response and what proteins are involved in it? Why are the proteins useful?
A
- Decreased appetite, raised HR, altered sleep etc
- CRP
- Haptoglobin
- Can be used as a marker of inflammation
24
Q
What separates acute inflammation from chronic inflammation?
A
- Chronic inflammation involves granulation tissue, fibrosis and healing by scarring in addition to the resolution occuring with a degree of dysfunction
- Macrophage is dominant in chronic vs neutrophil in acute
25
Describe the different types of giant cell and when they are seen
- Langhan -> nuclei around the periphery -> seen in TB
- Foreign body -> Random nuclei -> hard to digest material -> frustrated phagocytosis
- Touton -> nuclei arranged in a ring towards centre -> fatty tissues
26
Why does fibrosis occur in chronic inflammation? Why is it damaging?
-Prolonged or excessive cytokine stimulation of fibroblasts produces excessive collegen leading to fibrosis as the excess CT goes beyond healing a scar to replacing normal parenchyma and impair function
27
Liver cirrhosis is a form of chronic inflammation. What are the most common causes of liver cirrhosis
- Alcohol
- NAFLD
- hepatitis
28
What is a granuloma?
-Localised collection of cells characterised by the presence of epithelioid histiocytes, giant cells and lymphocytes which have formed in response to hard to clear infections/material
29
Name 4 diseases associated with granulomas
- Crohns
- Sarcoidosis
- TB
- Granulomatosis with polyangitis
30
Define regeneration of cells. Which cell populations can undergo regeneration? What helps to control regeneration of cells?
- The replacement of dead or damaged cells by functional differentiated cells
- Labile populations eg epithelia and stable populations eg hepatocytes
- Cell cycle and growth factors/gene modulators which control it, hormones, contact inhibition
31
What is fibrous repair? In which populations does it occur? Briefly describe the process
- The replacement of functional tissue with scar tissue
- Permanent cell lines eg myocytes
- Blood clot forms -> granulation tissue as infiltrated by macrophages and fibroblasts -> fibroblasts produce collagen and ECM. Angiogenesis occurs. Cell population falls and collagen increases -> fibrous scar
32
Briefly describe the process of angiogenesis
- Proteolysis of endothelial basement membrane of existing vessel
- Proliferation and migration of endothelial cells which arrnage themselves into a new vessel following a designated tip cell
- Remodelling and stablisation of new vessel making sure it connects with venous system
33
What are the constituents of ECM?
- GAGs
- Collagen/Elastin
- Proteoglycans
34
What is healing by primary or secondary intention?
- Primary intention = apposed edges with minimal clotting. Epidermis regenerates with minimal contraction
- Secondary intention = large wounds or ulcers -> Epidermis has to regenerate from base up forming a scab. more granulation tissue and fibrous repair -> contraction to make edges meet
35
Briefly explain what happens in a minor cut in successful haemostasis
-BVs contract to limit blood flow -> Platelets become activated by extrinsic pathway and adhere to the damaged vessel wall and each other and set off a cascade activating other platelets to form a platelet plug and stop the bleeding -> primary haemostatic plug -> more platelets adhere and fibrinogen is converted to fibrin by thrombin causing cross linking of platelets making a stable secondary haemodynamic plug
36
Name some endogenous proteins which help control the coagulation cascade to prevent thrombosis
-Anti-thrombin III, Protein C and S
37
What is fibrinolysis? Name an endogenous mediator and how this process is used clinically
- The breakdown of fibrin to control excessive clotting
- Plasmin
- tPA (alteplase) or streptokinase
38
What is thrombosis? What causes it to occur? What is Virchows traid?
- Inappropriate clot formation inside a blood vessel
- Inappropriate activation of the clotting cascade
- Abnormal BVs (atheroma, hypertension, toxins), abnomal consituents (OCP, smoking, surgery, blood disorders) and abnormal flow (stasis, AF, CCF, valvular disease). 2/3 needed for thrombosis
39
What are the possible outcomes of thrombosis?
- Propagation -> progressive spreas
- Occlusion
- Organisation -> lumen remains obstructed but turned to granulation tissue
- Resolution
- Embolism
- Recanalisation
40
What is an embolism?
-Blockage of a BV by part of a thrombus which has broken off from a different site (doesnt have to be thrombus)
41
Give some factors which predispose to DVT
- Smoker
- Immobility
- Pregnancy
- Post-surgery
- OCP/HRT
- Malignancy
42
Describe the intrinsic and extrinsic pathways
- Intrinsic is activated by endothelial damage which initiates the formation of the primary complex which becomes activated. Activated FXIIa activates FXI which activates FIX. FIXa activates FX which activates prothrombin which activates fibrinogen
- Extrinsic is activated by damage to the BV allwing FVII to be exposed to TF causing its activation -> FVIIa activates FX which activates prothrombin which activates fibrinogen
