Hannah's attempts Flashcards
1
Q
Give a definition for pathology in reference to wound repair.
A
These are the mechanisms by which cells, tissues and organs defend themselves against injury and insult
2
Q
What are the four main defence systems?
A
- Haemostasis (blood clotting)
- Inflammation
- Immunity and immune responses
- Wound repair
3
Q
What is the prevalence of skin injuries and tissue repair?
[EXTRA]
A
- 70m surgical procedures in the USA every year, estimated ~11m for lacerations
- ~11m people affected by burn injuries per year
- 4,500 deaths per year in the USA, ~10,000 deaths from burns-related infections
- ~100m patients worldwide with cutaneous fibrosis (scarring)
- Chronic wounds are an increasing problem
4
Q
What are the goals and outcomes of wound repair?
A
- Removal of dead and damaged cells
- Removal of the fibrin clot (fibrinolysis)
- Removal of other molecules in the exudate
- Restoration of damaged structures
5
Q
What are two important things to note about wound repair?
A
- Repair starts at the same time as inflammation
- Repair is a dynamic process
6
Q
What are the good outcomes of wound repair?
A
Resolution and repair
- Complete restoration of normal function
- E.g. haematopoietic system (blood lost through haemorrhage or trauma will be replaced relatively quickly by haemopoietic stem cells)
- E.g. damage to the gut epithelium (very high capacity for repair)
- E.g. bone fracture in young people (if set properly, complete restoration of structure and function)
7
Q
What are some examples of bad outcomes of wound repair?
A
- Excessive repair
- Hypertrophic scars (scar does not extend beyond the wound, raised scar tissue)
- Keloid (scar does extend beyond the boundaries of the wound, raised scar tissue)
- Replacement of normal tissue with fibrous scar
- E.g. in myocardial infarct, myocardium is replaced with scar tissue, which affects function through being less able to contract and upsetting the electrolyte balance around the tissue
- Continued ulceration
- Chronic, non-healing wounds
8
Q
What are the phases of cutaneous wound healing?
A
- Injury to epidermis and dermis
- Coagulation - platelet activation and fibrin deposition
- Early inflammation - occurs within the first 24hrs, PMN recruitment
- Late inflammation - occurs within 48hrs, macrophage recruitment and angiogenesis
- Granulation tissue formation (NOT to be mixed up with granuloma) - occurs at around 72hrs, defined by recruitment and proliferation of endothelial cells and fibroblasts
- Extracellular matrix deposition via fibroblast collagen synthesis
- Remodelling of collagen occurs over weeks to months
- Scar
9
Q
Label the different layers of the skin on the diagram
A
10
Q
What is healing by first intention?
A
- This is the healing that occurs when a clean laceration or surgical incision is made and then closed primarily, with sutures, Steri-Strips or another skin adhesive
- In general, these wounds heal fairly quickly (within 6-8 days)
11
Q
What is healing by second intention?
A
- This is where a wound is healed from the base upwards through the laying down of new tissue
- This occurs due to the edges of the wound not being merged/the wound not being closed, and so granulation occurs instead
- In some cases, infection must also be resolved first, with includes an acute inflammatory response and the generation of pus before granulation tissue can be generated
12
Q
What is granulation tissue?
A
- NB NOT the same as granuloma (small area of inflammation)
- Opposite of necrosis
- This is new connective tissue full of newly forming blood vessels that are needed for wound healing
- This tissue is created and modified by fibroblasts
- Pink in colour (due to new blood vessels)
- Granular due to punctate haemorrhage (small capillary haemorrhages into the skin that form petechiae, small brown/red spots)
- Fibroblasts lay down extracellular matrix (ECM), especially type III collagen
- This is later replaced by type I collagen, the main constituent of scar tissue
13
Q
What do fibroblasts initially lay down in granulation tissue, and then what is this later replaced by?
A
- Extracellular matrix in the form of type III collagen
- This is later replaced by type I collagen
14
Q
What does the histology slide show? What are the white arrows indicating, and what else can be seen?
A
- Arrows indicate macrophages in granulation tissue
- Also some indication of angiogenesis
15
Q
Describe the process of first intention wound healing.
A
- Platelet thrombus forms within minutes
- Monocyte, neutrophil and macrophage recruitment occurs within hours
- Fibroblast infiltration into the wound begins within days
- After 7-10 days, no neutrophils are seen and have instead been replaced with macrophages and fibroblasts
- Laying down of collagen begins to occur (1 month to 2 years)
- After 1 month - 2 years, there is remodelling and the deposition of a collagen-containing scar
- Some fibroblasts may still be seen
16
Q
How are stem cells important in wound healing?
A
- Important aspect of wound healing is the appearance of stem/mesenchymal cells which give rise to temporary wound-associated cells and then fully differentiated cells
- In the wound bed, mesenchymal derived cells are differentiating into fibroblasts
- Generation of endothelial cells gives rise to small capillary buds that will then allow for angiogenesis
- Microbes entering the wound site are attacked by macrophages in differing levels of differentiated status, allowing the microbes to be phagocytosed
17
Q
How are blood clots formed and broken down?
A
- Fibrin deposition is initiated by platelet activation
- Fibrinogen is converted into fibrin by Thrombin
- Fibrin is crosslinked by Factor XIII to form the clot
- Fibrinolysis occurs once the clot has formed
- Plasminogen is converted into plasmin, which is an enzyme that breaks down fibrin in clots
- Plasmin generation is sped up by plasminogen activators
- Tissue plasminogen activator (tPA, from endothelial cells0
- Urokinase plasminogen activator (uPA, derived from macrophages and neutrophils)
- There are also tissue and plasma inhibitors of plasmin, which are:
- PAI-1 (plasminogen activator inhibitor)
- ɑ2 antiplasmin
- ɑ2 macroglobulin
18
Q
What are plasminogen activators?
A
- Tissue plasminogen activator (tPA, found on endothelial cells, serine protease)
- Urokinase plasminogen activator (uPA, derived from macrophages and neutrophils, serine protease, can bind to receptors near the site to localise action)
19
Q
What are the tissue and plasma inhibitors of plasmin?
A
- Plasminogen activator inhibitor-1
- Mainly synthesised in endothelial tissue
- PAI-1, serine protease inhibitor acting on tPA and uPA (direct inhibition of, or binds to uPA-receptors and causes their degradation)
- ɑ2 antiplasmin
- Synthesised in the liver, found in the circulating plasma
- Serine protease inhibitor that directly inhibits plasmin (also inhibits neutrophil elastase)
- ɑ2 macroglobulin
- Found in the blood, locally synthesised by macrophages and fibroblasts (but also by the liver)
- Inhibits plasmin and kallikrein (anti-protease)
Function of these molecules is to prevent premature dissolution of fibrin clots, which would cause continued bleeding and the possibility for infection
20
Q
What is angiogenesis?
A
New capillary growth or ‘sprouting’
21
Q
How does angiogenesis occur and what is its role in wound repair?
A
Characterised by:
- Endothelial cell migration
- This is via fibronectin (glycoprotein involved in cell-adhesive interactions, induced intracellular signalling changes)
- Endothelial cell proliferation
- Mediated by vascular endothelial growth factors (VEGFs, secreted by macrophages and platelets) and transforming growth factor alpha (TGF-ɑ, likely to be secreted by cells of endothelial origin)
- Proteolysis of ECM
- This is achieved via collagenases, tPA and uPA
- Endothelial cell tube formation
In wound repair, angiogenesis forms new vessels from preexisting vessels through invasion of the wound clot and organisation of a microvascular network through the granulation tissue
*
22
Q
How can angiogenesis be detrimental?
[EXTRA]
A
- Angiogenesis is part of solid tumour growth
- Also seen in ‘wet’ macular degeneration (formation of abnormal blood vessels in the retina, can quickly lead to blindness)
- However, this process is useful and vital in wound repair
23
Q
What are the roles of macrophages in wound repair?
A
- Central role in tissue debridement
- This is the process of removing all nonviable (dead/necrotic) and infected tissue, alongside foreign debris and potential pathogens
- Source of growth factors and cytokines at the site of injury and repair
- Tissue remodelling and development
- Defence against infection
24
Q
What are the roles of fibroblasts in wound repair?
A
- Contribute to both initiation and resolution phases
- Primary source of ECM production, which provides a scaffold for cells and plays a key role in determining cell phenotype and function
- Fibroblasts secrete:
- Collagen III and then collagen I
- Glycosaminoglycans
25
Q
What cytokines regulate fibroblasts?
A
- PDGF - platelet derived growth factor, enhances cell proliferation and chemotaxis
- FGF - fibroblast growth factor, enhances proliferation
- TGFβ - transforming growth factor beta, promotes fibroblast proliferation and collagen deposition
26
Q
What are the different features shown on the cell type below?
A
27
Q
What are cytokines?
A
- Small proteins (5-20kDa) that are important in cell signalling
- Alter the behaviour of cells in an autocrine, paracrine or systemic manner, and have important effects on the immune response
- Include:
- Chemokines - induce directed chemotaxis
- Interferons - released in response to virus, induce and enhance anti-viral properties in target cells
- Lymphokines - produced by lymphocytes (typically T cells), helps to coordinate the immune system
- Monokines - mainly produced by monocytes and macrophages, act as chemoattractants for leukocyte recruitment
- Tumour necrosis factor - plays a role in cell survival, proliferation, differentiation and death
- These are not hormones and are generally considered to be different to growth factors
- Act through receptors and are very important in immune responses
- Modulate the balance between the humoral and cell-based immune responses
- Regulate the growth, maturation and responsiveness of target cell populations (e.g. immune cells)
- Some will inhibit or enhance the action of other cytokines (cross-interactions)
28
Q
What are the extremes of cutaneous wound healing?
A
29
Q
What are some experimental models of wound healing?
[EXTRA]
A
30
Q
What are some experimental examples of wound repair in knockout mice?
[EXTRA]
A
- Transgenic mice defective in endogenous glucocorticoid synthesis (GRdim mice)
- These show increased mass of granulation tissue in early wounds (glucocorticoids have anti-inflammatory action, and their excess can prevent wound healing - lack of presence therefore causes mass production of tissue?)
- CX3CL1 Fractalkaline and CX3CR1 KO mice
- The former is a chemoattractant cytokine (chemokine) that recruits monocytes to the site of injury
- The latter is the receptor through which the fractalkaline exerts its effects on monocytes and macrophages through (GPCR)
- Has anti-apoptotic effects on monocytes and other cell types via CX3CR1 (Greaves, 2012)
- Graph and data attached shows wound repair in WT and CX3CR1 KO mice (initial rate in wound closure is similar, but at approx day 3 there is a statistically significant difference in wound area reduction rate between the two strands)
- NB KO mice can be limited by the embryonic lethality of certain genes - newer technologies have allowed for more refined models, however
31
Q
Compare samples of type I collagen taken from WT and CX3CR1 KO mice and the significance of this.
[EXTRA]
A
- Expression of type I collagen taken at 0, 3 and 6 days
- Expression in KO mice reduced at days 3 and six
- Beta-actin was used as a control (cytoskeleton, therefore always present)
- When mRNA saples taken, levels of type I collagen significantly lower at days 3 and 6 in the KO mice
- This suggests the important role of the Fractalkaline receptor in cutaneous wound healing
32
Q
What are the limitations of mouse models in wound repair?
[EXTRA]
A
- Mouse wounds heal by contraction as opposed to collagen deposition and remodelling/scar formation
- No accepted models of scarring in mouse wounds, they either heal completely or fail to do so
- No good models of keloid or non-healing wounds
- Even if it was ethically appropriate to have these, which it arguably is not
HOWEVER, diabetic mice have identified changes in cytokine production in cutaneous skin wound repair, which has been beneficial.
33
Q
What are some examples of regeneration in wound healing?
[EXTRA]
A
- Newts, salamanders and axolotls are all able to regenerate limbs after sterile amputation
- Formation of blastema at site of amputation, with cells within being able to differentiate and reform the limb over time, replacing cells and reforming structures
- Recapitulation of embryonic development occurs
- The planarian (flat worm) can form neoblasts (non-differentiated cells) if the head or tail is amputated
- Formation of a wound epidermis and blastema, resulting in the outgrowth of the structures
- Zebrafish form a blastema and apical epithelial cap is a fin is cut off, from which it can then be regrown
- Amphibians exhibit blastema that can restore structures of amputated limbs
34
Q
What are the differences between foetal and adult wound healing?
[EXTRA]
A
- No inflammation in foetal wound repair
- No adaptive immune response in utero
- Foetal fibroblasts tend to secrete collagen III instead of collagen I
- Altered TGF-beta production in embryos
- This is an important cytokine in development and wound repair, but has altered production and possibly altered action in embryos
- Foetal cells have greater proliferative capacity
- Adult and late-gestational wounds heal with a scar, whereas early gestation embryos are remarkable for scar-free healing
- Fibromodulin is essential for scar-free healing, and restoration of recombinant Fm in late-gestational rat embryos was shown to restore scar-free healing capabilities
- In a mouse embryo, a limb was amputated in utero - healing process involved sheets of epithelial cells sweeping over the wound and resulting in the formation of no scar tissue
- Adult and late-gestational wounds heal with a scar, whereas early gestation embryos are remarkable for scar-free healing
35
Q
What are some examples of the failure of wound repair?
A
- Organisation and scarring
- Failure of hepatic regeneration and fibrotic response to toxic insult
- E.g. cirrhosis of the liver, causing hepatocytes to die and be replaced by fibroblasts
- Results in islands of healthy, functional hepatocytes surrounded by scarring
- Failure of hepatic regeneration and fibrotic response to toxic insult
- Excessive fibrotic response to foreign bodies
- E.g. silicosis - working with silica in the air and aerosols can result in the build-up of shadows on the lung, which are the result of massive swathes of fibrosis
- Replacement of normal tissue with fibrous scar
- E.g. folling ischaemia, seen in MIs as injury in the myocardium causes replacement with fibroblasts
- Repeated injuries
- Repeated head collisions resulting in traumatic brain injury
- These build up over time to result in chronic trauma encephalopathy (CTE)
- Classic signs of CTE can be seen in autopsy, reduction in brain tissue due to repeated inflammation/CNS injury
- Repeated head collisions resulting in traumatic brain injury
- Continued ulceration
- Venous and arterial ulcers
36
Q
How does continued ulceration occur?
A
- An ulcer is an open sore caused by a break in the mucosal lining or skin that then fails to heal
- This is a failure to restore normal function and develop due to a lack of ability to restore blood flow to the area/a lack of circulation
- Poor blood flow can occur as a result of diabetes, atherosclerosis and vein/valve issues
- When valves in the leg veins become damaged/are weak, there is a lack of blood flow back to the heart and accumulation of blood in the skin
- These are varicose ulcers
- Leg swelling and skin breakdown will result in formation of ulcers
- This can cause leakage of blood from the veins into the skin
- These are varicose ulcers
- Diabetic ulcers are related to failures in arterial flow, causing ischaemic areas to develop and ulcers to form
- Ulcers can also form as a result of pressure, which is often caused by prolonged immobility
37
Q
How can regenerative medicine be used in wound repair?
[EXTRA]
A
38
Q
How are lymphatic vessels involved in wound repair?
A
- Their regeneration and presence is important for wound healing, and this is seen through:
- VEGFR3 (vascular endothelial growth factor receptor 3)-expressing lymphatic vessels found in early granulation tissues, with regression in later stages
- The ligand for VEGFR3 (VEGFC) increases in response to tissue injury
- Wounds with impaired lymphatic systems are more susceptible to infection and a failure to heal properly
- This is because a function of the lymphatic system is to remove debris from a site of infection - preventing this could increase bacterial colonisation and trap other growth factors/matrix proteins
- Excessive oedema can also compress other vessels and limit blood flow, causing the area to become ischaemic
- The lymphatic system is also closely linked to the immune response, and so is necessary to fight infection
- VEGFR3 (vascular endothelial growth factor receptor 3)-expressing lymphatic vessels found in early granulation tissues, with regression in later stages
39
Q
Why is blood clotting important for wound healing?
A
- Blood clots form at sites of injury to prevent bleeding
- This occurs within minutes or even seconds
- They prevent further blood loss, which is obviously beneficial
- Blood clots also seal off a potential entrance into the body for pathogens
40
Q
What are the three stages of blood clotting?
A
- Vascular spasm/vasoconstrictin
- This is a brief and intense contraction of blood vessels to limit blood flow through this vessel - and therefore blood loss - through drastically increasing the resistance
- This is caused by thromboxane A2, which is produced by activated platelets and injured epithelial cells, which causes the vascular smooth muscle to contract
- This will also occur after direct injury to vascular smooth muscle and somewhat in the nervous system reflex to pain
- This vasoconstriction is brief, due to the inflammatory processes that follow, including the release of vasoactive cytokines
- Vasoconstriction should last until the fibrin plug is formed
- Vasoconstriction and haemostasis end as wound healing begins
- Formation of a platelet plug
- Subendothelial collagen is exposed due to damaged epithelial cells, and releases von Willebrand Factor (vWF)
- This causes platelets to form adhesive filaments which will bind to the subendothelial collagen on the damaged endothelial wall
- Binding to the collagen activates the platelet, causing it to release a series of chemical mediated and cytokines (degranulation)
- This includes: ADP, vWF (positive feedback), thromboxane A2, VEGF, serotonin and coagulation factors
- Platelets then aggregate into a barrier-like plug, as receptors on the platelets bind to vWF and fibrinogen molecules to hold platelets together
- In small wounds, this mesh may be enough to prevent blood loss, but in larger wounds the coagulation cascade will also be needed, which strengthens this platelet plug
- Subendothelial collagen is exposed due to damaged epithelial cells, and releases von Willebrand Factor (vWF)
- Coagulation
- Series of reactions that are divided into three pathways:
- Contact/intrinsic pathway, where a negatively charged particle initiates a cascade resulting in the formation of factor X
- Tissue factor/extrinsic pathway, where tissue damage caulses the release of tissue factor, creating a smaller cascade to facilitate the formation of factor X
- Common pathway, which merges both pathways in the production of thrombin from prothrombin due to the action of factor X
- Vitamin K, calcium and phospholipids are necessary cofactors for this process
- Production of thrombin then allows the cleavage of fibrinogen into fibrin, which forms the mesh that will adhese to and strengthen the platelet plug, therefore completing haemostasis
- Series of reactions that are divided into three pathways:
41
Q
How does infection inhibit wound repair?
A
- Infection of the wound triggers the body’s immune response
- This causes tissue damage and inflammation, alongside slowing down the healing process
- Prolonged inflammation in response to incomplete microbial clearance in an infected wound results in the prolonged elevation of inflammatory cytokines
- This elongated inflammatory phase prevents the transition to a healing phase
- Metalloproteases are also released as a result of inflammation, which degrade ECM
- Bacteria are also likely to form biofilms, which will slow healing
42
Q
How do glucocorticoids affect wound repair?
A
- They slow wound repair
- They are used as anti-inflammatories, which inhibit wound repair through global anti-inflammatory effects and suppression of cellular wound responses
- This includes fibroblast proliferation and collagen synthesis
- Systemic steroids cause wounds to heal with incomplete granulation tissue and reduced wound contraction
43
Q
How does malnutrition affect wound repair?
A
- Carbohydrate, energy, protein, fat, mineral and vitamin deficiency can all affect the healing process
- Energy sources (especially glucose as can be respired in anaerobic conditions) allow the synthesis of cellular ATP, which is needed for angiogenesis and deposition of new tissue
- Protein is needed for the synthesis of a number of components, with deficiency impairing angiogenesis, fibroblast proliferation, proteoglycan synthesis, collagen synthesis and wound remodelling
- Co-factors of iron and vitamin C are also needed for collagen synthesis
- Notable amino acids are arginine and glutamine
- Vitamins C, A and E show potent anti-oxidant and anti-inflammatory properties
- C and A deficiencies have also been shown to impair the wound healing process
- Magnesium, copper and zinc are all cofactors for various enzymes that are necessary for wound healing, iron is needed in some processes
- Mg in protein and collagen syntehsis
- Cu in cytochrome oxidase, superoxide dismutase (anti-oxidant) and optimal cross-linking of collagen
- Zn in RNA and DNA polymerase
- Fe is needed in hydroxylation of proline and lysine, which is necessary for collagen production
- Deficiency in vitamin K will also result in a failure of blood clotting
- So would hypocalcaemia, in theory, but toxic effects on the heart become significant before this has a chance to occur in vivo
47
Q
What is the duality of the immune response? What consequence does this have on the treatment of inflammation?
A
- Therefore, if the inflammatory response is suppressed through treatment, it may result in the same suppression occurring in the processes for host defence and repair
- [EXTRA] For example, COVID appears to give prolonged, residual and innappropriate inflammatory response, even long after the virus has been cleared
- This may give rise to some of the damage seen in late stages of an acute infection, or the pathology (e.g. pericarditis) seen in long-term COVID infections
- [EXTRA] For example, COVID appears to give prolonged, residual and innappropriate inflammatory response, even long after the virus has been cleared
50
Q
Briefly compare the adaptive and innate immune responses.
A
53
Q
Compare inflammation in the different sites shown in the image.
(Lung tissue on LHS, brain and spinal cord cross sections on the RHS)
[EXTRA]
A
- LHS image shows inflamed lung, animal was sensitised to an antigen and then exposed
- Excessive inflammatory response then occurs, causing the alterations in the tissue
- RHS image shows response of the tissues to injection with IL-1β, in red circles
- Spinal cord has a different response to the cytokine, as here it causes blood-spinal cord barrier breakdown and the infiltration of leukocytes, as seen by the large stained/brown region
- In the brain, there is very little BBB breakdown or recruitment of leukocytes
54
Q
Describe the response to an skin injury caused by a thorn.
A
- Upon entry, there is local tissue damage
- This activates complement systems (C5a and C3a, targeting mast cells) and generation of bradykinin (through the production of kinins from precursor molecules within the tissue)
- Pathogens may be introduced on the end of the thorn, which will bind to TLRs present of macrophages and other immune surveilling cells
- Depending on what the damage is, different responses will occur (see diagram)
- Initial responses are shown in pink on the diagram, downstream a series of responses will kick off very rapidly and via many different pathways, as shown in blue
- Effects spread to local neurons, which contribute to local inflammation through release of substance P (acts on mast cells) and CGRP
- Cytokines interact with fibroblasts, which will rapidly change their shape and start proliferating to aid repair
- These will release proteases to remodel the extracellular matrix (metalloproteinases, MMPs)
- Immature (type III) collagen is secreted initially and eventually replaced with type I collagen to reform the ECM
- Recruitment of leukocytes occurs through cytokines acting on local endothelial cells
56
Q
What is the model for hepatic control of CNS inflammation?
A
- After tissue injury, there is both a local and a peripheral response
- Signals are transported to the Kupffer cells of the liver, which response by activating NF-κB and upregulating the production of acute phase proteins
- These are responsible for the mobilisation of leukocytes from bone marrow into the circulation
- The acute phase response then regulates the systemic response to the tissue injury or disease
- [Circulating chemokines eliminate any evidence of a concentration gradient, as their concentration will be higher in the circulation as opposed to the injured tissue]
60
Q
How are lipid mediators of inflammation generated?
A
- Through the action of phospholipase A2 isoforms
- These are activated by many different mechanisms
- Enzyme is recruited to the cell surface by calcium-dependent translocation of its C2 domain
- The enzyme is then able to act on membrane phospholipids
- [Administration of glucocorticoids targets this translocation, causing the dissociation of heat-shock proteins from the receptors and therefore inhibiting its action]
- Diagram attached shows different functions of PLA2 isoforms
61
Q
What are the properties and derivatives of polyunsaturated fatty acids (PUFAs)?
[EXTRA]
A
The wide range of products generated means that derivatives can be pro- or anti-inflammatory
72
Q
How are leukotrienes synthesised from arachidonic acid?
[EXTRA?]
A
- Converted by 5’-lipoxygenase
- This produces LTB4, which is then converted into LTC4, LTD4 or LTE4 by P450 enzyme
- LTB4 is a potent neutrophil chemoattractant
- Choice in conversion depends on which cell type the reaction occurs in
- This produces LTB4, which is then converted into LTC4, LTD4 or LTE4 by P450 enzyme
- This pathway is targeted in the treatment of asthma (alongside treatment using glucocorticoids/steroids), as the derivatives of LTB4 cause potent bronchoconstriction in asthmatic attacks
77
Q
What are the features of an allergic reaction? Can anti-histamines be used?
A
- Sensitisation: initial interaction between the host and the allergen
- Early phase reaction: occurs within minutes of exposure to the allergen and lasts for 30-90 minutes
- Histamine release occurs during this phase, but is often only short-lived (as is seen in asthma)
- Leukotrienes quickly become dominant if the allergen is quickly removed, so targeting histamines is not overly effective in treating asthma
- Targeting histamine is effective when treating allergens present in the environment, however
- Late phase reaction: begins 4-8 hours after sensitisation and can last for several days, may lead to chronic inflammatory disease
- Treatment with anti-histamines are far less effective in this case
81
Q
What is the structure of a first generation antihistamine?
[EXTRA]
A
86
Q
What are some factors secreted by macrophages and their functions? Which are targets for therapeutics?
A
92
Q
Give some experimental evidence for the link between anti-inflammatory drugs and pain perception.
[EXTRA]
A
- IL-1 is expressed in the CNS, and is a potential target for treating inflammation alongside being important in the perception of pain, as is shown on the graphs
- If IL-1 is knocked out, the hind paw withdraw threshold is dramatically increased, meaning that the animal is significantly desensitised to pain
- If the accessory protein is knocked out (it is essential for IL-1 signalling), the same effect is seen
- If IL-1RA is overexpressed (the endogenous IL-1 antagonist), the increase in hind paw withdrawal threshold is again seen
- These IL-1RA is analogous to anakinra (non-glycosylated IL-1RA), so giving the drug may also have an effect on pain, alongside the anti-inflammatory effects
95
Q
What are the actions of TNF? What conditions can TNF-inhibitors be used for?
A
108
Q
Compare how steroids and NSAIDs work.
A
