Acute and chronic inflammation

Question 1

What is inflammation?

Answer 1

Inflammation is a protective response to tissue insult or injury aimed at eliminating the cause of injury, removing damaged cells and initiating repair.

Question 2

What does an inflammatory response do?

Answer 2

Allow for an injury to tissues to be identified, attempts to eliminate the cause of injury (by diluting, destroying or neutralising harmful actions) and initiates repair and healing.

Question 3

What are the 5 cardinal signs of inflammation?

Answer 3

Calor (heat)
Rubor (redness/erythema)
Tumor (swelling/oedema)
Dolor (pain)
Loss of function

Question 4

How are the signs of inflammation brought about?

Answer 4

Vascular changes and recruitment of leukocytes

Question 5

What are the major players that function in an immune response?

Answer 5

Circulating proteins - components of clotting systems and complement system
Circulating immune cells - phagocytic cells, neutrophils, monocytes (precursors to macrophages). These cells leave the blood vessels and enter our tissues then they turn into macrophages. Mast cells are important in triggering inflammatory responses by releasing histamine from pre formed granules.
Vascular system - cells that line blood vessels (endothelial) react in area of blood vessels closest to site of injury and allow inflammatory circulating cells to be recruited and exit blood vessels.
Liver - increases production of inflammatory response proteins that circulate and reach site of injury, some complement components, acute phase proteins and clotting factors.

Question 6

When is an inflammatory response triggered?

Answer 6

Inflammation is induced by chemical mediators produced in host cells in response to injurious stimuli. These host cells detect the inflammatory stimulus or injury and release chemical signals triggering response. Cells such as mast cells and tissue resident macrophages but also non immune cells at site of injury (epithelial or endothelial cells) can detect damage.

Question 7

What are inflammatory stimuli?

Answer 7

Infectious agents
Foreign bodies (surgical sutures)
Immune complexes - produced by antibodies binding to specific antigens. Self-antigens are known as auto-immune complexes.

Question 8

What can trigger an inflammatory response?

Answer 8

Trauma causes tissue damage - damage to host cells and vessels can be detected and elicit inflammatory response.
Trauma can be caused by physical injury, irridation (radioactive isotopes and UV radiation), thermal injry (hot and cold burns), ischaemia. Trauma can lead to tissue necrosis.

Question 9

What does apoptosis lead to?

Answer 9

Uninflammatory method of cell death where internal cell contents are not released in an uncontrolled manner but parcelled up for clearance by macrophages.

Question 10

What is necrosis?

Answer 10

Opposite of apoptosis, cell membrane loses its integrity allowing intracellular contents to leak out into extracellular space - contents is pro-inflammatory. Products of dying cells are released and can stimulate inflammation, act as a danger signal. Necrosis can be caused by ischemia - reduced supply of oxygen to tissues, cells die and release cellular components and chemicals that trigger inflammation.

Question 11

What are the 5 R’s (steps of inflammatory response)

Answer 11

Recognition
Recruitment
Removal
Regulation
Resolution

Question 12

What is recognition?

Answer 12

Inflammatory stimulus is recognised by host cells. Cells of our innate immune system (tissue resident macrophages/mast cells/epithelial cells) can initiate a response. These cells release chemical signals initiating inflammatory response. Chemical signals are cytokines - highlighting danger and detected by variety of receptors on other cells - vascular endothelial cells.

Question 13

What is recruitment?

Answer 13

Changes in vascular and chemical signals that are triggered by recognition, recruits inflammatory immune cells and molecules to site of injury.

Question 14

What is removal?

Answer 14

Leukocytes and molecules get to the site of inflammation and have a variety of activities leading to removal of the agent of injury. Eg phagocytic cells may engulf damaged or dead host cells/pathogen removing inflammatory stimuli.

Question 15

What is regulation?

Answer 15

Initiating a self-limiting anti inflammatory mechanism that prevents the response from getting out of control and causing unnecessary damage to host tissues. Inflammatory responses need to be regulated to prevent excessive tissue damage.

Question 16

What is resolution?

Answer 16

Following removal or the agent causing injury the anti-inflammatory mechanisms and regulation to control the response this phase brings inflammation to an end and repair mechanisms are initiated to heal damage caused by injury.

Question 17

How can inflammation cause damage to healthy tissue?

Answer 17

If regulation fails - if the inflammatory response is too amplified or prolonged.

Question 18

Why might regulation fail?

Answer 18

If the noxious stimulus cannot be removed and/or the acute inflammatory response cannot be resolved the injury will persist and may result in chronic inflammation - which can be very damaging.

Question 19

when may acute inflammation persist and become chronic?

Answer 19

If the initial response is very strong (severe infection)
If the initial inflammatory reaction is prolonged, possible due to inflammatory response resisting eradication.
The inflammatory response is inappropriate eg due to a self or harmless environmental antigen that will constantly be present.

Question 20

What is acute inflammation?

Answer 20

Very quick in onset but may only last a few days and last for a shorter time of only hours.
The cells that infiltrate in acute inflammation are predominantly neutrophils (and some macrophages present too).
It is self regulating and self limiting so has less capacity to cause tissue damage. Local and systemic signs are prominent (5 cardinal signs).

Question 21

What is chronic inflammation?

Answer 21

Slow in onset and of longer duration (days, weeks years). Majority of cellular infiltrate made up of macrophages and lymphocytes (time for adaptive system to get involved). Macrophages may have been activated differently and have different functions to those in acute inflammation. Subgroups of macrophages will differ between sites of acute and chronic inflammation. Chronic inflammation continues over a longer period and doesn’t resolve so can cause great tissue injury. Chronic inflammation can be more subtle and situation may not be apparent until severe damage has occurred, tissue damage is the thing that is detected.

Question 22

What does acute inflammation cause in response to injurious stimulus?

Answer 22

Rapid delivery of leukocytes (PMN’s) and plasma proteins to site of injury where they are needed - these clear the infection and remove dead cells.

Question 23

What are the vascular changes in blood vessels in acute inflammation?

Answer 23

Vasodilation - blood vessels open up and widen increasing caliber.
Vascular permeability - blood vessels become leaky allowing leukocytes and plasma proteins and fluid to exit the blood vessel more easily to reach site of injury.
Endothelial cells that line blood vessels become activated.

Question 24

What are the cellular events in acute inflammation?

Answer 24

Leukocytes most commonly neutrophils (polymorphonuclear leukocytes) migrate to the site of inflammation and are further activated including some monocytes that are recruited to site and further differentiate into macrophages.

Question 25

How do we recognise inflammatory triggers?

Answer 25

Neutrophils, tissue resident macrophages, dendritic and mast cells express pattern recognition receptors. PRR’s are able to recognise distinct molecular patterns that are not usually seen on healthy cells or in healthy tissues.

Question 26

What are PRR’s?

Answer 26

Their specificity of recognition is genome encoded and do not undergo VDJ recombination. They are expressed on all cells or a certain type or state of activation, expression is not unique to a clone of cells. Specificity with how a PRR binds to its ligand is promiscuous - will recognise many molecules from different species/strains. Unlike specific recognition of T and B cell antigen receptors. PRR’s are expressed on lots of cells in the initial response, more can be recruited quickly and production of cells may increase - clonal expansion.

Question 27

What do resident tissue macrophages do?

Answer 27

These cells engulf cell debris and pathogens, if this material is pro-inflammatory they release key cytokines and chemokines of central importance to the response: tumor necrosis factor a, interleukin-1-beta (chemokine), interleukin-6 and chemokine interleukin-8.

Question 28

What are cytokines?

Answer 28

Secreted in response to a stimulus - affecting the behaviour of cells. If it acts in an autocrine mechanism it means it acts on the same cell which secreted it. paracrine is a different cell to the one that secreted it in the vicinity. If it has an endocrine mode of action it acts upon cells that are distant and passes through circulatory system to have effects in distant organs.

Question 29

What are chemokines?

Answer 29

Chemoattractant proteins that stimulate migration of cells (phagocytes and lymphocytes) these cells migrate up a concentration gradient to where the chemokine concentration is strongest. Effects of chemokines are restricted by migration only.

Question 30

What are mast cells and where are they located?

Answer 30

Located in tissues found close to our body surfaces including mucosal, they respond quickly to damage and release pro-inflammatory histamine. They have to be stimulated to release the histamine granules.

Question 31

How are mast cells triggered to release granules?

Answer 31

B cells from previous immune response have IgE antibodies. Mast cells have Fc receptors that bind to IgE and hold on to it via receptors that the antigen binding site of IgE can still bind its specific antigen. The mast cell becomes coated with IgE molecules on the outer surface. If the IgE interacts with its antigen it clusters Fc receptors together and sends a signal to mast cell to degranulate. Granules are membrane bound and released into extracellular space after granule membranes fuse with plasma membrane.

Question 32

What do epithelial cells do in response to pathogens?

Answer 32

They express PRR’s and initiate inflammatory responses by secreting IL-8, TNF a, IL-1B and IL-18 and antimicrobial peptides. The cells can differentiate between pathogenic and commensal species and not respond unnecessarily and trigger a response when needed.

Question 33

What are toll like receptors?

Answer 33

Their receptors they encode help to monitor different locations in our cells for danger signals. They can either be heterodimeric or homodimeric structures and some span the plasma membranes of cells (TLR2/6 heterodimer, TLR1/2 heterodimer, TLR5 homodimer or TLR4 homodimer monitoring extracellular space and recognise outer structural components of pathogens like bacteria.

Question 34

What do intracellular TLR’s detect?

Answer 34

Components that are detected following engulfment and digestion of microbes. TLR3 recognises double stranded RNA in RNA viruses which could be taken up within a virus or a damaged infected cell containing intermediary replicative components that could be engulfed.

Question 35

What does TLR7 recognise?

Answer 35

Single stranded RNA, self ssRNA is not usually found in the endosome just in nucleus and cytoplasm but can be revealed by phagocytosis of an ssRNA virus being digested.

Question 36

What does TLR9 bind to?

Answer 36

Unmethylated CpG DNA which is most prevalent in bacterial genomes.

Question 37

Two types of TLR

Answer 37

Intracellular - within endosomes, recognises internal nucleic acid structures within phagocytosed infected cells or pathogens.
Extracellular - binds to structures present on the outside surface of pathogens.

Question 38

What do lectin like receptors do?

Answer 38

Bind to pathogen sugars and bind extracellular structures.

Question 39

What do NOD like receptors and RIG-I monitor?

Answer 39

Cytosolic space for pathogens

Question 40

What does RIG-I recognise?

Answer 40

Viral RNA from species when present but not eukaryotic RNA. Unmodified 5’ triphosphate group in viral RNA results in recognition. This needs to be able to distinguish between host and pathogenic RNA as there is a lot of host RNA ready for protein translation.

Question 41

What do NOD like receptors recognise?

Answer 41

Bacterial lipids and peptidoglycans. NOD1-2 recognises peptidoglycans present from cytosolic bacteria. They may have been endocytosed or phagocytosed but evaded destructuon escaping into the cell cytoplasm.

Question 42

What does the NLRPE3 inflammasome recognise?

Answer 42

NLRP3 receptor forms a complex with other proteins called NLRP3 inflammasome that recognises products of dead and dying cells in addition to some microbes. It also recognises urate crystals that trigger painful inflammation in gout.

Question 43

What does the NLRP molecule do?

Answer 43

Member of NOD like family of receptors that acts as the sensor and the formation of complex results in activation of Capsase 1, protease that once active is capable of cleaving the performed Pro-IL-1B to generate biologically active IL-1B - proinflammatory cytokine.

Question 44

Process of recruitment - vascular events

Answer 44

Blood vessels dilate (vasodilation) widening of vessel caliber increases blood flow but also slows it. Vasodilation causes the area local to injury becoming warm and red (erythema and calor). Permeability also increases, blood vessel walls become leakier as the gaps at junctions between endothelial cells become bigger due to endothelial cells contracting. Increased amount of fluid and protein from plasma to exit and enter tissues - oedema.
Cells that line blood vessels - endothelial cells become activated. They change the expression of receptors on surfaces and increases the expression of cell adhesion molecules that bind ligands on leukocytes allowing these to attach to vessel walls and pass out into the tissue to deal with injurious stimulus.

Question 45

What does increased movement of fluid into the tissues lead to?

Answer 45

Increases concentration of red blood cells, blood is more viscous and flow slows down - stasis. The fluid is rich in serum derived proteins called exudate (GCF is an example) Macrophages, mast cells and epithelial cells following recognition of stimulus release pro-inflammatory cytokines IL-1B and TNF-a activating vascular endothelial cells inducing vasodilation and increasing vascular permeability - increasing blood flow and exudate. Damage to vasculature through necrosis or auto immune damage can be detected by endothelial cells resulting in inflammation.

Question 46

What are the cellular events of recruitment?

Answer 46

Normally blood cells with leukocytes flow along vessels rapidly if they are to exit the vessel and enter tissues they need to slow and brought to a standstill. Smaller red blood cells tend to flow faster in the centre of the blood vessel lumen while larger leukocytes are pushed to the edges so they have more chance of interacting with the endothelium. Dilation of vessels slows blood flow and white blood cells accumulate at the edges of vessel lumen due to their larger size - Margination. Proinflammatory cytokines and histamine activate endothelial cells lining blood vessels so they express cell adhesion molecules (CAM) on luminal surfaces. P-selectin and E-selectin interact with glycoprotein Sialyl Lexis X on leukocyte that forms weak interactions repeatedly broken and remade as the leukocyte rolls along inside of the blood vessel. Lack of selectin expression on unactivated endothelium means rolling is restricted to areas close to site of inflammatory response.

Question 47

Recruitment in cells continued

Answer 47

Leukocytes must be more stably adhered to vessel lumen wall and mediated by interactions with types of glycoprotein molecules - integrins. Integrins are expressed already in a low affinity state. Pro inflammatory cytokines activate leukocytes and results in integrins being converted to a high affinity state. They now have a high affinity binding capacity for cell adhesion molecules like ICAM-1 on activated endothelium. Interactions between integrins and ICAM-1 stop the rolling leukocyte. Expression of PECAM-1 is upregulated on endothelial cells and this molecule mediates binding during transmigration of leukocyte as it passes through endothelial wall (diapedesis). Transmigration is assisted by contraction of endothelial cells and leaky junctions between them. Blood vessels have a basement membrane, leukoocytes secrete enzymes in order to pass through this and collagenases allow them to digest a hole and pass through. Cells then migrate to the site of inflammation up a concentration gradient of signals like chemokines and bacterial products.

Question 48

What are the differences in inflammatory infiltrate during different phases of inflammatory response?

Answer 48

Initial - exudate is predominate infiltrate
Neutrophils
Then macrophages predominate

Question 49

Activities of innate leukocytes

Answer 49

Phagocytosis carried out in inflammatory responses by macrophages, neutrophils and dendritic cells and results in engulfing of pathogens and other inflammatory material - cell debris. Leukocytes can also release microbicidal molecules - antimicrobial peptides and some reactive oxygen species (ROS) and nitric oxide specied (NO) which may escape into extracellular space and be cytotoxic to pathogens and host tissues. When activated macrophages release proinflammatory cytokines, further amplifying the inflammatory response - feedback loop. Neutrophils perform NETOSIS - extracellular traps to snare pathogens but results in the death of neutrophils that undergo this process.

Question 50

Phagocytosis recap

Answer 50

Phagocytes can recognise pathogens/material to be ingested through their receptors. Phagocytosis is enhanced if the target is coated in opsonins - increase efficiency with which phagocytic cells recognise target material. Complement components and antibody molecules can act as opsonins and be recognised by receptors on phagocytes surface. Phagocyte is triggered to engulf target, plasma membrane invaginates and the target is taken up in a phagosome, fusing with a lysosome - phagolysosome and digest the engulfed contents. Phagocytosis triggers respiratory burst where ROS and NOS are generated within phagolysosome at increased localised concentrations they can damage or kill engulfed microbes.

Question 51

What is respiratory burst?

Answer 51

Following phagocytosis phagocytes ramp up production of ROS to kill ingested microbes. Superoxide is produced by oxidation of NADPH carried out by the enzyme phagocyte oxidase located in the membrane of phagosome. This can be converted into hydrogen peroxide and then hypochlorite by myeloperoxidase - enzyme expressed in neutrophils and macrophages. They are myeloid cells.
Superoxide can also be converted to peroxynitrite, all products are toxic and help to kill engulfed pathogens and can cause damage to host structures inside and outside the cell - bystander damage.

Question 52

How can bystander damage occur?

Answer 52

• Lipid peroxidation- cell membranes are lipid bilayers so can damage these.
• Damage proteins by preventing them from no longer correctly folding - can prevent function or target them for destruction.
• ROS can damage our DNA causing breaks. Repair mechanisms can introduce DNA mutations and can accumulate. The more breaks increases the risk. Why prolonged inflammation is linked to cancer.

Question 53

What are the extracellular activity of phagocytes?

Answer 53

Neutrophils have different defensive molecules in different granules. They can secrete enzymes from azurophilic granules - primary granules including neutrophil elastase, proteinase 3 and cathepsin G which are proteolytic and can help degrade engulfed material or be secreted to help neutrophils move through tissue or activate other defence molecules.
Lysosomal enzymes, ROS and NO generated during phagocytosis can be released into the extracellular space as well as chemokines and cytokines secreted recruiting and activating additional inflammatory innate immune cells - largely the role of macrophages.
Netosis takes place outside of cells.

Question 54

What is NETosis?

Answer 54

The generation and release of Neutrophil Extracellular Traps (NETs). Neutrophils are stimulated by inflammatory stimuli to release NET traps. They are made of nucleosomal DNA (DNA in complex with histones). The neutrophil extrudes its nucleosomal DNA in response to infection or inflammatory stimuli. they also have granular components including degradative enzymes and microbicidal molecules (myeloperoxidase, neutrophil elastase, cathepsin G, LL-37 and proteinase 3). NET’s generate a dense net of fibres that can trap and bind to microbes. Trap produces a high concentration of enzymes and peptides and kill the microbes a useful strategy to deal with degrading material too large to phagocytose.

Question 55

How are NETs generated?

Answer 55

Prior to formation of a NET the neutrophil must release DNA from tight formation of coiled coils using Peptidyl Arginine Deiminase 4 (PAD4). Following neutrophil activation, the nuclear chromatin decondenses. PAD4 converts arginine and methylarginine in histone proteins into citrulline, which are positive electrostatic amino acids into a neutral charged amino acid. Reducing the electrostatic charges causes nucleosomal DNA to decondense. Membranes around granules and nucleus lose integrity and decondensed DNA mixes with contents of the granule to generate the NET extruded out the cell.

Question 56

Why is there a link between NETs and periodontal disease and what are the problems they cause?

Answer 56

There is an increased level of NETs in GCF in periodontal disease. NET’s release and expose our immune system to citrullinated proteins. Our immune system may not be tolerant to these modified proteins - may be autoantigens and stimulate an immune response for antibodies against them. Auto antibodies against citrullinated histones and host proteins are a biomarker for predicting development of rheumatoid arthritis.

Question 57

What are locally derived chemical mediators?

Answer 57

• vasoactive amines such as histamine and serotonin which cause vasodilation and increase vascular permeability
• metabolites of arachidonic acid such as prostaglandins and leukotrienes which affect the vasculature and act as chemotaxins
• macrophages secrete key proinflammatory cytokines and chemokines that promote response recruiting leukocytes and activate vascular endothelial cells - TNF-a, IL-1B, IL-6 and IL-8.
• Neutrophil elastase, proteinase 3, cathepsin C and collagenases.
• Products of respiratory burst ROS, NO.

Question 58

What are inflammatory mediators derived from circulating inactive precursors?

Answer 58

They ate mostly produced in the liver circulating in inactive (zymogen) forms that are activated at site of inflammation.
Examples: complement proteins which follow activation, function in leukocyte chemotaxis, opsonisation and formation of membrane attack complex.
- Coagulation proteins, activation can be triggered by activation of clotting factors and can activate endothelial cells and contribute to leukocyte recruitment.
- Kinins present as precursors activated by proteolytic cleavage affecting vasculature and sensitivity to pain.

Question 59

Why do mediators have a short half life and why is it important?

Answer 59

• Molecules may decay quickly as they aren’t stable once released - arachidonic metabolites
• They may be inhibited. Complement regulatory proteins will block the activation of some complement components. The complement system contains both effector molecules and regulating/inhibitory molecules.
• They may be eliminated and removed - antioxidants scavenge for ROS.

Question 60

What are acute phase proteins?

Answer 60

Pro inflammatory cytokines can activate hepatocytes to synthesise acute phase proteins. One acute phase protein is CRP (c-reactive protein) this is a pentraxin and with other pentraxins can act as an opsonin. It can activate the classical component pathway, meaning there is more activated complement components to act as opsonin - phagocytes at an inflamed site will work more efficiently.

Question 61

What is mannose binding lectin?

Answer 61

Performs opsonin and complement activation though MBL works via lectin activation pathway for complement. Levels of CRP and MBL increase massively during an infection. CRP is usually a marker or diagnostic test for someone if they have an infection.

Question 62

How does the production of opsonised pathogens augmented by increased numbers of neutrophils ready to dispose of them?

Answer 62

2 activities work together, pro inflammatory cytokines will activate bone marrow endothelium to increase production and release neutrophils into the bloodstream - leukocytosis.

Question 63

How does the inflammatory response skew the environment to favour our immune response?

Answer 63

IL-1B, IL-6 and TNF a are endogenous pyrogens so they raise body temperature to help eliminate infections. Major effect of cytokines is to act on the hypothalamus altering the body’s temperature regulation altering energy utilisation of muscle and fat cells to increase temperature. Bacterial and viral replication is less efficient whereas the adaptive immune response works more efficiently.

Question 64

What is the role of acute phase proteins?

Answer 64

Activates complement system, stimulated by cytokines released by macrophages. Include serum amyloid protein and CRP, fibrinogen and mannose binding lectin. CRP can bind to bacterial and fungal surfaces acting as an opsonin and activating the classical complement pathway by binding C1q to augment opsonisation by complement. Like CRP, MBL can act as an opsonin in its own right or activate lectin pathway of complement activation.

Question 65

What is arachidonic acid metabolites?

Answer 65

Metabolites of arachidonic acid are mediators of inflammation and can help to switch it off. They act locally to the site where it has been produced and have a short half life, thus limiting their ability to perpetuate and exaggerate the response.
One pathway features the cyclooxygenase enzymes COX-1 and COX-2 to generate prostaglandins and thromboxane. The other pathway acts via the activity of lipoxygenase enzymes to generate leukotrienes and lipoxins.

Question 66

How do anti-inflammatory drugs from NSAIDS work?

Answer 66

They are COX 1 and 2 inhibitors that inhibit activity of cyclooxygenase molecules and reduce fever and sensitivity to pain and inflammation. They impact upon clotting activity as thromboxane aggregates platelets that are negatively affected if the pathway is inhibited negatively impacting clotting capability. Lipoxygenase is the major arachidonic acid metabolising enzyme in neutrophils. The pathway generates leukotrienes which function in chemotaxis and increased vascular permeability. All chemical mediators have a short half life, signals cease once stimulus triggering inflammation is removed.

Question 67

What is resolution?

Answer 67

Loss of mediators switch off signal for inflammation. When the stimulus is removed, existing mediators and cells have short half life leading to loss of pro-inflammatory signals. It is not a passive process and does not reply on the short half lives of inflammatory mediators and cells. For a tissue to return to a healthy state of homeostasis after inflammation resolution must be initiated.

Question 68

How does resolution occur?

Answer 68

A switch from pro inflammatory mediators to anti-inflammatory mediators. Resolving mediators include interleukin 10, resolvins, protectins and maresins. And lipoxins - arachidonic acid metabolite.

Question 69

How does arachidonic metabolism switch from producing pro-inflammatory mediators?

Answer 69

Once leukocytes enter tissues they start to change their metabolism of arachidonic acid to produce lipoxins that inhibit adhesion of neutrophils to endothelium surfaces and inhibit chemotaxis, reducing recruitment and preventing perpetuation of inflammatory response.

Question 70

How is resolution initiated?

Answer 70

• activated macrophages that secrete the anti-inflammatory cytokine IL-10.
• arachidonic acid metabolism switches to produce Lipoxins
• other anti-inflammatory mediators such as Resolvins which also inhibit of leukocyte infiltration as produced.

Question 71

How does chronic inflammation occur?

Answer 71

When regulation and resolution fail and don’t bring an acute inflammatory response to an end.

Question 72

what is chronic inflammation?

Answer 72

Chronic inflammation is inflammation of a prolonged period (weeks to years) in which continuing inflammation, tissue injury and attempts to repair damaged tissue (which often includes fibrosis) will all continue and proceed simultaneously.

Question 73

What are the tissue injury and repair mechanisms of chronic inflammation?

Answer 73

Tissue injury may occur as bystander damage caused by effects of host defences such as effector functions of innate immune cells. Repair mechanisms may involve angiogenesis (growth of new blood vessels) and fibrosis where damaged tissue is replaced through growth of fibroblast cells which produce connective tissue. Although the tissue is repaired the damaged tissue is not replaced with cells and tissues with the same original specialist function but with non specialist function so some function is lost.

Question 74

How does chronic inflammation arise?

Answer 74

Through persistent infections (pathogens that are difficult to eradicate) can arise due to stimulus being an autoantigen that evoke a self perpetuating immune reaction - causing tissue damage and persistent inflammation like in rheumatoid arthritis. And through prolonged exposure to toxic agents that can be either foreign (exogenous) or can be self (endogenous) such as cholesterol or uric acid crystals.

Question 75

How is chronic inflammation characterised?

Answer 75

• Inflammation with mononuclear cells becomes predominant, Including monocytes and macrophages, lymphocytes, plasma cells (B cells producing Ig), though some neutrophils are still likely to be recruited to the site.
• Tissue destruction due to inflammatory products - release of of toxic oxygen species and NET formation cause some bystander damage to host tissues.
• Granulatomous tissues present by fibroblasts
• Repair involving angiogenesis and fibrosis, replacement tissue will not have the same function as original tissue and may compromise function of surrounding tissue and organ.

Question 76

Example of both acute and chronic inflammation

Answer 76

Dental abscesses - Acute inflammation might fail to resolve but the neutrophil dominated response remains but becomes “walled off” and surrounded by macrophages and monocytic cells. So there are parts of the pathology that resemble both a chronic and acute response present.

Question 77

Example where chronic inflammation at a particular site may have been present from the outset but triggered by inflammatory event at a distant site

Answer 77

Rheumatoid Arthritis (RA) which is a multifactorial disease. Individuals may have a genetic predisposition increasing their risk, but this is not sufficient to cause disease. An infection at a site distant from the joints that will become damaged initiates an inflammatory response that generates self-reactive lymphocytes, this results can result in damage occurring at a distant joint where the initiating inflammation did not occur.

Question 78

What are the dominant cells of chronic inflammation?

Answer 78

Macrophages which can be pro or anti inflammatory. The classical pathway of activation known as M1 produced proinflammatory M1 macrophages. This is followed when cells are activated by microbial products/crystals alongside another signal interferon gamma (IFN-y) a cytokine produced by Th1 cells - subgroup of CD4 T cells. So this depends on the adaptive immune system being initiated. These drive the macrophages to differentiate and activate in a particular phenotypic direction - proinflammatory effector functions - phagocytosis, respiratory burst, release of degradative enzymes and release of pro-inflammatory cytokines. alternatively activated macrophages are produced when they receive signals from Th2 cells (another sub group of CD4 cells) in form of IL-13 and IL-4. These cytokines push the macrophage to activate and differentiate into alternative anti inflammatory M2 macrophage and these cells have effector functions that promote repair and downregulate inflammation. They are anti-inflammatory and produce cytokines such as IL-10 and tumor growth factor beta.

Question 79

What is the directional interaction between lymphocytes and macrophages?

Answer 79

Bidirectional and can propagate chronic inflammation. after taking up material and being activated in the presence of IFN-γ becomes an M1 macrophage and produces IL-1 and TNF-α to recruit further leukocytes. M1 macrophages will also present antigens to T cells and the resultant activated T cells are the subtype that will generate IFN-γ thus perpetuating the process. These Th1 and Th17 T cells also produce additional cytokines can recruit additional leukocytes to the site of inflammation. The result is an ongoing cycle of cellular reactions that fuels and sustains chronic inflammation.

Question 80

What is the relationship between periodontitis and diabetes?

Answer 80

The inflammation present in periodontal disease might raise systemic levels of inflammatory mediators, increasing insulin resistance and making it harder to control blood sugar levels. But in the opposite direction exposure to hyperglycaemia can alter the biochemistry of some of the proteins in our tissues, affecting collagen turnover which can impact our gingival tissues. Our proteins can also be modified in a way that can make them an inflammatory stimulus.