31. Inflammation Flashcards

Question

What disease can exemplify the importance of respiratory burst? Outline it

Answer 1

* **The importance of respiratory burst can be exemplified in chronic granulomatous disease** * **Chronic granulomatous disease (CGD)** is a **primary immunodeficiency** * Cause * Caused by mutations in the many genes such as **NOX2 (NADPH oxidase 2) gene** encoding NADPH oxidase subunits * Typically inherited in an **X-linked recessive** fashion * Mainly affects young males * Prevents generation of superoxide (O_2-) leading to no respiratory burst * ROS required for pathogen destruction, making phagocytes unable to kill pathogens * Effects * Increased susceptibility to bacterial and fungal infection * **Candida fungi** * **Staphylococcus aureus** * **Salmonella** * Patient tissues frequently exhibit granuloma * Granuloma = collections of macrophages and dead neutrophils formed around the uneliminated pathogen * A collection of immune cells when the immune system attempts to trap substances that is unable to eliminate * Symptoms Typically present before the age of one * Recurrent infections * Dermatitis * Bloody diarrhoea * Failure to thrive * Treatment * Administration of prophylactic (preventative) antibiotics and antifungals throughout lifetime * Haemopoietic stem cell transplantation * Generate functional phagocytes

Answer 2

* Neutrophil extracellular traps (NETs) = networks of **extracellular chromatin** * **Sequester antimicrobial substances at high concentrations** * Myeloperoxidase * (neutrophil) elastase * Cathepsin G * **Restrict pathogen spread by trapping** * NET formation * Extrusion/loss of nucleus leading to neutrophil death * Fast mechanism * Involves degranulation and expulsion of chromatin from the cell * Slow mechanism * **Nuclear delobulation** * **Nuclear envelope degradation** * **Chromatin condensation** * Plasma membrane rupture and NET release * Potential drawback of the NET is the activation of **blood coagulation** and promotion of **thrombosis** * **Bacterial evasion of NETs** * Certain bacteria can evade NETs via a number of strategies * They may secrete enzymes such as: * Catalase * Interferes with NET formation * Nuclease * Degrades the DNA in NET chromatin * Some bacteria such as Streptococcus pneumoniae express a polysaccharide capsule that blocks NET binding

Answer 3

* It should be noted that the neutrophil is the principal phagocytic cell in AI while macrophages mediate the removal of damaged tissue and wound repair * Neutrophil death * Neutrophil is a short-lived cell, dying by apoptosis within **6-24 hours** are extravasation * **Pus** * Mixture of fluid, dead tissue, pathogens/foreign material as well as living and dead WBCs * Neutrophil death leads to the formation of pus at the site of acute inflammation * Abscess * Localised collection of pus in a body compartment that is associated with **liquefactive necrosis** of solid tissue * **Liquefactive necrosis** = digestion of dead cells to form a viscous liquid mass * **Coagulative necrosis** = tissue architecture is maintained * **Caseous necrosis** = combination of coagulation and liquefactive typically caused by mycobacteria e.g. tuberculosis, amorphous granular debris * **Treatment** * Difficult to treat as they are **poorly vascularised**, making the delivery of therapeutic drugs difficult * Surgical drainage followed by antibiotics to kill remaining bacteria * Fates * Resolution with no scarring * Resolution with scarring * External rupture * Internal rupture, forming a septic embolus * Cyst formation * Macrophages are important phagocytic cells in **chronic inflammation**

Answer 4

**TEC** **_1. Tight junction breakdown_** * Opening of **tight junctions** between the lateral membranes of the endothelial cells increases **paracellular permeability** * Tight junctions = protein complexes at cell-cell junctions * Occludin * Claudin * Junction adhesion molecule * Adherens junctions = protein complexes at cell-cell junctions usually more basal than tight junctions * Cell junction whose cytoplasmic face is linked to the actin cytoskeleton * Mechanism * Histamine action on endothelial **H₁** stimulates intracellular cascades that result in the phosphorylation of MLCK * **Relaxation** of cytoskeletal filaments attached to tight junctions in the lateral membrane **_2. Endothelial damage_** * Direct damage to the endothelium by toxins, burns or mechanical stress leading to rupturing of the endothelium and leakage of cells and proteins from the blood plasma **_3. Contraction of endothelial cells_** * #### **Lateral contraction** of endothelial cells result in an increase in the width of **the paracellular spaces**

Answer 5

* #### **_Complement_** * **C2a, C4b, C3b (alternative pathway activator)** * **_Coagulation proteins_** * **Fibrinogen** **_Complement_** * Activation of the complement cascade via the alternative, lectin and classical pathways ultimately generates terminal complement proteins that mediate complement effector mechanisms * **Opsonisation** * Opsonins * Facilitating more efficient phagocytosis by binding macrophage surface receptors * **C2a** and **C4b as well as C3b** act as opsonins * **Membrane attack complex** * Complement proteins can form a **pore** in the membranes of bacterial and eukaryotic pathogens known as the **membrane-attack complex (MAC)** * Causing cell lysis * Generation of **C5 convertase** and recruitment of **C6**, **C7**, **C8** and **C9** to form the pore * **Anaphylatoxins** * Certain complement proteins act as inflammatory mediators, generating a positive feedback signal * **C5a** * Effects * Mast cells and basophils * Trigger degranulation and the release of histamine * Phagocyte recruitment * C5a acts directly on circulating neutrophils and monocytes, recruiting them to be infected tissue by mediating extravasation and acting as a chemoattractant **_Coagulation proteins_** * Entry of serine proteases * Entry of coagulation cascade serine proteases leads to the generation of **thrombin** which cleaves **fibrinogen** to form a **fibrin** **network** in the inflamed tissue * The fibrin mesh limits haemorrhage and the spread of pathogens to the bloodstream * An important lipid derived activator of this process is **platelet activating factor (PAF)**

Answer 6

* The microvascular changes in inflammation result in an increase in filtration across the capillary wall according to the **Starling equation** **J_V=K_f S[(P_c-P_i )-σ(π_p-π_i )]** J_v = filtration rate K_f= hydraulic conductivity S = surface area P = hydrostatic pressure σ = Staverman’s reflection coefficien π_p = plasma oncotic pressure π_i = interstitial oncotic pressure * Vasodilation * Increases the **capillary surface area (S)** * Movement of plasma proteins into the interstitium * Increases the **interstitial fluid colloid osmotic pressure** (**p_i**) * Increased endothelial permeability * Increases the **hydraulic conductance (K_f)** of the vessel wall

Answer 7

* **Acute respiratory distress syndrome (ARDS)** = accumulation of fluid into the interstitium of the lungs resulting in the flooding of the lungs; microscopic air sacs which can cause **pulmonary consolidation** * Pulmonary consolidation = region of normally compressible lung tissue that has been filled with liquid not air * It is characterised by widespread inflammation in the lungs resulting in: * Shortness of breath * Rapid breathing * Death * In 40% of cases * Causes * Pneumonia * Sepsis * Acute injury * Treatment * **Mechanical ventilation** * Antibiotic therapy * Osmotic diuretics * Mannitol * Metabolically inert and works by raising plasma osmotic pressure and decreasing filtration

Answer 8

Antigen presentation * The antigen presenting cells (APCs) of the IIS are: * **Macrophages** * **Dendritic cells** * They are transported with pathogenic material (from the infected tissue) to **secondary lymphoid tissues** where they are exposed to a large number and variety of naïve T-lymphocytes * Secondary lymphoid organs = lymph nodes, spleen * This increases the probability of meeting a T-cell with a receptor complementary to the antigen * **Evidence that macrophages are important in AIS activation was obtained in an experiment performed by Hoffmann and Dutton – (Science, 1970)** * Method * **Sheep erythrocytes** (foreign material/antigen source) were added to **mouse spleen cell** suspensions and the number of B cells were measured by assay after five days * Suspensions in which the **macrophages** had been **removed by attachment to a glass surface** were observed to contain fewer B cells after sheep erythrocyte addition * Suggesting a depression of the immune response * Addition of macrophage was observed to restore immune response * Extracted from **mouse peritoneum** MHC * The APCs acquire antigens by phagocytosis, process the antigens internally and present antigen fragments on cell surface major histocompatibility complex (MHC) glycoproteins * **MHC class I** present antigens from **intracellular** pathogens to **CD8 T-cells** * Cytotoxic T-cells * **MHC class II** present antigens from the **extracellular** pathogens to **CD4 T-cells** * Helper T-cells * The **antigen/MHC complex** specifically binds to **T-cell receptors** and **CD4/CD8 co-receptors** on the small proportion of naïve T-lymphocytes that express complementary receptors * This triggers **T-cell activation** and **differentiation** into **effector T lymphocytes** and thus initiating the adaptive immune response

Answer 9

* Acute inflammation is normally limited to a localised region of tissue by control mechanisms. * Defects in control can lead to **systemic inflammation**, which is detrimental to the host. * The **cytokines** produced by tissue-resident macrophages and mast cells have **systemic effects** if produced in large quantities, contributing to the symptoms of AI * IL-1 * IL-6 * TNF-a * Other symptoms: * CNS symptoms * Malaise * Loss of appetite * Chills * Cardiovascular * Tachycardia * Raised cardiac output Fever * Core body temperature greater than around **38****° C** * Action of **IL-1**, **TNF-****a**,**IL-6**and**PGE₂**on the**hypothalamus**elicits a rise in the set point of the**core body temperature (CBT)** * Mediators act on **myocytes** and **brown adipocytes** to promote heat generation * Fever promotes pathogen inactivation * Pathogen replicate less rapidly at temperatures higher than the normal CBT * AIS is more potent at higher temperatures Acute phase proteins * **IL-1**, **TNF-****a**and**IL-6**act on**hepatocytes**, altering the types of molecule secreted by the liver * This is known as **acute phase response** and the proteins that increase in synthesis and secretion are known as **acute-phase proteins** * These proteins include **mannose-binding lectin (MBL)** and **C-reactive protein (CRP)** that respectively initiate the lectin and classical pathways of complement activation Neutrophil mobilisation * **IL-1**, **TNF-**a and **IL-6** act on bone marrow endothelium, promoting mobilization

Answer 10

Septic Shock * One severe consequence of systemic inflammation is septic shock * **Septic shock (SS)** * Septic shock (SS) = decrease in systemic tissue perfusion caused by systemic inflammation in response to infection * Pathogenesis * Pathogens (bacteria & fungi) enter the blood and spread to systemic tissue via the circulation * This triggers a systemic inflammatory response by the recognition elements of the IIS (sensors0 * Systemic cytokine release (in particular TNF-a) has a number of pathological effects * **Systemic vasodilation** * Causes a large fall in blood pressure * Decrease in TPR * **Increased vascular permeability** * Results in systemic oedema, decreasing cellular nutrient delivery and waste removal * **Systemic blood clotting** * AKA **disseminated intravascular coagulation** which contributes to ischaemia * Effects * **Hypoperfusion** * Tissue ischaemia & hypoxia à cell death & multiple organ failure * Septic shock is a life-threatening condition with a mortality rate of 20-50% * Treatment * Intravenous fluids * To raise ECV and perfusion pressure * Hypertensive drugs * Oxygen supplementation * Antibiotics Endotoxic shock * 70% of septic shock is caused by **lipopolysaccharide (LPS)** in the **outer membrane of Gram negative bacteria**, explaining the use of the term endotoxic shock * LPS recognised by TLR4 and other PRRs

Answer 11

1. The elimination of noxious stimuli followed by resolution and repair of damaged tissue 2. Persistent injury leading to chronic inflammation

Answer 12

Resolution * Under normal conditions, AI **resolves** and the tissue returns to a normal state. 1) Elimination of noxious stimulus * Removes inducer molecules from the tissue 2) Breakdown of inflammatory mediators * Inflammatory mediators spontaneously breakdown their short half-lives 3) Anti-inflammatory mediators * **Lipoxins** * Inhibit the recruitment and activation of neutrophils * Promote the recruitment of monocytes * Remove dead cells and repair tissue * **IL-10** * Stimulates the secretion of **TGF-****b** from macrophages * Promotes repair 4) Tissue repair (GER) * AI is then concluded with the **repair** of damaged tissue 1. **Granulation tissue formation** * Forms by the proliferation of **mesenchymal stem cells (MSC)** as well as **endothelial cells** * New connective tissue with new blood vessels that grow by **angiogenesis** * Pink in colour * Angiogenesis * Characterised by: * **Endothelial migration** * Via fibronectin * **Endothelial cell proliferation** * **VEGFs** * **TGF-alpha** * **Proteolysis of the ECM** * Collagenases * tPA * uPA * **Endothelial tube formation** * Results in capillary sprouting 1. **ECM deposition** * Fibroblasts lay down ECM such as collagen type 2 1. **Remodelling** * **Type 2 collagen replaced by type 1 collagen** * Type 2 = collagen of cartilage * Type 1 = skin/bone * This process is regulated by signalling molecules acting in an autocrine / paracrine / endocrine manner * Chemokines * Interferons * Interleukins * Lymphokines * Monokines * Tumour necrosis factor

Answer 13

* ***Non-steroidal anti-inflammatory drugs (NSAIDs)*** act by inhibiting **cyclo-oxygenase (COX) enzymes** * COX enzymes * **COX1** * **COX2** * This reduces the COX-mediated synthesis of **prostaglandins** (inflammatory mediators) from arachidonic acid * Effects & Uses * **Anti-inflammatory** * Decrease in prostaglandin-mediated vasodilation and indirectly oedema * Therefore, used for symptomatic relief in **chronic inflammatory disorders** such as **rheumatoid arthritis** and **gout** * **Analgesia** * Reduction in prostaglandin-mediated sensitization of nociceptors (peripheral sensitisation) to inflammatory mediators * Inflammatory mediators such as **bradykinin** and **5-HT** * Uses * Headache * Back ache * Postoperative pain * **Anti-pyretic** * Reduction in core body temperature * Reduction in **IL-1** stimulated synthesis of **PGE₂** in the **hypothalamus** * Therefore prevent the elevation of setpoint for core body temperatures by PGE₂ * Examples * **Aspirin** * **Ibuprofen** * **Naproxen** * Side effects * Thought to be due to inhibition of widely and constitutively express **COX1** isoenzyme * Gastrointestinal disturbance * NSAIDs inhibit the upregulation of **PGE₂** in the stomach, **reducing** the **inhibitory** effect on gastric acid secretion by the **parietal cells** * Upregulation of acid secretion can lead to: * Gastritis * Peptic ulcers * Gastric bleeding * Co-administration of prostaglandin analogues such as **misoprostol** can reduce this effect * Skin rashes * Renal insufficiency * Cardiovascular events * Stroke * Myocardial infarction

Answer 14

* **Glucocorticoids** * **Exogenous glucocorticoids (GCs**) such as **dexamethasone** are potent anti-inflammatory drugs * Uses * Allergic inflammatory conditions * Asthma * Eczema * Chronic inflammation * Rheumatoid arthritis * Inflammatory bowel disease * Immune suppressive effect * Preventing of immunorejection from a graft/transplantation * Mechanism * Glucocorticoids enter several different inflammatory cells (e.g. WBCs, endothelial cells) and activate the intracellular **GC receptor (GR)** * The GR migrates to the nucleus and influences the transcription of many genes encoding proteins involved in inflammation * Effects * Overall effect is inhibition of the entire inflammatory process 1. **Inflammatory mediators** * Reduced transcription of cytokines such as **IL-1** and **TNF-****a** downregulate inflammatory effector mechanisms * Reduced transcription of **COX2**, downregulating prostaglandin synthesis 1. **Neutrophil recruitment** * Decrease in expression of cell adhesion molecules in neutrophils and endothelial cells prevent neutrophil recruitment * **IL-1** and **TNF-****a** upregulate E-lectin transcription 1. **Annexin A1** * Non-transcriptional effect is the release of **annexin A₁**, an anti-inflammatory protein that **inhibits** **phospholipase A₂** and thus reduces prostaglandin and leukotriene synthesis * Side effects * Immunosuppression * Can result in opportunistic infection * Tissue repair * Decreased synthesis of extracellular matrix proteins by fibroblasts preventing tissue repair after inflammation * Iatrogenic Cushing’s syndrome * Effect of glucocorticoids on non-immune cells can lead to iatrogenic Cushing’s syndrome * Symptoms * Fat redistribution * Muscle wasting * Osteoporosis * Infertility

Answer 15

* Inflammation is an adaptive response triggered by noxious stimuli and conditions such as **infection** and **tissue injury** * Facilitates the **localisation** of **circulation cells** and **molecules** involved in **defence** to the stimulus site * **Chronic inflammation** is defined by the length of time the inflammation persists as it follows many of the same mechanisms and same mediators of acute inflammation

Answer 16

* Dysregulation of acute inflammation that leads to persistence * Establishing methods to control chronic inflammation is important for developing cures and treatments against various diseases and disorders and thus requires an understanding of the pathogenesis and how this can be made a therapeutic target * Role of inflammation is well-established for many diseases such as **RA**, **osteomyelitis** and **silicosis** but is less well characterised for **metabolic syndromes**, **neurodegenerative diseases** and **cardiovascular** disease * Research into cardiovascular disease has become increasingly important with the rise in **obesity** and **type 2 diabetes** * Perhaps an even better approach would be to **prevent its onset** through an understanding of the bridge between acute and chronic inflammation * One challenge to achieve this has been the ability to distinguish chronic and acute inflammation based on molecular biology diagnostics

Answer 17

* It is characterised by several features at the site of inflammation: * Hard / indurated (hardened) * Erythematous / red * Swelling / little oedema * Angiogenesis / repair * Collagen deposition with time * It is characterised by several features at the site of inflammation: * Hard / indurated * Erythematous / red * Swelling / little oedema * Angiogenesis / repair

Answer 18

* Chronic inflammation by way of disease shows many phenotypes / cardinal signs depending on the area that is affected * However, the mechanism by which it arises have been organised into the categories below * **Prolonged acute inflammation** * Chronic osteomyelitis * **Repeated acute inflammation** * Cirrhosis * **Non-immunologically specific** * Silicosis * **Immunologically specific** * Tuberculosis * **Autoimmune** * Rheumatoid arthritis

Answer 19

**Chronic osteomyelitis** = chronic inflammation of the bone * Definition * Rare but serious inflammation of the bone resulting in necrosis and progressive los * Initiation * It is usually secondary to infection with a pyogenic organism * **Staphylococcus aureus** * Enterobacter (rare) * Environmental factors * IV lines * Trauma * Surgery * Diabetes * Immunosuppression * Current treatment * Surgical debridement * Prolonged antibiotics (**gentamycin**) delivered by nanoparticles to the bone * Necessary as blood is poorly vascularised * Bone grafts * Current outcomes * Loss of a part of the bone * Amputation * In severe cases * Ideal outcome * Prevent the loss of function and spread of infection to the bone * Pathogenesis: * Microorganisms that have breached the epithelial barriers are able to enter the bone by 3 main methods: * Bloodstream * Near-by areas of infection * Penetrating trauma to the bone * Including iatrogenic causes * Once the pathogen has infected the bone, it stimulates an immune response **(L PPI SI)** * **Leukocyte entry** * Upon pathogenic stimulation of immune cells, there is recruitment of leukocytes to the bone * **Protease release** * Leukocytes such as **macrophages** and **NK cells** release proteases in attempts to kill the pathogen/phagocytose it * These proteases are able to lyse bone tissue through decalcification * **Pus** * PMN are recruited to the area, phagocytose the pathogen and die, releasing pus that can spread to and block the vasculature of the bone * **Impaired blood flow** * This leads to an impaired blood flow to infected areas of bone and precipitates **necrosis** of bone cells * **Sequestrum** * The area of **necrotised bone** forms the sequestrum that becomes separated from the rest of the calcified area * **Involucrum** * Initiation of repair by the formation of new bone around the sequestrum results in the formation of the involucrum * Chronic pathology: * The chronic nature of the inflammation is mediated by the persistence of the pathogen intracellularly within bone cells and can spread to adjacent cells * This results in the persistence of the immune reaction and inflammation that gradually leads to the further destruction of the bone * The areas of necrotised bone may be replaced with connective tissue

Answer 20

* **Alcohol cirrhosis** is an example of chronic inflammation due to repeated bouts of acute inflammation * Definition * Late stage of alcoholic liver disease * Liver is fibrosed and swollen * Due to death of **hepatocytes** * Initiation * Chronic ethanol intake leads to **necrosis** and **oxidative stress** in **hepatocytes** * Key cell type * **Kupffer cells** release cytokines that attract leukocytes in response to hepatocellular damage * Environmental factors * Chronic alcohol intake * Malnutrition * Loss of vitamin cofactors * Infection with HepC * Women are twice more likely than men * Diagnosis * Liver enzyme assay * Aspartate amino transferase * X-ray appearance of nodules in the liver * Distended abdominal veins * Current outcomes * Increased risk of oesophageal varices that can lead to GI haemorrhage * Current treatment * Liver transplant * Pathogenesis * Ethanol is converted into acetaldehyde by alcohol dehydrogenase * **Acetaldehyde increases fatty acid synthesis pathways** * Leads to fat accumulation in hepatocytes * Acetaldehyde results in **greater NADH** * NADH results in greater oxidative stress of hepatocytes * Decreased reduction of **ROS** and **H₂O₂** * Hepatocytes die by apoptosis promoting the secretion of cytokines by Kupffer cells and recruitment of leukocytes * This can increase the stimulus for fibrocyte deposition of collagen forming fibrosis scar tissue

Answer 21

Silicosis * Definition * Inflammation that results from **long term exposure** to low amounts of **silica dust** that lead to the **formation of nodules** and **scarring** in the **chest** and **lymph** **nodes** * Key cell type * Macrophages * Alveolar & monocytes * Environmental factors * Silica exposure * Symptoms * Chronic cough * Breathlessness * Current treatment * Managing respiratory distress * Ideal outcome * Prevent fibrosis and decrease macrophage recruitment * Pathogenesis 1. Silica particles are deposited in the alveoli 2. Phagocytosis of silica by macrophages 3. Lysosomal disruption leads to death of macrophages by necrosis 4. Release of cytokines: IL-1 beta and growth factors 5. This increases the recruitment of macrophages and fibroblasts 6. Collagen deposition and fibrosis

Answer 22

Tuberculosis * Macrophages * CD4⁺ T-cells * Environmental factors * HIV co-infection * Smoking * Alcohol * Current treatment * Containment of the infection * Pathogenesis * In the primary TB infection, there is immune activation involving CD4+ cells and macrophages * In 95% of people, the infection is controlled in this way * In 5-10% of people, there is reactivation of TB leading to secondary TB * This can become disseminated to give military TB/active TB causing pneumonia 1. Mycobacterium tuberculosis enters the lung in airborne particles, where it is phagocytosed by macrophages in which **survival strategies** prevent its degradation in the phagolysosomes. 2. The classic location of primary lesions is surrounding the **lobar fissure**s, either in the upper part of the lower lobe or lower part of the upper lobe, known as a **Ghon focus**. 3. Macrophages and DC carry the pathogen to the lymph node for induction of cellular immune responses; this combination of **parenchymal lung lesion** and nodal involvement is referred to as the **Ghon complex** or primary complex. Revealed by X-ray and histological investigations. 4. Hyperactivated CD4 T cells (recruited due to antigen presentation with MHC class II) release cytokines that activate macrophages to kill infected cells and activate epithelioid macrophages fuse together to form **Langerhans Giant Cells.** 5. The **epithelioid** macrophages form a granuloma at the infected area, surrounded by a cuff of **CD4+ cells,** **preventing dissemination** of the bacterial infection

Answer 23

**Rheumatoid arthritis** * Definition * Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disease that primarily affects the joints, leading to synovial hyperplasia and bone destruction. *The pathogenesis of RA is not completely understood but will be discussed in the context of what is known through this essay.* * *Formation of autoantibodies to modified self-epitopes.* * Importance * Understanding the disease process in RA is essential for the development of effective treatment; not only does RA reduce the QOL of suffers by immobilisation and painful symptoms, but also greatly increases the risk of CVD, as there is a higher prevalence of CVD risk factors in RA sufferers. * Introduction of treatments * The premature mortality once observed with RA has been reduced due to a better understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools over the last decade. * One of these strategies has been the use of therapeutic antibodies – which will be discussed in this essay. * Perceptive * The limited range of motion & drastic reduction in QOL observed in the autoimmune, chronic inflammatory disease, RA, highlights the immense capability of the immune system to destroy and derange perceived threats to the human host. In protection against pathogens, this has been vital to human survival, but the emergence of autoimmune disorders highlights the susceptibility of this system to perturbation. * **TNF-alpha** * Local effects * Increased monocyte activation, cytokine release * Increased endothelial adhesion molecule expression * Decreases synovial fibroblast proliferation and collagen synthesis * Increase MMP and cytokine release * Systemic Effects * Acute phase reactant production * HP-Adrenal axis dysregulation (fatigue and depression) * CVD promotion through endothelial changes, insulin resistance (endothelial dysfunction) * dyslipidaemia * **IL-6** * Local effects * Osteoclast activation * Neutrophil recruitment * Pannus formation via VEGF production * B cell and T cell proliferation * Systemic effects * Similar to TNF * Increased liver hepcidin (leads to anaemia) * **IL-1** * Local effects * Increased cytokine, MMP and PG release * Osteoclast activation * Endothelial adhesion molecule expression