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31. Inflammation Flashcards

1
Q

What functions do resting endothelial cells have?

A

1. Prevent coagulation

  • Shielding tissue factor
  • Secreting platelet inhibitors
    • Nitrogen oxide synthase (NOS)
    • ADP
    • PGI2 (prostacyclin)
  • Thrombin inactivation
  • Protein C receptor
  • Thrombomodulin expression
    • Thrombin cleaves protein C into active form
  • Express heparin sulphate

2. Inhibits inflammation

  • Nitrous oxide production
  • Downregulate adhesion molecules
    • ​Selectins
      • ​P-selectin
      • E-selectin
      • L-selectin
    • Integrins
      • VCAM1 (ligand for VLA4)
      • ​ICAM1 (ligand for LFA1)

3. Vasodilation

  • Nitrous oxide
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2
Q

What are the mechanisms that can elucidate endothelial activation?

A
  • There are 2 types of activation:
    • Type 1 - Gq receptor activation
      • Response
        • Increased blood flow
          • Increased leukocyte delivery
        • Increased permeability
        • Activation of neutrophils
      • Time course
        • Rapid
        • Last 10-20 minutes
  • Type 2 - Pro-inflammatory cytokines e.g. IL-1 & TNF
    • Description
      • Spontaneously evolve from neutrophil recruiting phenotype to monocytes and T cells
      • Polarizing cytokines such as interferon-γ or IL-4
        • can modify the activated endothelial cell phenotype to preferentially support TH1 cells or TH2 cell-type inflammatory reactions, respectively
    • Response
      • Increased blood flow
      • Leukocyte recruitment
      • Protein synthesis & translocation dependent
  • Time
    • Slower onset
    • Last hours to days
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3
Q

Define inflammation

A
  • Inflammation is an adaptive response triggered by noxious stimuli and conditions such as infection and tissue injury that facilitates the localisation of circulation cells and molecules involved in defence to the stimulus site
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4
Q

What is the function of inflammation? What happens if the disturbaces are transient? What happens if the disutrbances are sustained?

A
  • Function
    • Restore functionality and homeostasis in the tissue
      • If the abnormal conditions are transient, then a successful acute inflammatory response returns the system to the basal homeostatic set points
    • Elimination of noxious stimuli
      • Allow host to adapt to disturbance and ultimately
      • If by contrast, the abnormal conditions are sustained, then an ongoing inflammatory state shifts the system to different set points as occurs during chronic inflammation
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5
Q

What are the cardinal signs?

A
  • Cardinal signs (PRISH)
    • Pain
    • Redness
    • Immobility (loss of function)
    • Swelling
    • Heat
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6
Q

Perceptive opening

A
  • There is much debate as to whether evolution got inflammation right. Inflammation’s primary functions are the restoration of homeostasis in the tissue and the elimination of noxious stimuli. Its dysfunction is associated with often debilitating disease. Thus, it is commonly questioned why we evolved a system that it so susceptible to dysfunction.
  • This essay will discuss the mechanisms and functions of inflammation, their dysfunction and clinical management
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7
Q

Draw a diagram summarising the AI pathway

A
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8
Q

Outline the exogenous and endogenous stimuli that could result in AI induction.

A
  • Exogenous stimuli
    • Microbial
    • Non-microbial
  • Endogenous stimuli
    • Plasma derived
    • Tissue derived
    • ECM derived
    • Cell derived
      • Damage-associated molecular patterns (DAMPs)
        • Released from injured cells upon mechanical trauma
        • Stimulates mast cells cells stimulate to degranulate and release histamine
  • The inducer molecules e.g. DAMPS/PAMPS associated with these stimuli are recognised by a variety of receptor proteins (sensors) e.g. PRRs/APCs
    • The sensors are located in the interstitial fluid, on the cell surface, and in the intracellular space
      • Cells with high densities of these receptors include tissue resident macrophages
  • There are many examples of sensors, only a few of which are discussed.
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9
Q

Outline the complement system

A

​

  • Classical pathway
    • Lysophosphatidylcholine on dead or dying cells is recognised by C-reactive protein
    • Activates complement system via C1q
  • Alternative pathway
    • C3b binds directly to a microbe
    • Results in a cascade and in the production of fluid-phase C3 convertase (serine protease) resulting in proteolytic cleaving
  • ​Lectin pathway
    • Mannose-binding lectin recognises mannose residues (found only on pathogens)
    • Activates C4 and C2
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10
Q

What are PRRs? Which cells express them? Give examples of PRRs

A
  • Microorganisms are sensed by pattern recognition receptors (PRRS) which detect pathogen-associated molecular patterns (PAMPs)
  • PAMPs constitute common and conserved structural features expressed by pathogens
    • Bacterial cell wall components
    • Viral nucleic acids
  • PRRs are expressed by several different cell types
    • Epithelial cells
    • Macrophages
    • Dendritic cells
    • Mast cells
  • Notable PPR examples (TOMS N)
    • Toll-like receptors
      • Family of PRRs
      • TLR4 is a transmembrane domain expressed by macrophages that detect lipopolysaccharides
    • Opsonin receptors
      • The major opsonins are: IgG and C3b
        • Critical in facilitating phagocytosis
    • ​​Mannose receptors
      • Binds to mannose residues resulting in activation of C2 and C4
        • Lectin pathway
    • Scavenger receptors
      • Bind to polyanions and modified forms of low-density lipoprotein (LPL)
      • e.g. MARCO (macrophage receptor with collagenous structure
  • NOD-like receptors (intracellular)
    • Detect LPS, viral RNA, mannose and flagellin
    • Intracellular PRR
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11
Q

Define DAMPs and outline an example

A
  • Mechanical tissue damage provokes the release of damage-associated molecular patterns (DAMPs) from injured and necrotic cell
  • DAMPs are detected by DAMP receptors
    • Expressed on immune cells such as macrophages
  • Examples
    • RAGE
      • Receptor for advanced glycation end-products (RAGE) which recognises advanced glycation end products (AGE)
        • AGE = proteins/lipids that become glycated as a result of exposure to sugars
          • Ageing
          • Development of degenerative diseases
            • Diabetes
            • Atherosclerosis
            • Chronic kidney disease
            • Alzheimer’s disease
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12
Q

List markers of intracellular damage

A
  • Intracellular damage is detected by cytosolic receptors that recognise intracellular molecules in abnormal conditions
    • Normally sequestered in subcellular compartments or at abnormal conditions
  • Examples (KADU)
    • K+
    • ADP
    • DNA
    • Uric acid
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13
Q

Outline the principal inflammatory mediators

A
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14
Q

Describe the function and action of inflammasomes

A
  • Structure
    • Inflammasome complexes are activated by a subset of cytosolic PRRs
      • recognize PAMPs and DAMPs
    • Assembly of proteins that serve as a scaffold for the activation of pro-caspase 1
  • Function
    • Activates caspase-1 which cleaves IL-1 into bioactive forms IL-1β and interleukin 17 that leads to pyroptosis
      • Pyroptosis = inflammatory cell death
        • Lytic & pro-inflammatory unlike apoptosis
  • Multiple sclerosis
    • One of the most common types of autoimmune disorders characterised by the myelin reactive CD4+ T-cells that enter the CNS and induce demyelination
    • Animal models used to mimic MS have shown delayed progression of MS-like disease when there is a deficiency in the NRP3 inflammasome
  • Alzheimer’s disease
    • Direct link between the NRP3 inflammasome and the development of AD has been shown in APP/PS1 mice
      • APP/PS1 mice = transgenic mice that develop chronic deposition of amyloid plaques with NLRP3 and caspase-1 deficiency

These mice have reduced AD-related pathogenesis, reflected

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15
Q

Describe the action of Hageman Factor

A

AKA factor 12

  • Structure
    • Plasma protein of the serine protease class
    • Factor 12 is unique in that is both a sensor and mediator of inflammation
  • Sensor of vascular damage
    • Activated endotoxins
      • Lipid A
  • Mediator actions
    • Active factor 12 activates the Kallikrein-kinin cascade leading to bradykinin formation
      • Bradykinin is a potent vasodilator and pro-algesic
    • ​Plasmin = fibrolytic
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16
Q

Describe the components of inflammatory exudate and its function

A
  • The key features of the effector components of acute inflammation include:
    • Cells
      • Role in defence and repair
    • Macromolecules
      • Host defence
    • Fluid
      • Oedema
  • All these components are found in the inflammatory exudate, the principle effector mechanism of acute inflammation
    • Inflammatory exudate = extravascular fluid containing plasma proteins and phagocytic white blood cells (WBCs) such as neutrophils and monocyte/macrophages that have been drained from the circulation
      • Neutrophils
      • Monocyte/macrophage
    • The exudate is generated by physiological changes in the tissue microvasculature in response to inflammatory mediators
  • Exudate is generated by physiological changes in the tissue microvasculature in response to inflammatory mediators leading to:
    • Vasodilation
    • White blood cell recruitment
    • Increased vascular permeability
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17
Q

Describe vasodilation in terms of its function and its mechanisms of activation

A
  • Inflammatory mediators promote vasodilation of the microvasculature (arterioles, capillaries and venules) in the stimulated tissue
  • H2 = direct on VSM = Gs
  • H1 = indirect on endothelum = Gq –> NO
  • Functions of vasodilation
    • Increases blood flow
      • (Greater lumen size so greater volume)
      • Increases white blood cell delivery to the stimulated tissue
      • Produces the cardinal signs of heat and redness at the site of inflammation
    • Decreases blood velocity
      • (Decreased pressure)
      • Limiting pathogen spread within the host
      • Facilitating WBC margination in the process of extravasation (discussed later)
  • Mechanism of vasodilation
    • Elicited by actions of inflammatory mediators on both vascular smooth muscle (arterioles, some venules) and the endothelium
  • Vascular smooth muscle
    • Histamine released from mast cells activates Gs-linked H2 receptors on vascular smooth myocytes (VSM) promoting relaxation via a rise in [cAMP]i, stimulating PKA and phosphorylating and inhibiting myosin light chain kinase (MLCK)

Endothelial cells

  • #### Type 1 endothelial cell activation
    • Action of histamine on endothelial H1 GPCRs
      • Gq-linked
    • Release of prostaglandin I2 (PGI2) AKA prostacyclin
      • Binds to prostacyclin receptor, activating Gs pathway
    • Release nitric oxide (NO)
      • Diffuse into VSM, activates guanyl cyclase converting GTP into cGMP
        • cGMP stimulates protein kinase G which phosphorylates and inhibits MLCK
  • #### Type 2 endothelial cell activation
    • IL-1 and TNF-a
      • Upregulate COX2 expression and thus promote PGI2 synthesis
        • Binds to prostacyclin receptor, activating Gs pathway in VSM
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18
Q

Outline the stages of white blood cell recruitment

A
  1. Extravasation
    1. Margination
    2. Rolling (PEL)
    3. Firm adhesion
    4. Diapedesis
    5. Importance
    6. Pharmacology
  2. Chemotaxis
  3. Pathogen destruction
    • Phagocytosis
      • Pathogen recognition
      • Engulfment
      • Granule fusion
        • Chronic granulamtous disease
    • Lysosome fusion
    • Neutrophil extravastion
  4. Increased vascular permeability
    • Tight junction breakdown
    • Endothelial damage
    • Contraction of endothelial cells
  5. Migration of plasma proteins
    • ​Albumins
    • Globulins
    • Fibrinogen
  6. Oedema
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19
Q

Outline the stages of extravasation. Which cytokines upregulate extravasation and how? Name a relevant clinical condition

A

MR FD

1) Margination

  • Margination = WBCs are displaced to the edge of the venule lumen in contact with the apical surface of the endothelium
  • There is decreased blood velocity and loss of fluid from microvasculature
    • Due to loss of fluid from the microvasculature due to increased endothelial permeability and increased vessel diameter
  • The reduced volume increases the concentration of red blood cells in the central column (longitudinal axis) of the vessel, increasing blood viscosity
  • This forces the WBCs towards the apical surface of the endothelium, facilitating interactions between WBCs and endothelial cell adhesion molecules (CAMs)

2) Rolling (PEL)

  • The WBCs transition from free flowing in blood to rolling along the apical surface of the endothelium
  • This is mediated by reversible interactions between selectins
    • Selectins = group of carbohydrate binding proteins on the surface of the endothelial cell and WBC
    • P-selectin and E-selectin on the apical endothelium interact with Sialyl-Lewisx (sLex) on the WBC
      • Sialyl Lewisx = tetrasaccharide carbohydrates usually attached to O-glycans on neutrophils
      • TNF-a and IL-1 upregulate E-selectin transcription
    • L-selectin on the WBC interact with endothelial Sialyl-Lewis
    • The attachment between the CAMs are weak therefore the interactions at the back of the neutrophil break and new interactions form under the force of the blood flow
  • Congenital disorder of glycosylation type IIc
    • Mutation in SLC35C1
    • Deficiency in neutrophil sialylyl-Lewis
    • Recurrent severe bacterial infections
      • Pneumonia
      • Peridonitits
      • Otitis media
      • Cellulitis

3) Firm adhesion

  • The WBC stops rolling and adheres firmly to the endothelium
  • This is mediated by interactions between integrins and their ligands
    • TNF-aandIL-1increase the expression of integrin ligandson theendothelium
      • VCAM-1 = ligand for VLA-4
      • ICAM-1 = ligand for LFA-1
    • Exposure of the WBC to platelet activating factor, C5a and CXCL8 (from tissue macrophages) induces conformational changes to the WBC integrins VLA-4 and LFA-1
      • These conformational changes mediate conversion from low-affinity to high-affinity state, strengthening their adhesion and stopping them rolling
      • NOT an increase in expression

4)Diapedesis

  • Diapedesis = WBCs migrating across the blood vessel wall
    • Diapedesis is simply the last step of extravasation (movement of WBCs from post-capillary venule to tissue interstitium)
  • Chemokines such as CXCL8 stimulate the migration of WBCs through the paracellular (interendotheial space)
    • Number of intercellular adhesion molecules are involved in this process such as CD31 AKA PECAM-1 (platelet endothelial cell adhesion molecule)
    • The WBC then secretes proteases (neutrophil elastases, monocyte collagenases) that degrade the basement membrane of the endothelium, promoting movement into the interstitium
20
Q

Outline a disease which shows the importance of neutrophil extravasation

A
  • The importance of neutrophil extravasation and the CAMs involved is highlighted by leukocyte adhesion deficiency (LAD)
    • Leukocyte adhesion deficiency (LAD) is an autosomal recessive primary immunodeficiency
    • Cause
      • Mutations in genes encoding the WBC CAMs involved in extravasation such as integrins
      • LAD type 1
        • Defect in the b2 subunit of integrins such as LFA-1
      • LAD type 2
        • Defect in fucosyl transferase, enzyme involved Sialyl Lewisx synthesis leading to Sialyl Lewisx deficiency
      • LAD type 3
        • Defect in kindlin-3 in haematopoietic cells resulting in failure of activation of all b-integrins e.g. VLA-4 and LFA-1
      • Effect
        • As a result, the firm adhesion of WBC to the endothelium is prevented
        • This prevents the recruitment of WBCs such as neutrophils to infected tissues (in response to signals e.g. cytokines) thus reducing pathogen destruction
      • Symptoms
        • Recurrent bacterial infections particularly in neonatal period
          • Gingivitis
          • Pneumonia
          • Peritonitis
            • Inflammation of peritoneum
      • Diagnosis
        • Neutrophilia is a diagnostic marker of LAD
          • Neutrophilia = increased concentration of neutrophils in the blood
          • Stimulated neutrophils are unable to extravasate (leave blood vessels)
      • Treatment
        • Prophylactic administration of antibiotics
          • Initial treatment
        • Haematopoietic stem cell transplant
          • Generate wild type (normal) neutrophils
          • Current and only cure
  • Excess PMN cell recruitment shows hwo excess function just like loss of a function can also lead to disease
    • Acute appendicitis
    • Meningitis
    • Lobar pneumonia
21
Q

Outline experimental evidence of the importance of cell adhesion molecules (CAMs)

A
  • Evidence that CAMs are essential in WBC recruitment comes from experiments in which CAM function is inhibited
    • Bestebroer et al in 2007 provided evidence that Staphylococcal superantigen-like protein 5 (SSL5) inhibits neutrophil extravasation
    • Method
      • Flow chamber consisting of glass coverslips coated in P-selectin was perfused with neutrophils at differing concentrations of SSL5
      • After 5 minutes, the number of attached neutrophils/mm2 was measured
    • Observation
      • In the absence of SSL5, 95% of neutrophils were found to be rolling
      • As the [SSL5] increased, the number of attached neutrophils decreased in a dose-dependent manner
      • This is because SSL5 binds to the neutrophil CAM P-selectin glycoprotein ligand 1 (PSGL-1) interfering with its interaction between P-selectin
    • Discussion
      • The results suggests that SSL5 contributes to immune evasion by Staphylococcus aureus via a reduction in neutrophil recruitment
    • Criticism
      • Other selectins are involved and thus do not have a quantifiable effect on how extravasation would be affected
      • How did they know if the neutrophils were rolling?
    • Future directions
      • The authors therefore proposed SSL5 as a potential model for the development of anti-inflammatory drugs associated with excessive WBC recruitment
22
Q

What drug is used to tackle WBC extravasation?

A
  • Drugs that target the molecules involved in WBC extravasation are used to block WBC recruitment in chronic inflammation.
  • TNF blockers
    • One of the most successful therapies developed that are mainly used in chronic inflammation
    • Infliximab
      • Binds to TNF-alpha
    • Drawbacks
      • Loss of WBC recruitment for anti-microbial defence increases susceptibility to infection
        • Could be said about any potential and current anti-inflammatory drug e.g. corticosteroids
23
Q

Outline chemotaxis. Which inflammatory mediators influence it?

A
  • The second step of WBC recruitment is chemotaxis
    • Chemotaxis = migration of WBC towards the centre of infection or tissue damage up the concentration gradients of various PAMPs and endogenous inflammatory mediators
  • The chemotactic agents bind to GPCRs in the WBC plasma membrane, activating intracellular signalling cascades that drive rearrangements of the actin cytoskeleton
    • The WBC migrates by the extension of filopodia extending from the lamellipodium in the direction of the higher [chemoattractant] and the dragging of the trailing cell body
      • Lamellipodium = cytoskeletal protein actin projection on the leading edge of the cell
    • The leading edge of the cell expresses more receptors for the chemoattractant resulting in directional receptivity and movement
  • Inflammatory mediators that drive WBC chemotaxis include:
    • CXCL8
    • IL-8
    • Complement anaphylatoxins
      • C5a
    • Leukotriene B4
24
Q

Discuss the steps of pathogen destruction by WBCs

A
  • After chemotaxis, neutrophils and macrophages destroy the inductive agent, often dead cells or most often a pathogen
  • WBCs express two mechanisms of pathogen destruction:
  1. Phagocytosis
  2. Neutrophil extracellular traps (NETs)

NETS

  • NETs disarm pathogens with antimicrobial proteins such as neutrophil elastase, cathepsin G and histones that have a high affinity for DNA
  • NETs provide for a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly independent of phagocytic uptake.
  • ##### Phagocytosis
  • The most important mechanism of pathogen destruction is phagocytosis which performed by both neutrophils and macrophages

1) Pathogen recognition

  • Phagocytosis begins with recognition of the pathogen by membrane bound pattern recognition receptors - (TOMS)
    • Toll-like receptors
      • Only on
    • Opsonin receptors
      • The major opsonins are: IgG and C3b
        • Critical in facilitating phagocytosis
    • Mannose receptors
    • Scavenger receptors
      • Bind to polyanions and modified forms of low-density lipoprotein (LPL)
      • e.g. MARCO (macrophage receptor with collagenous structure

2) Engulfment

  • The pathogen is then engulfed by the phagocyte membrane, becoming enclosed in an intracellular phagosome
  • Membrane folding involves rearrangement of cytoskeletal actin filaments

3) Granule fusion (MELD PC & LNL)

  • In neutrophils, the phagosome fuses with two types of preformed granule
  • Azurophilic (primary) granules
    • Contain enzymes that destroy the pathogen (MELD PC)
      • Myeloperoxidase
        • Produces hypochlorous acid (HOCl) and Cl-
          • Destroys pathogens by halogenation or oxidation of proteins/lipids
      • Elastase
      • Lysozyme
      • Defensins
  • Proteinase 3
  • Cathepsin G
  • Specific (secondary granules) - LNL
    • Lactoferrin
      • Competes with pathogens for iron and copper
    • Lysozyme
    • NADPH oxidase
      • NADPH oxidase = enzyme converts O2 and produces superoxide radicals (O2-)
        • O2- then converted into hydrogen peroxide (H2O2) by superoxide dismutase
      • Oxidation reaction consume H+, raising the phagosome pH to 8.0 and activating antimicrobial factors
      • NADPH oxidase is associated with a transient increase in O2 consumption, known as the respiratory burst

4) Lysosome fusion

  • Phagosome then fuses with lysosomes containing acid and degradative enzymes
    • Acid hydrolases – activated at low pH that denature and digest pathogenic macromolecules
25
Q

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

A
  • 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 (O2-) 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
26
Q

What are neutrophil extracellular traps?

A
  • 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
27
Q

Discuss neutrophil death

A
  • 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
28
Q

Outline the stages of increased vascular endothelial permeability

A

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
29
Q

Outline the key plasma proteins that migrate into the site of inflammation

A
  • #### 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)
30
Q

Discuss what causes oedema

A
  • The microvascular changes in inflammation result in an increase in filtration across the capillary wall according to the Starling equation

JV=Kf S[(Pc-Pi )-σ(πp-πi )]

Jv = filtration rate Kf = hydraulic conductivity S = surface area

P = hydrostatic pressure σ = Staverman’s reflection coefficien πp = plasma oncotic pressure πi = interstitial oncotic pressure

  • Vasodilation
    • Increases the capillary surface area (S)
  • Movement of plasma proteins into the interstitium
    • Increases the interstitial fluid colloid osmotic pressure (pi)
  • Increased endothelial permeability
  • Increases the hydraulic conductance (Kf) of the vessel wall
31
Q

Discuss what excess oedema can result in

A
  • 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
32
Q

An important function of AI is the stimulation of the adaptive immune system (AIS) by antigen presentation. This is important because despite its speed and broad specificity, the innate immune system (IIS) is sometimes not powerful enough to eliminate the infection and thus requires AIS support.

Discuss the mechanisms of antigen presentation

A

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
33
Q

What causes fever in acute inflammation? Name and explain the cytokines involved

A
  • 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-6andPGE2on thehypothalamuselicits a rise in the set point of thecore 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-aandIL-6act onhepatocytes, 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
34
Q

Define septic shock, its pathogenesis and treamtent

A

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
35
Q

What are the two major outcomes of acute inflammation?

A
  1. The elimination of noxious stimuli followed by resolution and repair of damaged tissue
  2. Persistent injury leading to chronic inflammation
36
Q

Outline the stages of normal resolution of acute inflammation

A

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
  2. ECM deposition
    • Fibroblasts lay down ECM such as collagen type 2
  3. 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
37
Q

How are NSAIDs anti-inflammatory?

A
  • 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
38
Q

How are corticosteroids anti-inflammatory?

A
  • 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
39
Q

Define chronic inflammation

A
  • 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
40
Q

Perceptive opening on chronic inflammation

A
  • 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
41
Q

Histological appearance of chronic inflammation

A
  • 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
42
Q

Types of chronic inflammation

A
  • 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
43
Q

Explain in detail, an example of prolonged acute inflammation

A

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
44
Q

Explain in detail, an example of repeated acute inflammation

A
  • 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
45
Q

Discuss in detail, a non-immunologically specific disease

A

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
46
Q

Discuss in detail, an immunologically infective type of inflammation

A

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 fissures, 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
47
Q

Outline in detail, a chronic inflammatory condition

A

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

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