Week 1: Inflammation and repair 1

Question 1

Define inflammation

Answer 1

A localised response resulting color,tumor, rubor, dolor and function laesa due to infection or injury.

Question 2

What is the purpose of inflammation?

Answer 2

Protective response against damage/pathogens
Trigger homeostasis

Question 3

What is the mechanism behind calor, rubor and tumour in inflammation?

Answer 3

Vasodilation increases blood flow
Increased vascular permeability and causes vascular status
More blood closer to the surface

Friction from diapedisis may also contribute to heat

Question 4

What is the mechanism behind dolor from inflammation?

Answer 4

Action of inflammatory mediators on free nerve endings to activate or sensitize the endings.
Typically prostaglandins (leukocyte release) and bradykinin released from mast cells.

Question 4

What causes functio de laesa during inflammation?

Answer 4

Damage to cells necessary for tissue function including parenchymal and stromal cells

Question 4

What are the kinetics of acute inflammation?

Answer 4

Rapid and short lived reponse to injury.
Develops over minutes/hours
May persist over a few days
Starting with edema, neutrophil infiltrate the monocyte/macrophage infiltrate

Question 4

What is the process behind vasodilation in inflammation?

Answer 4

Microbes/ nectrotic tissue release PAMPs/DAMPs that are recongised by PRR on tissue resident immune cells.
Results in the release of inflammatory mediators
In particular histmane release from mast cells.
Histamine binds to H1 receptors on endothelial cells, results in the production of NOx. NOx results in the relaxation of smooth muscle in capillary walls - acting as a vasodilator

Question 4

What are the key phsyiological features of acute inflammation?

Answer 4

Vasodilation
Increased vascular permeability
Vascular statis
Pain

Question 4

What is the mechanism behind increased vascular permeability during inflammation?

Answer 4

Vasodilation
Inflammatory mediators such as histamine, prostaglandins and leukotrienes cause endothelial cells to contract, disrupting the tight junctions to widen the gaps.

Question 5

What is the mechanism behind vascular statis in acute inflammation?

Answer 5

Increased vascular permeability - loss of fluid from blood plasma
This increases the viscosity of blood hence slower flow
Fibrin clots may also form - due to increased pro-coagulant factors such as fibrinogen and thromboxane

Question 5

What is the process of leukocyte extraversion in inflammation?

Answer 5

Vasodilation and increased vascular permeability from inflammatory mediators.
Vascular stasis allows immune cells to lone up near endothelium (imagination)
Leukocyte forms low affinity bonds with the endothelial walls by E-selectin on endothelial cells and sialyl-Lewis on leukocyte, alongside L selecting on leukocyte walls and ligand on endothelial cells.
Breaking and reformation of these bonds allows the leukocyte to roll along endothelium.
Chemokine signalling in leukocyte cause a higher affinity adhesion molecule, this tighter bond is where the leukocyte will pass through widened gaps in the endothelial layer (from endothelial cell contraction), squeezing into intersitial fluid by diapedesis (may secrete collagenases to help degrade BM)
Follows chemokine gradient to site of injury, chemokines rearrange the cytoskeleton of the lymphocyte to allow it to move forward.

Question 5

Answer 5

Basophil

Question 5

What is the process by which a macrophage can lead to pain sensation?

Answer 5

A resident activated macrophage releases inflammatory mediators such as TNF and PGE2, which bind to cytokine receptors on the surface of nociceptor terminals.
Leads to a cascade of signalling inside the nocicpetor including the activation of adenylate cyclase.
This leads to increased Ca2+ mobilisation
Increased voltage or ligand gated channel activation
Increased neuropeptide transcription and release
Increased transcription or receptor and channel proteins.
Leads to sensitisation to or activation of a pain signal

Question 6

Answer 6

Lymphocyte

Question 7

Answer 7

Monocyte

Question 8

Answer 8

Macrophage

Question 9

Answer 9

Eosinophil

Question 10

What are the main cell types involved in acute inflammation?

Answer 10

Neutrophils
May be followed by monocytes and macrophages (typically in smaller numbers)

Question 11

What is the role of neutrophils in acute inflammation?

Answer 11

Dominate for 6-24 hours
Die and replaced by monocytes

Phagocytose pathogens, debris and dead cells, will secrete cytokines and produce NETs

Question 12

What is the key way to distinguish between histological monocytes and macrophages?

Answer 12

Macrophages tend to have more cytoplasm (and lack of rbcs in background)

Question 13

What is the role of macrophages in acute inflammation?

Answer 13

Phagocytic
Secrete cytokines
Activate T cells

Question 14

What are the Non-cellular effectors in acute inflammation?

Answer 14

Complement
Enzymes
NETs

Question 15

What is the key role of complement?

Answer 15

Activated by:
Classical pathway - C1 binds to antigen antibody complex on pathogen surface
Lectin Pathway - C4/C2 binds to sugars on pathogen surface e.g MBL binds to mannose on surface
Alternative - C3b binds directly to pathogen surface

Enzyme cascade - compliment proteins are cleaved to be activated

Outcomes:
C3a and C5a recruit phagocytic cells by chemotaxis and promote inflammation!!!!!!!! acute inflammation
C3b - membrane attack complex
C3b - opsonisation

Question 16

What is the role of NETs in acute inflammation?

Answer 16

Netosis in. neutrophils released NETs
Consist of antimicrobial proteins and nuclear chromatin to immobiliser and destroy pathogens

Question 17

What is the role of MMP in acute inflammation?

Answer 17

Break down extracellular matrix.

Question 18

What are the symptoms of systemic inflammation?

Answer 18

Tachycardia Hypotension Leukocytosis Fever

Question 19

What brings on the effects of systemic inflammation?

Answer 19

Cytokines, particularly IL-1beta, TNFalpha and IL-6, all of which have longer lasting effects than histamine Act on hypothalamus to cause fever SNS to cause cardiovascular changes Liver - to release APP such as CRP Bone marrow - to produce more leukocytes

Question 20

Identify the key features of acute inflammation in this histological image

Answer 20

Dilated and congested blood vessels Neutrophils in the tissue Tissue oedema (white space)

Question 21

What are the different types of acute inflammation? How are they different?

Answer 21

Serous Fibrinois Purulent Ulcerative All have different morphological features

Question 22

What are the key features of serous inflammation?

Answer 22

Accumulation of exudate in a cavity Cavity may be natural e.g peritoneum or created by an injury (under epithelium) Exudate originates from plasma or mesothelium Exudate is sterile and free of leukocytes E.g skin blister

Question 23

What are the key features of fibrous inflammation?

Answer 23

High deposition of fibrin Occurs at lining of body cavities Normally after highly vascular leakage and a procoagulant stimuli resulting in fibrin deposition. If not resolved scar formation disrupts function

Question 24

What are the key features of purulent/suppurative inflammation?

Answer 24

Formation of pus - necrotic debris and tissue fluid (causes liquifaction on necrosis) Usually caused by a pyogenic bacteria (staphylococci aureus) In chronic inflammation the abcess may be surrounded by fibrotic connective tissue

Question 25

What is an abscess?

Answer 25

Localised collection of pus inside a tissue Type of purulent inflammation

Question 26

What are the key features of ulcerative inflammation?

Answer 26

Local defect in tissue from disintigration of inflamed necrotic tissue Found where inflammation occurs at or near a surface May have areas of acute and chronic inflammation.

Question 27

Describe what is depicted in the histological image?

Answer 27

Loss of mucosal layer A - artery close to hemorrhage F - is a fibrous scar shown by high collagen deposits

Question 28

What are the different outcomes of acute inflammation?

Answer 28

Resolution - cause eliminate and no tissue damage, normal function restored Healing/repair by fibrosis - extensive tissue damage results in connective tissue replacing functional tissue, can not regenerate Progression to chronic inflammation

Question 29

What medication typically used to treat acute inflammation?

Answer 29

Cox-inhibitors: prevent prostaglandin production, relieve pain Steroids: such as dexamethasome, binds to intracellular glocorticoid receptor, acts as transcription factor to decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines

Question 30

What are the key features of chronic inflammation?

Answer 30

Prolonged inflammatory response of weeks or months Characterised by simultaneous inflammation, tissue damage and attempts at repait

Question 31

What are the origins of chronic inflammation?

Answer 31

Follow acute or begin insidiously 1. Persistent infection 2. Unresolved inflammation 3. Continuing exposure to a stimuli (e.g dog hair or asbestos) 4. Hypersensitivity diseases (inappropriate activation of immune system)

Question 32

What conditions can be classified as acute inflammation?

Answer 32

Allergic reactions Chemical irritants infection trauma injury Burns Laceration, cuts, wounds. Frostbites

Question 33

What conditions may be classified as chronic inflammation?

Answer 33

Cardiovascular disease Neurological disease Autoimmune disease Rheumatoid arthiritis Cancer Fibromyalgia Chronic Fatigue Syndrome

Question 34

What are the morpholigical features of chronic inflammation?

Answer 34

Tissue infiltrate - is mainly mononuclear cells (macrophages, lymphocytes and dendritic cells) Destruction of normal tissue architecture leading to loss of tissue function Angiogenesis and fibrosis - as part of ongoing repair attempts

Question 35

What cell type is present?

Answer 35

Plasma cell Eccentrically placed nucleus Chromatin collects near nuclear membrane giving a clock face appearance.

Question 36

What are the features of chronic inflammation in this slide?

Answer 36

Lymphocytes Plasma cells Macrophages Lots of collagen deposits Loss of normal structures - such as hair follicles and sweat glands in the skin (replaced by scar tissue)

Question 37

What are the outcomes of chronic inflammation?

Answer 37

Healing by fibrosis Immune Mediated Inflammatory Disease.

Question 38

What are some of the causes of a disregulated inflammatory response?

Answer 38

Genetic Acquired - cancer, disease etc

Question 39

What medications may be given to treat chronic inflammation conditions?

Answer 39

NSAIDs - e.g ankylosing spondylitis Corticosteroids - e.g inhaled budesonide for chronic asthma Immunosuppressants - methotrexate for rheumatoid arthiritis Biologics - adalimumab for severe active chrons disease.

Question 40

What is the process of complete resolution of an acute inflammatory response?

Answer 40

Causes localised and low grade damage to cells – hence cells retain ability to regenerate and stem cell population survives – combined with low grade damage to the ECM – tissue is able to regenerate when stimulated by growth factors released by macrophage. Combined with the reabsoprtion of exudate into lymphatics and macrophages clearing pathogen and necrotic tissue. Inflammation is said to be completely resolved. **exam answer should include detailed from resolution of inflammation year 1.