S2) Acute Inflammation

Question 1

What is inflammation?

Answer 1

Inflammation is a response to injury of vascularised living tissue (indicated by the suffix -itis)

Question 2

Identify 4 purposes of inflammation

Answer 2

• Deliver defensive materials (blood cells and fluid) to a site of injury
• Protect the body against infection
• Clear damaged tissue
• Initiate tissue repair

Question 3

In terms of time, distinguish between acute and chronic inflammation

Answer 3

• Acute inflammation evolves over hours or days (innate and stereotyped)
• Chronic inflammation evolves over weeks, months or even years

Question 4

What is acute inflammation?

Answer 4

Acute inflammation is a rapid response to an injurious agent which aims to deliver mediators of host defence (leucocytes and plasma proteins) to the site of injury

Question 5

In acute inflammation, leucocytes and plasma proteins need to be delivered because local defences are not adequate.

Describe the mechanism of delivery of these defences

Answer 5

• Most defensive agents circulate in the blood in inactive form and when needed, they are delivered and activated
• They leave the blood vessels at the site of the injury without interrupting blood flow to other tissues
• This process is controlled by chemical mediators

Question 6

Identify 5 major causes of acute inflammation

Answer 6

• Foreign bodies e.g. splinters, dirt, sutures
• Immune reactions
• Infections e.g. bacterial, viral, parasitic
• Tissue necrosis
• Physical and chemical agents e.g. burns, frostbite, irradiation

Question 7

What are 5 cardinal signs of acute inflammation?

Answer 7

Question 8

Describe the initial tissue change in acute inflammation, how it is achieved and result of this

Answer 8

• Brief period of arteriolar vasoconstriction (lasting a few seconds)
• Vasodilatation of the arterioles occurs due to vasoactive mediators e.g. histamine
• Resultantly, flow accelerates in the capillaries and capillary pressure rises

Result = increased fluid and leucocyte delivery to the area of injury

heat and redness

Question 9

What follows vasodilation in acute inflammation?

Answer 9

• Venular leakage (increased permeability)
• Plasma escapes through gaps between endothelial cells
• Resultantly, an increased haematocrit within the venules increases resistance to blood flow within them

Question 10

In 5 steps, outline the effects of vasodilation and increased venular permeability in acute inflammation

Answer 10

• Hampers blood outflow from the area of injury
• Increases pressure upstream causing vasodilation of upstream vessels
• Blood flow slows down
• Thus, there’s greater exudation of fluid into the tissue spaces = increased oncotic pressure
• Greater delivery of plasma proteins to the site of injury

= odema (fluid builds up in the interstitual space so dilutes toxins)

Question 11

Outline the properties, location, action and effects of histamine in acute inflammation

Answer 11

• Properties: vasoactive amine, readily available in cells/platelets
• Location: stored in granules of mast cells, basophils and platelets
• Action: released in response to stimuli such as physical damage, immune reactions and complement components
• Effects: pain, arteriolar dilatation and venular leakage

Question 12

Outline the properties, location and effects of serotonin in acute inflammation

Answer 12

• Properties: vasoactive amine, readily available
• Location: stored in the granules of platelets
• Effects: similar vascular effects as histamine

Question 13

What are prostaglandins and what do they do in inflammation?

Answer 13

• Prostaglandins are substances produced in inflammation from cell membrane phospholipids
• They cause vasodilatation, fever and increase pain sensitivity

Question 14

Describe how the production of prostaglandins can be blocked to reduce pain and swelling

Answer 14

• Production can be blocked by aspirin and NSAIDs
• These drugs inhibit cyclo-oxygenase (the enzyme that produces prostaglandins from arachadonic acid)

Question 15

Identify 2 other substances with vasoactive properties

Answer 15

• Leukotrienes
• Bradykinin

Question 16

Acute inflammation throws off the equilibrium of fluid exchange in the microcirculation. Starling’s law describes the forces involved in this equilibrium.

What are the forces?

Answer 16

Question 17

Discuss the roles of endothelium in acute inflammation

Answer 17

• The endothelium of the capillaries and venules acts as a semipermeable membrane
• This allows the escape of water and electrolytes but retains plasma proteins

Question 18

The exchange between the blood and tissue spaces depends on the four forces below.

Describe this

Answer 18

• The main force driving fluid out of the vessels is the hydrostatic pressure of the blood
• The main force driving fluid back into the blood is the colloidal osmotic pressure of the plasma proteins

Question 19

What is the impact of the altered vascular elements (vasodilation and venular leakage) on the forces in Starling’s law?

Answer 19

• Arterioles dilate increasing capillary pressure as pressure in the veins increase, hence, driving more fluid out of the blood
• Plasma proteins escape into the tissue spaces, raising the osmotic pressure there and reducing colloid osmotic pressure

Question 20

What is the significance of vasodilation and increased permeability in acute inflammation?

Answer 20

• Increased flow of fluid (with its plasma proteins) out of the vessels into the tissue spaces
• Delivery of plasma proteins to the site of injury

Question 21

What happens to the excess fluid in the tissue spaces during acute inflammation?

Answer 21

Excess fluid drains from the tissues in the lymphatics taking with it micro-organisms and antigens which are presented to the immune system within the lymph nodes

Question 22

Identify the three main types of defensive proteins in the exudate and describe their actions

Answer 22

• Opsonins – coat foreign materials to enhance phagocytosis
• Complement – a group of proteins locally assembled to produce a bacteria-perforating structure
• Antibodies – bind to the surface of micro-organisms and also act as opsonins

Question 23

Compare and contrast exudate and transudate

Answer 23

• Exudate is the protein-rich tissue fluid that develops in inflammation
• Transudate is the protein-poor ultrafiltrate of plasma occurring in normal vessels

Question 24

Identify the chemical mediators involved in vascular leakage

Answer 24

• Histamine
• Serotonin
• Bradykinin
• C3a, C4a and C5a
• increase the spaces in between the endothelial cells and increase permeability

Question 25

What are neutrophils?

Answer 25

**Neutrophils** are the primary type of leucocyte involved in acute inflammation (cellular phase) release inflammatory mediators

Question 26

Describe the structure, function and location of neutrophils

Answer 26

- **Structure**: contains about 2,000 granules containing bactericidal substances - **Function**: escapes from blood vessels into tissue spaces in response to chemical ‘calls’ from bacteria, injured cells or other inflammatory cells - **Location**: normally only found in the blood and bone marrow, and in tissue during inflammation - **opsonisation:** neutrophil has a corresponding receptor to the pathogen

Question 27

In 6 steps, outline the processes that occur when a neutrophil captures and kill a bacterium in the tissue space

Answer 27

⇒ **Chemotaxis:** be summoned to the place of injury ⇒ **Activation**: switch to a higher metabolic level ⇒ **Margination**: stick to the endothelial surface ⇒ **rolling**:roll through the endothelium - **adhesion**: moves through vessel ⇒ **Recognition-attachment:** recognise the bacterium and attach to it -**emigration/dapedisis: leaves** ⇒ **Phagocytosis**: engulf the bacterium

Question 28

What is a cytokine?

Answer 28

**Cytokines** are polypeptides that are produced by many cells and act as messengers between cells

Question 29

What is chemotaxis?

Answer 29

**Chemotaxis** is directional movement towards a chemical attractant (chemotaxin) happens to neutrophil after it leaves the blood vessel leukotriene B4, C5a and C3a

Question 30

What are chemokines?

Answer 30

**Chemokines** (short for chemotactic cytokines) are a group of cytokines which are involved in chemotaxis

Question 31

Identify some chemotaxins

Answer 31

- Bacterial products *e.g. endotoxin* - Injured tissues - Substances produced by leucocytes - Spilled blood

Question 32

What is an endotoxin?

Answer 32

An **endotoxin** is a lipopolysaccharide from the outer membrane of gram negative bacteria

Question 33

Fresh blood isn’t chemotactic, why is clotted blood chemotactic?

Answer 33

- When blood clots a cascade of plasma enzymes is activated resulting in the formation of thrombin and fibrin - Both thrombin and fibrin degradation products are chemotactic, therefore clotting blood is chemotactic

Question 34

What happens when a complement is activated?

Answer 34

- Release of fragments of C3, C4 and C5 called C3a, C4a and C5a - All of these are chemotactic (especially C5a)

Question 35

Activated cells are stickier than normal cells. Why is this?

Answer 35

- Within five seconds of the chemotaxin binding to cell surface receptors, Ca²⁺ and Na⁺ rush into the cell - The cell swells and reorganises its cytoskeleton - It assumes a triangular shape pointing in the direction of the chemotactic stimulus and sends out pseudopodia

Question 36

Leucocytes can also produce chemotaxins. Identify one

Answer 36

**Leukotriene B4** is the most powerful chemotaxin from leucocytes

Question 37

What is margination?

Answer 37

**Margination** is the process whereby leucocytes assume marginal positions in the vessels

Question 38

Outline rolling and adhesion

Answer 38

- Leucocytes stick to the walls of venules as they heed the chemotactic ‘call’ - They **roll** along the wall but then become ‘trapped’ (**adhesion**), stop and crawl out of the vessel

Question 39

Distinguish between rolling and adhesion

Answer 39

The number of selectins and the activation of integrins are increased by **inflammatory mediators** and **chemotaxins:** - When the leucocytes roll along the endothelium, their receptors are binding to **selectins (rolling)** - When they adhere and stick firmly, their receptors are binding to **integrins** such as ICAM-1 **(adhesion)**

Question 40

What is diapedesis?

Answer 40

- **Diapedesis** is when leucocytes ‘dig’ their way out of the venules as they don’t use the endothelial gaps through which the exudate escapes (takes 3-9 minutes) - They produce **collagenase** which digests the basement membrane

Question 41

What is recognition-attachment?

Answer 41

**Recognition attachment** is when the phagocyte (leucocyte – neutrophil) recognises a pathogen and attaches to it through means of opsonisation/ PAMPs & PRRs

Question 42

What is phagocytosis?

Answer 42

**Phagocytosis** is when a phagocyte engulfs a pathogen/ necrotic tissue by extending its membrane around the particle and engulfing it

Question 43

Explain the 2 pathways in which phagocytosed organisms can be killed

Answer 43

- **Oxygen-dependent:** respiratory burst using oxygen derived free radicals *e.g. hydrogen peroxide (H₂O₂), superoxide anion (O₂^-) and hydroxyl (OH^-)* - **Oxygen-independent:** using enzymes *e.g. proteases, phospholipases, nucleases and lysozyme*

Question 44

What is a mediator?

Answer 44

A **mediator** is any molecule that is produced in a focus of inflammation and modulates the inflammatory response in some way chemical messengers

Question 45

What are the common responses to mediators in acute inflammation?

Answer 45

- **Motion**: I. Contraction/relaxation of vascular smooth muscle cells II. Contraction of venular endothelial cells III. Movement along a chemotactic gradient IV. Phagocytosis by neutrophils - **Secretion**

Question 46

Inflammation needs to be controlled otherwise it would be on-going and spread around the body. Describe its control

Answer 46

- Inhibition of mediators - Mediators have short lives (seconds to minutes) - Effects of mediators last minutes to hours

Question 47

Endogenous mediators are supplied by the plasma, leucocytes and local tissues How can mediators be grouped?

Answer 47

**- Vasoactive amines** *e.g. histamine and serotonin* **- Vasoactive peptides** *e.g. bradykinin* **- Complement components** e.g. C3a, C5a **- Mediators derived from phospholipids** *e.g. prostaglandins, leukotrienes* **- Cytokines and chemokines** *e.g. interleukins and tumour necrosis factor (TNF)* **- Exogenous mediators of inflammation** *e.g. endotoxin*

Question 48

Identify the main roles of inflammatory mediators

Answer 48

**- Vasodilatation** (histamine and serotonin) **- Increased vascular permeability** (histamine, serotonin and bradykinin) **- Chemotaxis** (leukotriene B4, C5a, C3a, chemokines and endotoxins) **- Phagocytosis** (C3b) **- Pain** (bradykinin and prostaglandins)

Question 49

Acute inflammation can result in problems locally within the tissues. Identify 5 local complications involved

Answer 49

- Damage to normal tissue ​ - Obstruction of tubes & compression of vital structures - Loss of fluid - Pain - Loss of function

Question 50

Explain how acute inflammation can lead to fluid loss

Answer 50

- Fluid accumulates in tissue spaces as the tissue pressure increases until it reaches a level that prevents further exudation - However, fluid can continuously leak from a surface wound, resulting in large amounts of fluid loss

Question 51

Explain how acute inflammation can lead to damage of normal tissue

Answer 51

Secondary to substances produced by neutrophils are released to the surroundings during the process of phagocytosis, resulting in damage

Question 52

Explain how acute inflammation leads to the obstruction and compression of structures

Answer 52

Vital structures, intestinal/fallopian tubes can be obstructed or compressed secondary to the swelling produced by the inflammatory exudate

Question 53

Although produced locally, inflammatory mediators can enter the blood stream in significant amounts and have systemic effects. What are the four main systemic effects of acute inflammation?

Answer 53

- Fever - Leucocytosis - The Acute Phase Response - Shock

Question 54

Describe how fever occurs as a systemic effect of acute inflammation

Answer 54

- **Fever** occurs when the thermostat of the body (situated in the anterior hypothalamus) is switched to a higher setting - **Macrophages** produce pyrogenic **cytokines** (TNF, interleukin-1) when stimulated by exogenous **pyrogens** - These cytokines cause an increase in synthesis of **prostaglandin E2** within the anterior hypothalamus, resulting in fever

Question 55

What is leucocytosis?

Answer 55

- In leucocytosis, the number of circulating leucocytes increases - Neutrophilia is seen during bacterial infection

Question 56

Describe how the acute phase response occurs as a systemic effect of acute infammation

Answer 56

- The **acute phase response** is a change in the levels of some plasma proteins, triggered by cytokines, seen because the liver changes its pattern of protein synthesis - Some proteins are produced in smaller amounts *e.g. albumin* and others are produced in larger amounts *e.g. fibrinogen, C3, alpha-1 antitrypsin, C-reactive protein*

Question 57

What is shock?

Answer 57

**Shock** is a dramatic drop in BP due to widespread vasodilatation and increased vascular permeability with resultant fluid exudation, hypotension

Question 58

Describe how shock occurs as a systematic effect of acute inflammation

Answer 58

**Shock** occurs when bacterial products or inflammatory mediators spread around the body in the blood stream inducing inflammation throughout the body

Question 59

In 5 steps, outline the resolution of acute inflammation

Answer 59

- Inflammation **mediators** degrade - Normal **vascular structure** returns - **Exudate** is reabsorbed into the venules / lymphatics - **Fibrin** is degraded - **Neutrophils** undergo apoptosis and are phagocytosed

Question 60

Outline the sequelae of acute inflammation

Answer 60

- Pus/abscess (purelent exudate) - Haemorrhagic exudate - Serous exudate - Fibrinous exudate

Question 61

What is purelent exudate?

Answer 61

**- Pus** is the cream/white exudate found in an abscess thatis rich in neutrophils - It is typical of infections by chemotactic bacteria

Question 62

What is haemorrhagic exudate?

Answer 62

**- Haemorrhagic exudate** is a type of exudate that is bloody because of the large component of red blood cells released from ruptured blood vessels - It indicates that inflammation and significant vascular damage have occurred and is seen in destructive infections/malignant tumours

Question 63

What is serous exudate?

Answer 63

**- Serous exudate** is a clear exudate which contains plasma proteins but few leucocytes suggesting that there is no infection by micro-organisms - They are seen typically in blisters *e.g. after a mild burn*

Question 64

How do serous exudates differ from transudates and plasma?

Answer 64

- Serous exudates differ from transudates because they **contain plasma proteins** - Serous exudates differ from plasma because they **don’t contain fibrinogen**

Question 65

What is a seroma?

Answer 65

A **seroma** is a tissue space filled with clear, sterile fluid that occurs as a post-operative complication

Question 66

What is fibrinous exudate?

Answer 66

- **Fibrinous exudate** is a type of exudate where there is significant deposition of fibrin i.e. a blood clot without the RBCs - Can occur in the pericardial/pleural spaces preventing the serosal surfaces from sliding smoothly over each other creating a rubbing sound

Question 67

Identify 4 clinical examples of acute inflammation

Answer 67

- Bacterial meningitis - Lobar pneumonia - Liver abscess - Acute apendicitis

Question 68

What is hereditary angio-oedema?

Answer 68

**- Hereditary angio-oedema** is an extremely rare autosomal dominant condition in which sufferers have an inherited deficiency of C1-esterase inhibitor - Patients have attacks of non-itchy cutaneous angio-oedema and experience recurrent abdominal pain due to intestinal oedema

Question 69

cvfcWhat is α1-antitrypsin deficiency?

Answer 69

**- α1-antitrypsin deficiency** is an autosomal recessive disorder resulting in low levels of alpha-1 antitrypsin, a protease inhibitor which deactivates enzymes released from neutrophils at the site of inflammation - Patients develop emphysema as proteases released by neutrophils within the lung destroy normal parenchymal tissue

Question 70

Explain how α1-antitrypsin deficiency can also present with liver disease?

Answer 70

- **Hepatocytes** produce an abnormal version of the protein which is incorrectly folded - It polymerises and cannot be exported from the ER causing hepatocyte damage and eventually **cirrhosis**

Question 71

What is chronic granulomatous disease?

Answer 71

- **Chronic granulomatous disease** is a genetic condition wherein phagocytes cannot form superoxide and initiate a respiratory burst - This results in many chronic infections in the first year of life as well as the formation of numerous granulomas and abscesses affecting the skin, lymph nodes, lung, liver and bones

Question 72

What is the difference between lobar and bronchopneumonia?

Answer 72

- **Lobar pneumonia** affects all or part of a lobe with other areas generally normal - **Bronchopneumonia** has a patchy distribution and generally involves more than one lobe and often both lungs (seen in young & old patients)

Question 73

Identify the four pathological stages of lobar pneumonia

Answer 73

- Congestion - Red hepatisation - Grey hepatisation - Resolution

Question 74

Identify 5 complications which can arise following lobar pneumonia

Answer 74

- Bacteraemia (resulting in meningitis, arthritis or endocarditis) - Lung abscesses - Empyema - Pleural effusion - Lung fibrosis

Question 75

Outline congestion in lobar pneumonia

Answer 75

- Vascular congestion - Lobe is heavy, red and boggy - Alveoli contains fluid, scattered neutrophils and many bacteria - cough out lots of mucous

Question 76

Outline red hepatisation in lobar pneumonia

Answer 76

- Occurs after a few days - Affected lung has a liver-like consistency - Alveolar spaces are packed with neutrophils, red cells and fibrin - Fibrinous/fibropurulent exudate on the adjacent pleura

Question 77

Outline grey hepatisation in lobar pneumonia

Answer 77

- Lung tissue is dry, grey and firm - Red cells get lysed - Fibrous exudate persists within alveoli

Question 78

Outline resolution in lobar pneumonia

Answer 78

- Exudate is enzymatically digested and resorbed or expectorated - Basic architecture of the lung is left intact

Question 79

definition of acute inflammation

Answer 79

- immediate response - short duration - innatr - same response for all acute injury

Question 80

name 2 types of pressure

Answer 80

- **hydrostatic pressure** (pressure exterted on a vessel wall by fluid) pushes fluid out of vessel this is balanced out with - **oncotic pressure** (pressure exerted by proteins) fluid moves towards proteins in vessel both exist in blood vessels and interstitual space

Question 81

name 2 types of interstitual fluid

Answer 81

- exudate - transudate

Question 82

describe exudate interstitual fluid

Answer 82

- incrases vascular permeability - protein ruich fluid - occurs in inflammation - vasodialation

Question 83

describe transudate fluid

Answer 83

- permeability unchanged - fluid moves out hydrostatic pressure\>oncotic (odema) occurs during heart failure - low protein content and few cells

Question 84

3 reasons for vascular leakage

Answer 84

- neutrophils - chemical species - toxins that damage the cell

Question 85

role of proteins in the vascular phase

Answer 85

creates a mesh around injured area preventing spread

Question 86

where does the interstitual fluid drain into

Answer 86

lymph nodes

Question 87

summarise the vascular phase (as soon as there has been an injury)

Answer 87

- vascoconstriction - prolonged vasodialation - increased vascular permeability - fluid moves into interstitusl space - fluid is an exudate - at the fluid inside the vessel is stasis - proteins (antibodies, fibrin)

Question 88

The cellular stage

Answer 88

2nd stage involves releasing neutrophils from blood vessels helps remove pathogens and necrotic tissue release inflammatory mediators

Question 89

2 mechanisms that neutrophils use to kill

Answer 89

1. oxygen dependent (ROS RNS) 2. oxygen independent (lysozyme, hydrolytic enzymes)

Question 90

complications of acute inflammation

Answer 90

- exudate build up so compresses organs - loss of fluid so dehydration - pain - induces rest via acute phase proteins

Question 91

bacterial meningitis

Answer 91

- brain expands but the skull cannot expand so gets compressed and this is fatal - see fibrin building up on the side of the brain (yellow, orange liquid)

Question 92

vasoactive amines

Answer 92

eg histamine, seratonin key player in early parts of inflammation they are available immediately as they are already present within cells

Question 93

role of histamine

Answer 93

pain, vasodialation, venule leakage

Question 94

seratonin role

Answer 94

similar vascualr effects to histamine

Question 95

starlings law

Answer 95

forces that equate to the equilibrium of fluid exchange: capillary pressure interstitiual free pressure plasma colloid osmotic pressure (main force driving fluid back into blood) interstitual fluid colloid osmotic pressure

Question 96

phagocytosis ( inflammatory mediator)

Answer 96

C3b