Session 3

Question 0

What are the characteristics of acute inflammation?

Answer 0

• Innate
• Immediate and early
• Stereotyped (same response every time)
• Short duration - minutes/hours/few days
• Protective response but can lead to local complications and systemic effects.

Question 1

What is Acute Inflammation?

Answer 1

Response of living tissue to injury, initiated to limit the tissue damage

Question 2

What are the causes of Acute Inflammation?

Answer 2

• Microbial infections e.g. Pyogenic (Pus-inducing) organisms, particularly bacteria
• Hypersensitivity reactions (acute phase)
• Physical agents that damage tissues
• Chemicals Tissue necrosis of any cause

Question 3

What are the main Clinical Signs of Acute Inflammation?

Answer 3

• Rubor (redness)
• Tumor (swelling)
• Calor (heat)
• Dolor (pain)
• • loss of function

Question 4

What are the changes in tissues?

Answer 4

1. Changes in blood flow (vascular phase)
2. Exudation of fluid into tissues (vascular phase)
3. Infiltration of inflammatory cells (cellular phase)

Each step is tightly controlled by a variety of chemical inflammatory mediators derived from plasma or cells.

Question 5

Describe changes in blood flow (vascular phase of acute inflammation)

Answer 5

1. Transient vasoconstriction of arterioles (few seconds)
2. Vasodilation of arterioles and then capillaries –> increase in blood flow (heat and redness)
3. Increased permeability of blood vessels –> Exudation of protein rich fluid into tissues and slowing of circulation (swelling)
4. Concentration of RBCs in small vessels and increased viscosity of blood - STASIS. Circulation slows - [RBC] increases. This leads to swelling

Question 6

What is the immediate early response (1/2 hour)?

Answer 6

Histamine: released from mast cells, basophils and platelets in response to many stimuli including physical damage, immunological reactions, C3a, C5a, IL-1, factors from neutrophils and platelets

It causes vascular dilation, transient increase in vascular permeability and pain.

Question 7

What is the persistent response?

Answer 7

Cause can be varied

Many and varied chemical mediators, interlinked and of varying importance.

Incompletely understood e.g. Leukotrienes (derived from arachidonic acid) and bradykinin (take over from histamine to support a sustained response)

Question 8

What is fluid flow across vessel walls determined by?

Answer 8

Fluid flow across vessel walls is determined by the balance of hydrostatic and colloid osmotic pressure comparing plasma and interstitial fluid.

Question 9

Explain about Exudation of fluid into tissues

Answer 9

Increased hydrostatic pressure –> increased fluid flow out of vessel

Increased colloid osmotic pressure of interstitium (amount of protein in the tissue fluid increases) –> increased fluid flow out of vessel

Arteriolar dilation leads to increase in hydrostatic pressure

Increased permeability of vessel walls leads to loss of protein into the interstitium (tissue space). Therefore net flow of fluid out of vessel –> oedema (increased fluid in tissue spaces).

Question 10

What are the consequences of oedema (excess fluid in interstitium)?

Answer 10

Can be transudate (specific to inflammation) or exudate

Oedema leads to increased lymphatic drainage (from these tissue spaces)

Question 11

Explain exudate and transudate

Answer 11

Exudate: fluid loss in inflammation (high protein content)

Transudate: fluid loss due to hydrostatic pressure imbalance only (low protein content) e.g. Cardiac failure or venous outflow obstruction

Question 12

What are the Mechanisms of Vascular leakage?

Answer 12

• Endothelial contraction –> gaps (histamine and leukotrienes)
• Cytoskeleton reorganisation –> gaps (cytokines IL-1 and TNF)
• Direct injury - toxic burns (e.g. Severe sun burns), chemicals
• Leukocyte dependent injury - toxic oxygen species and enzymes from leucocytes.
• Increased transcytosis - channels across endothelial cytoplasm (VEGF - Vascular Endothelial Growth Factor)

Question 13

What does an exudate result in?

Answer 13

Delivery of plasma proteins to site of injury.

Fibrin becomes activated during inflammation. I

t localises inflammatory response - prevents it spreading out.

Question 14

What is a neutrophil?

Answer 14

Primary type of WBC involved in inflammation.

Neutrophils are a type of granulocytes also known as polymorphonuclear leukocyte.

Neutrophil = Polymorph

Question 15

Describe the Infiltration of Neutrophils

Answer 15

Vascular stasis causes neutrophils to line up at the edge (normally they are at the centre of the blood vessel) of blood vessels along the endothelium - MARGINATION

Neutrophils then roll along the surface of the endothelium, sticking to it intermittently - ROLLING

Then stick more avidly to the surface and to each other - ADHESION and AGGREGATION

Followed by EMIGRATION of neutrophils through blood vessel wall.

Question 16

How is the movement of neutrophils controlled?

Answer 16

Receptors exposed on the surface of the endothelium bind with ligand in the neutrophils during inflammation

Each step is controlled by a mediator:

• Rolling - by selectins
• Primary adhesion: Integrins
• Stable adhesion and aggregation: Integrins

Question 17

How do neutrophils escape from vessels?

Answer 17

Relaxation of inter-endothelial cell junctions.

Digestion of vascular basement membrane

Movement from inside to outside (Transendothelial migration)

Question 18

How do neutrophils move?

Answer 18

Diapedesis (emigration) and chemotaxis.

Chemotaxis = movement along concentration gradients of chemoattractants

Chemotaxins: C5a (activated component of complement cascade), LTB4, bacterial peptides

Receptor-ligand binding leads to rearrangement of cytoskeleton leads to production of pseudopod

Question 19

What do neutrophils do?

Answer 19

Phagocytosis which involves:

• Contact
• Recognition (of something that needs to be removed)
• Internalisation Recognition is facilitated by opsonins (Fc- fixed component of immunoglobulin, and C3b, an activated component of complement cascade)
• Cytoskeletal changes
• Phagosomes fuse with Lysosomes to produce secondary lysosomes

Question 20

Describe the steps of neutrophil chemotaxis and phagocytosis

Answer 20

1. Neutrophils migrate to site of injury by chemotaxis
2. Neutrophils phagocytose microorganisms
3. Activated neutrophils may release toxic metabolites and enzymes causing damage to the host tissue

Question 21

Describe the O2 dependent killing mechanisms

Answer 21

Produces superoxide and hydrogen peroxide

Or

H2O2-Myeloperoxidase-Halide System: Produces HOCl- (very potent)

Question 22

Describe the O2 independent killing mechanisms

Answer 22

Lysozyme and hydrolases

or

Bactericidal Permeability Increasing Protein (BPI) Or Cationic proteins (‘defensins’)

Question 23

What are proteases?

Answer 23

Chemical mediators; plasma proteins produced in liver

Circulate in blood but become activated during inflammation

• Kinins cause vasodilation and smooth muscle contraction
• Complement system C3a, C5a
• Coagulation/fibrinolytic system

Question 24

What are Prostaglandins and Leukotrienes?

Answer 24

Chemical mediators; Metabolites of arachidonic acid Prostaglandins increase blood flow Leukotrienes increase vascular permeability

Question 25

What are cytokines and chemokines?

Answer 25

Chemical mediators; produced by WBCs Many and varied types such as Interleukins (especially IL-1), TNF alpha

Question 26

Which Chemical Mediators result in Increased Blood flow?

Answer 26

Histamine Prostaglandins

Question 27

Which Chemical Mediators result in Vascular Permeability?

Answer 27

Histamine Leukotrienes

Question 28

Which Chemical Mediators result in Neutrophil Chemotaxis?

Answer 28

C5a LTB4 Bacterial peptides

Question 29

Which Chemical Mediators result in Phagocytosis?

Answer 29

C3b

Question 30

What is the hallmark of acute inflammation?

Answer 30

EXUDATE of [oedema] FLUID INFILTRATE of [inflammatory] CELLS

Question 31

How does Exudation of fluid combat Injury?

Answer 31

Delivers plasma proteins (immunoglobulins - although not necessarily needed, inflammatory mediators, fibrinogen) to area of injury Dilutes toxins (potentially limits extent of tissue damage) Increases lymphatic drainage Delivers microorganisms to phagocytes and antigens to immune system (immune system and inflammation overlap and work in parallel)

Question 32

How does infiltration of cells, vasodilation, pain and loss of function combat injury?

Answer 32

Infiltration of cells removes pathogenic organisms, necrotic debris Vasodilation increases delivery, increases temperature Pain and loss of function enforces rest (limits tissue use), reduces chance of further traumatic damage

Question 33

What are the local complications of acute inflammation?

Answer 33

Varies depending on site Swelling leads to blockage of tubes e.g. Bile duct, intestine Exudate could cause compression e.g. Cardiac tamponade - pericarditis; Serositis (inflammation of the serous tissues e.g. Tissues lining the heart, lungs and inner linking of the abdomen and organs within) Loss of fluid e.g. Burns Pain and loss of function especially if prolonged.

Question 34

What are the systemic effects of acute inflammation?

Answer 34

Fever (endogenous pyrogens produced: IL-1 and TNF-alpha, prostaglandins). Aspirin (antipyretic reduces fever by causing the hypothalamus to override the interleukin-induced increase in temperature) Leukocytosis

Question 35

Explain about Leukocytosis

Answer 35

IL-1 and TNF-alpha produce an accelerated release of leukocytes from marrow. Macrophages and T-lymphocytes produce colony-stimulating factors Bacterial infections - neutrophils Viral- lymphocytes

Question 36

Describe the Acute Phase Response as part of the systemic effects of acute inflammation

Answer 36

Decreased appetite Raised pulse rate Altered sleep patterns Changes in plasma concentrations of Acute Phase Proteins: C-reactive protein (CRP- clinically useful), alpha-1 antitrypsin, Haptoglobin, Fibrinogen, Serum amyloid A Protein (These molecules are clinically useful - parameters can be measured)

Question 37

What if the Local Response isn't enough?

Answer 37

Acute Phase response follows but if that isn't enough... Spread of microorganisms and toxins..... SHOCK (a clinical syndrome of circulatory failure)

Question 38

What may happen after the development of acute inflammation?

Answer 38

1) Complete Resolution 2) Continued acute inflammation with chronic inflammation = abscess 3) Chronic inflammation and fibrous repair, probably with tissue regeneration 4) Death

Question 39

Describe the morphology of Resolution

Answer 39

Changes gradually reverse and vascular changes stop. Neutrophils no longer marginate and emigrate Vessel permeability returns to normal Vessel calibre returns to normal Therefore exudate drains to lymphatics, fibrin is degraded by plasmin and other proteases, neutrophils die, break up and are carried away or phagocytosed, damaged tissue might be able to regenerate.

Question 40

But what if tissue architecture is destroyed?

Answer 40

Complete resolution is not possible. Fibrous repair could result in scarring

Question 41

What are the mechanisms of Resolution?

Answer 41

Complicated, lots of things happening at the same time All mediators of acute inflammation have short half-lives (no long term consequences) May be inactivated by degradation e.g. Heparinase Inhibitors may bind e,g, various anti-proteases May be unstable e.g. Some arachidonic acid derivatives May be diluted in the exudates e.g. Fibrin degradation products Specific inhibitors of acute inflammatory changes e.g. Lipoxins and endothelin can specifically inhibit components of immune response

Question 42

Explain about Bacterial Meningitis

Answer 42

Acute inflammation in meninges (between arachnoid and Pia mater) can cause vascular thrombosis and reduce cerebral perfusion Increased fluid can cause compression in the brain and lead to death Very important to recognise and determine the right antibiotics quickly

Question 43

Explain about Lobar Pneumonia

Answer 43

Streptococcus pneumoniae causes Lobar Pneumonia (bacterial infection) Clinical cause: worsening fever, prostration (physical exhaustion/weakness), hypoxaemia over a few days. Dry cough and breathlessness. High WBC count. If treated, can be resolved completely.

Question 44

Explain about a skin blister

Answer 44

Causes: heat, sunlight, chemical Predominant features: profuse exudate and pain Collection of fluid strips off overlying epithelium Inflammatory cells relatively few - therefore exudate clear UNLESS bacterial infection develops Resolution or scarring Now there is no barrier as the epidermis has been damaged. Risk of secondary infection

Question 45

Explain about an Abscess

Answer 45

Occurs in solid tissues Inflammatory exudate forces tissues apart Liquefactive necrosis in centre May cause high pressure therefore PAIN May cause tissue damage and squash/extend adjacent structures Can lead to scarring Surgical treatment releases pressure

Question 46

Explain about Acute Inflammation in Serous Cavities

Answer 46

Exudate pours into cavity Ascites (Ascites= accumulation of fluid in the peritoneal cavity, causing abdominal swelling), pleural or pericardial effusion Respiratory or Cardiac impairment/failure Localised fibrin deposition 'bread and butter pericarditis'

Question 47

List some disorders of Acute inflammation

Answer 47

Rare (due to natural selection) * Hereditary Angio-oedema (angio neurotic oedema) Alpha-1 anti trypsin deficiency * Inherited complement deficiencies * Defects in neutrophil function * Defects in neutrophil numbers

Question 48

Explain about Streptococcus pneumonia

Answer 48

* attaches to narsopharyngeal cells through interaction of bacterial surface adhesions. * once inhaled, the organism's polysaccharide capsule makes it resistant to phagocytosis - macrophages cannot adequately kill the pneumococci * the orgnism spreads to the blood stream and is carried to joint spaces, bone and perionteal cavity and may result in menignitis, brain abscess, septic arthritis or osteomyelitis. * Neutrophils release cytokines causing a general activation of the immune system. * This leads to the fever, chills and fatigue symptoms. * The neutrophils, bacteria and exudate fluid from surrounding vessels fill the alveoli with fluid, hindering oxygenation. * antibiotics are given - often takes a few weeks for most symptoms to resolve.

Question 49

90% of Lobar pneumonia is due to Streptococcus Pneumoniae. What are the pathological stages?

Answer 49

1. Congestion: lasts for about 24 hours and represents the outpouring of protein-rich exudate into alveolar spaces with venous congestion. The lung is heavy, oedematous and red. 2. Red Hepatisation: lasts for a few days, there is massive accumulation in the alveolar spaces of polymorphs together with some lymphocytes and macrophages. Many red cells are also extravasated from the distended capillaries. The overlying pleura bears a fibrinous exudate. The lung is red, solid and airless. 3. Gey Hepatisation: lasts for a few days, there is further accumulation of fibrin with destruction of white cells and red cells. The lung is now grey-brown and solid. 4. Resolution: occurs at abou 8-10 days in untreated cases and represents the resorption of exudate and enzymatic digestion of inflammatory debris, with preservation of the underlying alveolar wall architecture. Most cases of acute lobar pneumonia resolve this way.

Question 50

What is Inherited Angio-Oedema?

Answer 50

* Disease that causes repeated episodes of swelling beneath the surface of the skin. The swelling and associated inflammation can be confined to the face, hands, feet, arms and legs however dangerous swelling of the airways or intestinal tract can also occur. * Mild HAE may require no treatment. * Others may need to be hospitalised for life-saving treatment e.g. intubation or tracheotomy.

Question 51

What are the different types of HAE?

Answer 51

* Type I: mutation resulting in insuficient C1 inhibitor production so inflammation cannot be controlled - C1 inhibitor is part of the complement system. * Type II: mutation results in defective C1 production * Type III: too much Factor XII is produced which stimulates inflammation * Symptoms of Intestinal swelling: severe abdominal pain, ccramping, dehydration, diarrhoa and shock (in severe cases). * Symptoms of Throat inflammation: hoarse voice, difficulty swallowing and difficulty breathing

Question 52

What is Chronic Granulomatous Disease?

Answer 52

* inherited Immunodeficiency disorder resulting from an inability of phagocytes to kill bacteria and fungi that they have ingested. * This leads to ongoing and severe infection. * Caused by any of several possible defects of NADPH OXidase enzyme complex which normally generates oxidative burst essential for the clearance of phagocytosed microorganisms. * Suffers are suceptible to both bacterial and fungal infections. Vascular damage to the liver, joint infections, bone infections, skin infectons and swollen nodes are very common. * Only cure is bone marrow or stem cell transplant, can be treated with antibiotics.