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Personal ESA 2 Mechanisms of Disease > Session 3 > Flashcards

Session 3 Flashcards

0
Q

What are the characteristics of acute inflammation?

A
  • 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.
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1
Q

What is Acute Inflammation?

A

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

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2
Q

What are the causes of Acute Inflammation?

A
  • 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
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3
Q

What are the main Clinical Signs of Acute Inflammation?

A
  • Rubor (redness)
  • Tumor (swelling)
  • Calor (heat)
  • Dolor (pain)
    • loss of function
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4
Q

What are the changes in tissues?

A
  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.

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5
Q

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

A
  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
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6
Q

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

A

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.

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7
Q

What is the persistent response?

A

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)

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8
Q

What is fluid flow across vessel walls determined by?

A

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

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9
Q

Explain about Exudation of fluid into tissues

A

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).

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10
Q

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

A

Can be transudate (specific to inflammation) or exudate

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

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11
Q

Explain exudate and transudate

A

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

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12
Q

What are the Mechanisms of Vascular leakage?

A
  • 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)
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13
Q

What does an exudate result in?

A

Delivery of plasma proteins to site of injury.

Fibrin becomes activated during inflammation. I

t localises inflammatory response - prevents it spreading out.

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14
Q

What is a neutrophil?

A

Primary type of WBC involved in inflammation.

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

Neutrophil = Polymorph

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15
Q

Describe the Infiltration of Neutrophils

A

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.

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16
Q

How is the movement of neutrophils controlled?

A

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
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17
Q

How do neutrophils escape from vessels?

A

Relaxation of inter-endothelial cell junctions.

Digestion of vascular basement membrane

Movement from inside to outside (Transendothelial migration)

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18
Q

How do neutrophils move?

A

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

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19
Q

What do neutrophils do?

A

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
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20
Q

Describe the steps of neutrophil chemotaxis and phagocytosis

A
  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
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21
Q

Describe the O2 dependent killing mechanisms

A

Produces superoxide and hydrogen peroxide

Or

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

22
Q

Describe the O2 independent killing mechanisms

A

Lysozyme and hydrolases

or

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

23
Q

What are proteases?

A

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
24
Q

What are Prostaglandins and Leukotrienes?

A

Chemical mediators; Metabolites of arachidonic acid

Prostaglandins increase blood flow

Leukotrienes increase vascular permeability

25
Q

What are cytokines and chemokines?

A

Chemical mediators; produced by WBCs

Many and varied types such as Interleukins (especially IL-1), TNF alpha

26
Q

Which Chemical Mediators result in Increased Blood flow?

A

Histamine

Prostaglandins

27
Q

Which Chemical Mediators result in Vascular Permeability?

A

Histamine

Leukotrienes

28
Q

Which Chemical Mediators result in Neutrophil Chemotaxis?

A

C5a

LTB4

Bacterial peptides

29
Q

Which Chemical Mediators result in Phagocytosis?

A

C3b

30
Q

What is the hallmark of acute inflammation?

A

EXUDATE of [oedema] FLUID

INFILTRATE of [inflammatory] CELLS

31
Q

How does Exudation of fluid combat Injury?

A

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)

32
Q

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

A

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

33
Q

What are the local complications of acute inflammation?

A

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.

34
Q

What are the systemic effects of acute inflammation?

A

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

35
Q

Explain about Leukocytosis

A

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

36
Q

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

A

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)

37
Q

What if the Local Response isn’t enough?

A

Acute Phase response follows but if that isn’t enough…

Spread of microorganisms and toxins….. SHOCK (a clinical syndrome of circulatory failure)

38
Q

What may happen after the development of acute inflammation?

A

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

39
Q

Describe the morphology of Resolution

A

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.

40
Q

But what if tissue architecture is destroyed?

A

Complete resolution is not possible.

Fibrous repair could result in scarring

41
Q

What are the mechanisms of Resolution?

A

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

42
Q

Explain about Bacterial Meningitis

A

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

43
Q

Explain about Lobar Pneumonia

A

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.

44
Q

Explain about a skin blister

A

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

45
Q

Explain about an Abscess

A

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

46
Q

Explain about Acute Inflammation in Serous Cavities

A

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’

47
Q

List some disorders of Acute inflammation

A

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
48
Q

Explain about Streptococcus pneumonia

A
  • 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.
49
Q

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

A
  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.

50
Q

What is Inherited Angio-Oedema?

A
  • 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.
51
Q

What are the different types of HAE?

A
  • 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
52
Q

What is Chronic Granulomatous Disease?

A
  • 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.

Personal ESA 2 Mechanisms of Disease (11 decks)

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