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Cardio & Thoracic Biology > CTB9: Respiratory and cardiovascular disease > Flashcards

CTB9: Respiratory and cardiovascular disease Flashcards

1
Q

What are the symptoms of asthma?

A
  • Shortness of breath
  • nasty cough / coughing fits
  • associated with being allergic to things
  • wheezing (especially from cold air and dampness)
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2
Q

Why does the epithelium around the airways crumple in bronchoconstriction?

A

The surrounding smooth muscle has contracted, and the epithelium needs to crumple to accommodate that constriction

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3
Q

What does it mean if an airway is occluded?

A

Blocked

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4
Q

In asthma patients what contributes to their shortness of breath?

A
  • mucus hypersecretion (goblet cell hyperplasia)
  • bronchoconstriction
  • infiltration of inflammatory cells (predominantly eosinophils)
  • epithelium exhibits fragility (some areas missing)
  • basement (reticular) membrane becomes thicker
    Airway smooth muscle mass increases (smooth muscle hypertrophy)
  • mucus-producing submucosal glands increase in size (hypertrophy)
    -Blood vessels become more prominent (‘congested’ with blood)
    -Blood vessels increase in number (angiogenesis)
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5
Q

What is a central inflammatory cell in asthma?

A

eosinophils

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6
Q

What are the initiating cells in asthma?

A

Mast cells and T-helper-type 2 lymphocytes

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7
Q

What do mast cells and T-helper-type 2 lymphocytes do in asthma?

A

release cytokines that will ‘recruit’ other cells, for example eosinophils, a ‘central’ cell in asthma

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8
Q

What do the cytokines released by mast cells and T-helper cells do?

A

They will release chemokines that recruit more cells and inflammatory mediators that can initiate airway smooth muscle cell contraction (bronchoconstriction), mucus secretion, plasma exudation (leading to airway narrowing) and vasodilation

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9
Q

At some stage in asthma there will be epithelial damage, what does this lead to?

A

This can expose sensory nerve endings

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10
Q

What may nerve endings be activated by?

A

Inflammatory mediators (e.g. bradykinin), thereby setting up a cholinergic reflex to airway constriction and mucus secretion

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11
Q

What does release of growth factors lead to?

A

Activation of fibroblasts, they initiate laying down of connective tissue and basement membrane thickening, and enlargement of airway smooth muscle and submucosal glands, and increased numbers of goblet cells

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12
Q

What does epithelium damage also lead to?

A

Oedema (plasma leak)

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13
Q

What is the current treatment for asthmatics?

How do they work (brief)

A
  • use of bronchodilators (to prevent/reverse bronchoconstriction)
  • anti-inflammatory glucocorticosteroids (to inhibit inflammatory cell gene transcription of inflammatory mediators)
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14
Q

What are asthmatics called if they do not respond to treatment?

A

severe asmatics

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15
Q

What is the effectiveness of the treatment dependent on?

A

patients taking their medications, and taking them correctly (termed ‘treatment compliance’)

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16
Q

What does COPD stand for?

What are they?

A

Chronic Obstructive Pulmonary Disease

a group of lung conditions that cause breathing difficulties

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17
Q

What is COPD caused by?

A

Long-term inhalation of noxious gases and particles sets up an inflammatory response in the airways and lungs, so in the UK that’s usually tobacco smoke, so it’s associated with smoking very strongly. Around the world other sources of smoke, so people are breathing in smoke from cooking or heating or lighting, pollution more broadly, that can also damage the lungs.

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18
Q

What are the three main processes that make up COPD?

any individual person might have a different proportion of these

A

1) Chronic bronchitis: airways in the lung are damaged/inflamed, and this is often associated with cough and coughing up sputum.
2) Emphysema where the lung tissue itself is damaged, so the walls of alveoli are broken down, and as they break down the lung becomes baggy and full of holes and air can get trapped in there. So a person can’t exhale down to a normal comfortable lung volume and they’re always breathing up here in an uncomfortable way.
3) Damage to the blood vessels in the lung. Lungs are inefficient at taking up oxygen. Also in some people it puts a strain on the heart, so the heart has to work harder to pump blood through the lungs because the blood vessels are so damaged.

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19
Q

What is the most effective way to reduce your symptoms and prevent COPD from getting worse?

A
  • Stop smoking if you currently smoke
  • Have the flu jab every year
  • Pulmonary rehabilitation (keeping active)
  • use your inhaler properly
  • be able to bring up sputum from your chest
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20
Q

Explain the pathology of COPD

A

This smoke activates macrophages to recruit more macrophages and induce neutrophil influx. Cytotoxic T-cells are also activated. Proteases (from macrophages and neutrophils) and oxidants (predominantly from smoke and neutrophils) damage lung tissue and induce increased mucus-production – e.g. via goblet cell hyperplasia (via induction of epidermal growth factor, EGF). Under normal circumstances the body’s own antiproteases and antioxidants nullify the effects of proteases and oxidants. However, the vast increase in COPD overwhelms these defences. Growth factors from epithelia cells (e.g. transforming growth factor-β) activate fibroblasts, which in turn lay down extracellular matrix, leading to fibrosis.

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21
Q

Where do most cardiovascular diseases originate from?

A

Endothelial injury

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22
Q

What causes cardiovascular diseases?

A
  • Inflammation: infectious (bacteria, viruses) and/or non-infectious (immune-mediated)
  • Apoptosis and necrosis (toxins)
  • Oxidative stress (hypoxia/reoxygenation)
  • Mechanical injury (shear stress, stretch)
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23
Q

Define atherosclerosis?

A

a disease of the arterial wall in which the layer thickens, causing narrowing of the channel and thus impairing blood flow.

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24
Q

When is atherosclerosis most serious?

A

when it happens in the heart, or blood vessels leading to the brain. It is caused by excessive inflammatory-fibroproliferative response to numerous different forms of vascular insult.

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25
Q

What is atherosclerosis the principal cause of?

A
  • Myocardial infarction (heart attack), stroke and gangrene of the extremities
  • Ischaemic heart disease and stroke are the world’s biggest killers (exceeding by far deaths caused by cancer)
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26
Q

List the 4 stages of the development of an atherosclerosis plaque

A

1) Initial lesion
2) Fatty streak
3) Atheroma
4) Advance atheroma

27
Q

Explain how an initial lesion develops

A

Endothelial damage may be caused by low or turbulent shear stress. Endothelial cells in large vessels are subjected to high laminar flow and are well aligned, but in branching points, where shear stress is low or turbulent, endothelial cells lack alignment (see image above - click to enlarge). These areas are prone to the formation of atherosclerotic plaques.

Atherosclerosis preferentially develops at arterial branches and curvatures.

Another cause of endothelial injury involves oxidised low density lipoproteins (oxLDL). Endothelial cells have an ability to capture and oxidise low density lipoproteins (oxLDL). oxLDL induce expression of adhesive glycoproteins and chemokines that attract monocytes and lymphocytes.

28
Q

Explain how fatty streaks develop

A

Monocytes adhere to the endothelium and then migrate between the endothelial cells into the medial smooth muscle cell layer. Monocytes then differentiate into macrophages. Macrophages engulf lipids to produce ‘foam cells’. The cells look as if they were filled with lipid foam, hence the name. At this stage the lesion is a fatty streak. Fatty streaks can be found in 50% of 10-14 year old children.

29
Q

Explain how an atheroma develops

A

Foam cells die and form a lipid core. Continued cell influx and proliferation leads to the production of a dense cap of connective tissue overlying a core of lipid and necrotic debris.

Activated cells release a number of growth factors and chemokines that are not expressed in normal artery and can stimulate smooth muscle and fibroblast cell proliferation and migration (such as PDGF, bFGF, HB-EGF, IGF-1, IL-1, TNFα).

In addition to growth factors, cells release substances that further enhance inflammatory response: colony stimulating factors (CSFs), MCP-1, interleukins, interferon gamma (IFNɣ), TGFβ.

Changes seen in fatty streak and early atheroma are fully reversible (for instance by changes in lifestyle, such as proper diet and exercise).

A real problem begins when the fibrous plaque ruptures and the plaque becomes unstable. Contact of platelets with lipid core and matrix proteins induces thrombosis. The newly formed thrombus may become fragmented or may be incorporated into the vessel wall. However, it often happens that the thrombus grows and occludes the vessel lumen. Occlusion of coronary vessels causes heart attack and occlusion of blood vessels supplying the brain with oxygen causes stroke.

30
Q

Explain how an advanced atheroma develops

A 
Advanced atheroma (complicated lesion)
Some plaques continue to grow and completely obliterate the vascular lumen. Thrombosis, neoangiogenesis (new channel formation within the plaque) and sometimes plaque calcification are features of these complicated lesions.
31
Q

What is pulmonary hypertension?

A

a disease characterised by high blood pressure in pulmonary arteries (blood vessels that supply the lungs)

32
Q

How is high blood pressure in the lungs form pulmonary hypertension brought about?

A

The narrowing of the arteries in the lung creates resistance and an increased work load for the right ventricle of the heart. The heart becomes enlarged from pumping blood against the resistance. If untreated, the prognosis is poor (>3 years adult, 1>child)

33
Q

Who does PH affect more?

A

Females

34
Q

What are the symptoms of PH?

A

Chest pain, weakness, shortness of breath, fatigue, swelling in the ankles, abdomen or legs, bluish lips and skin. Symptoms range in severity and a given patient may not have all of the symptoms.

35
Q

Why is PH difficult to detect?

A

It is difficult to measure blood pressure in the lung – it requires right heart catheterization (where a catheter is threaded into the right ventricle and pulmonary artery).

36
Q

What are the causes of PH?

A

It is difficult to measure blood pressure in the lung – it requires right heart catheterization (where a catheter is threaded into the right ventricle and pulmonary artery).

37
Q

Name the 5 groups of PH? (app you don’t have to remember these - just be aware they exist)

A

Group 1 PH — pulmonary arterial hypertension (PAH)
Group 2 PH — pulmonary hypertension due to left heart disease
Group 3 PH — pulmonary hypertension due to lung diseases and/or hypoxia
Group 4 PH — pulmonary hypertension caused by chronic thrombotic or embolic disease
Group 5 PH — pulmonary hypertension with unclear and/or multifactorial mechanisms (inflammation, obstruction, or compression of pulmonary vasculature)

38
Q

What is the pulmonary circuit like in healthy individuals?

A

Low pressure
Low resistance
High volume circuit

39
Q

What leads to the increased pressure in the lungs in PH?

A

Increase in the resistance of the pulmonary circulation: The increased pulmonary vascular resistance increases the afterload placed on the right ventricle and in time can lead to right heart failure.

40
Q

What is the most serious form of pulmonary hypertension? Explain it

A

When the normally thin walled peripheral pulmonary arterioles undergo a process known as remodelling. During this process the smooth muscle layer grows uncontrollably inwards thus narrowing the lumen of the vessel and increasing the tone of the vessel wall. This leads to a rare disease called Pulmonary Arterial Hypertension.

41
Q

How do you diagnose the different PH?

A

perform an echocardiogram, or ultrasound of the heart, to look at the workings of the right ventricle

42
Q

If an echocardiogram, or ultrasound of the heart show a rise in pulmonary pressure, what procedure can be carried out?

A

confirmatory test called a right heart catheterization

43
Q

What does a confirmatory test called a right heart catheterization procedure involve?

A

This involved passing a wire through a vein in the elbow pit and threading the wire into the right heart and round into the lungs. A pressure transducer on the end of the wire then enables us to measure the pressure in the pulmonary circulation.

44
Q

What is the prognosis of pulmonary arterial hypertension (PAH) if left untreated?

A

3 years

45
Q

With modern therapy what is the prognosis of PAH?

A

7-10 years

46
Q

Give examples of the most commonly used animal models of PH

A 
Hypoxia-induced pulmonary hypertension (rodents, pigs, cattle) 
Genetic models (knockout and transgenic mice)
47
Q

List the four main mechanisms contributing to PH

A

1) Vasoconstriction
2) Arterial remodelling and inflammation
3) Plexiform lesion
4) Thrombotic lesion

48
Q

Explain what vasoconstriction is caused by

A

An increase in the levels of vasoconstrictors and decrease in the level of vasorelaxants.

Increase in endothelium-derived vasoconstrictors: endothelin-1, angiotensin II, and non-endothelial vasoconstrictors: serotonin (5HT: 5-hydroxytryptamine, produced by enterochromaffin cells, stored in platelets), thromboxane (platelets)

Decrease in endothelium-derived relaxing factors (EDRFs) : prostacyclin, NO; decrease in non-endothelial vasorelaxants: vasoactive intestinal peptide (neuropeptide VIP), adrenomedullin.

Reduced expression/activity of voltage-gated potassium channels (Kv)

Please note that many vasoactive substances have multiple functions. For example, many vasoconstrictors can also stimulate proliferation of vascular smooth muscle cells and induce thrombosis.

49
Q

Explain what arterial remodeling and inflammation is caused by

A

Arterial remodelling is a result of clonal expansion of apoptosis-resistant highly proliferative endothelial cells and smooth muscle cells. Vascular cells proliferate and migrate into the vessel lumen, forming an occlusion. In PH, vascular remodelling is often preceded by endothelial damage and apoptosis caused by toxins, reactive oxygen species, autoimmune mechanisms, and shear stress. Endothelial cell death is followed by a selection of apoptosis-resistant clones.

50
Q

What is increased vascular cell proliferation is associated with?

A
  • Increased circulating levels of growth factors such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), endothelin-1, transforming growth factor beta (TGFβ)
  • Increased levels of inflammatory cells and cytokines TNF-α, IL-1. IL-6, IL-8, monocyte chemoattractant protein 1(MCP-1)
  • Genetic mutations: mutations in 11 genes have been identified so far. The best characterized are mutations in the bone morphogenetic protein receptor 2 (BMPRII).
  • Inhibition of BMPR2 signalling in PH which enhances pro-proliferative and pro-fibrotic effects of TGF-β
    Increased levels of matrix metalloproteinases
  • Oxidative stress (reactive oxygen species generation)
    Activation of the transcription factor hypoxia-inducible factor-1 (HIF-1)
  • Inhibition of mitochondrial respiration (Krebs cycle) and metabolic shift towards glycolysis.
51
Q

Severe PAH is also characterised by what?

A

The formation of plexiform lesions consisting of proliferating endothelial cells that form a network of disorganised, immature blood vessels

52
Q

What vascular remodelling in pulmonary arterial hypertension takes place?

A

Hematoxylin and eosin staining showing (A) neointimal proliferation (double arrow) in an elastic pulmonary artery; (B) medial hypertrophy and neointimal proliferation leading to occlusion of the vessel lumen (arrows) in muscular pulmonary arteries; and (C) a plexiform lesion, comprising a plexus of capillary-like channels, in a patient with plexogenic arteriopathy.

53
Q

Which inflammatory cell accumulate in plexiform lesions?

A

Mast cells, monocytes, macrophages, neutrophils, T-lymphocytes, dendritic cells

54
Q

What is thrombosis caused by?

A

1) an imbalance in the levels of pro-thrombotic and antithrombotic factors (an increase in pro-thrombotic factors, such as vWF, endothelial factor VIII, monocyte chemoattractant protein 1 (MCP-1), plasminogen activator inhibitor, and a decrease in anti-thrombotic factors, such as nitric oxide, prostacyclin, thrombomodulin, annexin 5 and urokinase)
2) a decrease in endothelial barrier: as a result of increased endothelial permeability, platelets can gain access to the subendothelial matrix proteins, which induces platelet activation and thrombosis)
3) exposure of platelets to fibrin.

55
Q

KEY concepts for Respiratory disease:

A

1) Asthma and COPD are very different diseases – different ‘causes’, different pathology, different pathophysiology.
2) Current treatment regimens for asthma are generally effective in the majority of patients, as long as they are compliant.
3) In contrast, current treatment regimens for COPD are similar to those for asthma and, consequently, are poorly effective.
4) Patients with severe asthma may also be poorly controlled on current therapy.
5) It should be noted that some patients exhibit features of both diseases – for example, they may be asthmatics who are exposed to inhaled smoke (intentional – cigarettes/cigars – or not easily avoided – cooking using biomass fuels).

56
Q

KEY concepts for Cardiovascular disease:

A

1) Atherosclerosis is a fibroproliferative, inflammatory disease initiated by endothelial damage. Inflammation, turbulent or low shear stress and accumulation of low density lipoproteins trigger the disease.
2) Pulmonary hypertension is a multifactorial disease. Vasoconstriction and remodelling of pulmonary vessel wall caused by progressive proliferation of intimal and medial cells and their resistance to apoptosis, play a key role.

57
Q

In asthma, give 3 reasons why current treatments may be less effective than expected?

A
  • patient may have severe asthma
  • patient may also have concomitant COPD
  • poor compliance with medication (s)
58
Q

In COPD, give 3 reasons why current treatments are relatively ineffective?

A

1) little or no bronchoconstriction (airway smooth muscle contraction), so bronchodilators not expected to work
2) inflammation not inhibited by glucocorticoids - oxidative stress considered relevant to this resistance
3) poor compliance with medication

59
Q

In asthma, name 3 specific inflammatory mediators involved in pathophysiology

A
  • histamine
  • LTC4
  • PGF2a
60
Q

List factors contributing to endothelial injury

A
  • inflammation
  • apoptosis and necrosis
  • oxidative stress (hypoxia/reoxygenation)
  • mechanical injury (shear stress, stretch)
61
Q

What are foam cells?

A

Macrophages filled with lipid droplets

62
Q

List the substances contributing to the growth of atherosclerosis

A
  • VEGF
  • bFGF
  • PDGF
  • TGF-B
63
Q

List the substances contributing to the growth of atherosclerotic plaque by promoting inflammatory responses

A
  • TNF-a
  • IL-1
  • IL-6
  • IL-8
  • MCP-1

Cardio & Thoracic Biology (11 decks)

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