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Respiratory System > Lung cell biology > Flashcards

Lung cell biology Flashcards

1
Q

What are the external insults to the lungs

A

Smoking, pollution

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2
Q

What is the effect of tobacco on the lungs

A

COPD- puts holes in the lung- can lead to emphysema

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3
Q

What are the knock on effects of things that affect the airways

A

May have knock on effects on the CVS- systemic effects

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4
Q

What can respiratory bronchioles have

A

Alveoli

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5
Q

Describe the shape of the lungs

A

The lungs have a funnel shape, the respiratory bronchioles and alveoli have the largest surface area

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6
Q

What happens to the cross-sectional area of the lungs

A

Cross sectional area of the lung: increases peripherally, with respiratory bronchioles and alveoli occupying the largest surface area (extends to up to 23 generations)
10^4cm^2 at airway generation 23

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7
Q

Describe the surface area of the lungs relative to the lung lining liquid

A

surface area of lungs equal to the area of a tennis court, but lining liquid volume equal to a wine glass

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8
Q

Describe lung surfactant

A

Phospholipid rich substance in the alveoli- prevents the alveoli from collapsing
Produced by type 2 pneumocytes
Prevents alveolar collapse (by giving them stability)
Increases lung compliance by reducing surface tension of alveolar lining fluid
Prevents transudation of fluid in alveoli.

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9
Q

What happens in babies delivered before the 24th week

A

No surfactant- thus they need respiratory support to keep the lungs open and to perform gas exchange

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10
Q

What happens to gas exchange in COPD

A

Lungs rot away, see holes- less gas exchange

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11
Q

Describe the basic functions of the respiratory epithelium

A
  • Forms a continuous barrier, isolating external environment from host
  • Produces secretions to facilitate clearance, via mucociliary escalator, and protect underlying cells as well as maintain reduced surface tension (alveolae)- secretions can protect the lung from external insults
  • Metabolises foreign and host-derived compounds •Releases mediators
  • Triggers lung repair processes
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12
Q

What is key to remember about mediators

A

they are important- but can go out of control in disease

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13
Q

What does the epithelium need to be able to do

A

Regenerate itself

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14
Q

Describe goblet cells

A

§ Found in the large, central and small airways.

§ Make up 20% or 1/5th of the epithelium.

§ Synthesise and secrete mucous.

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15
Q

What is different about goblet cells in smokers

A

In smokers -
* goblet cell number at least doubles * secretions increase
* secretions are more viscoelastic
Modified gel phase traps cigarette smoke particles but also traps and harbours microorganisms, enhancing chances of infection (frequent bronchitis)

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16
Q

What happens to mucous production in patients with COPD

A

Increased goblet cell numbers (goblet cell hyperplasia) & increased mucus secretion
Cigarette smoke causes hyperplasia and hypertrophy of mucous-secreting glands of the large cartilaginous airways.
Hyperplasia of the goblet cells occurs at the expense of cilia
Mucous gland hypertrophy is express as gland:wall ratio and Reid index, normally <0.4

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17
Q

Describe ciliated cells

A

Large, central and small airways
* Normally ~60-80% of epithelial cells
* Cilia beat metasynchronously -
Imagine a field of corn with wind blowing to form “flow waves”

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18
Q

What is different about ciliated cells in smokers

A
  • ciliated cells are severely depleted
  • cilia beat asynchronously
  • ciliated cells found in bronchioles
  • cilia unable to transport thickened mucus
    Reduced mucus clearance leading to respiratory infection and bronchitis. Airways obstructed by mucus secretions.
     Reduced mucous clearance leading to respiratory infection and bronchitis.
    o Metaplasia to form ciliated cells in the bronchioles.
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19
Q

Describe the roles of the alveolar walls

A 
intact walls hold airways open (elastic walls)
Alveolar attachemts (septa) creates tensile forces on the airways (positive pressure upon exhalation to prevent collapse)
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20
Q

What is the diameter of small, bronchiolar airways

A

2mm

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21
Q

What happens to the small, bronchiolar airways in COPD

A

in COPD fibrosis and destroyed alveoli lead to collapsed airways - walls disrupted due to inflammatory cell proteinases and mechanisms - irrevocable damage; stenosis can occur, preventing gas exchange distal to the closure

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22
Q

What is the consequences of this damage to the bronchiolar airways in COPD

A

In COPD, the small airways collapse to <2mm diameter due to decreased elasticity and destruction of peri-bronchiolar support. This leads to: mucous becoming trapped, airway narrowing, cell breakdown by enzymes and inflammatory cells (this reduces peripheral gas exchange). BE AWARE OF STENOSIS OF THE SMALL AIRWAYS.

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23
Q

What causes alveolar destruction (emphysema) in COPD

A

Cigarette smoke and other inhaled noxious particles cause inflammatory cell activation within the lung, inducing these cells to release inflammatory mediators and proteases
In COPD, smoking induces the release of neutrophil elastase, which destroys alveolar attachments. As the distal airways are held open by alveolar septa, destruction of alveoli causes the airways to collapse, resulting in airway obstruction.
Decreased elasticity of supporting sturcture
Destruction of peribronchiolar support
Plugging, inflammatory narrowing and plugging of small airways

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24
Q

Why does fibrosis occur

A

In an attempt to repair damage
when this happens in a collapsed airway- cannot repair
lots of inflammatory cells- play a role in small lung cell disease

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25
Q

Summarise the causes of small airway obstruction

A

More secretions, more glandular tissue, loss of elasticity, intraluminal mucus plugs, mucosal oedema, Sm hypertrophy and peribronchial fibrosis
Obstruction, increasing resistance to air flow. Mismathc in V:Q- impairing gas exchange

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26
Q

Describe club (Clara) cells

A

non-ciliated secretory bronchiolar epithelial cells; replace damaged epithelium; contain secretory granules for xenobiotic metabolism - detoxifying enzymes present; enriched in bronchiolar regions; lower in smokers.
 Found in the large, central, small, bronchi and bronchiole airways – increase proportionally distally (more later on).
 Major role is xenobiotic metabolism.
~ 20% of epithelial cells

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27
Q

Describe ciliated bronchiolar epithelium

A

BRONCHIOLAR CILIATED CELLS – increased in smokers and COPD

Beat synchronously to move mucus up to epiglottis and clear trapped debris, cells etc

28
Q

What does smoking cause in susceptible subjects (i.e those with COPD)

A

many holes form in the alveoli

Emphysematous alveoli in COPD

29
Q

Summarise COPD

A

COPD = bronchitis + emphysema + small airways disease. Affects 10-20% smokers.

30
Q

Describe alveoli

A

An alveolus is a blind-ending terminal sac of respiratory tract. Most gaseous exchange occurs in the alveoli. because alveoli are so numerous, they provide the majority of lung volume and surface area
the majority of alveoli open into alveolar sacs.
Communication between adjacent alveoli is possible through perforations in the alveoli wall called pores of Kohn.
The alveoli are lined with type 1 and 2 pneuomocytes which sit on the basement membrane
Type 1- structural
Type 2- produce surfactant

31
Q

Summarise the alveolar unit

A

 In smokers, holes appear in alveoli which reduce surface area of the lungs (elastic tissue loss).
 Alveolar walls consist of:
o Type 1 Epithelial Cells.
o Type 2 Epithelial Cells – Cover 5% of the surface BUT much smaller so NUMBER RATIO is T2:T1 = 2:1.
o Stromal fibroblasts – make ECM and divide to repair.
o Alveolar macrophages.
o Capillary endothelium.
See diagram!

32
Q

Describe type 1 pneumocytes

A

TYPE I EPITHELIAL CELL COVERS 95% ALVEOLAR SURFACE
To aid gaseous diffusion, they are very thin; they contain flattened nuclei and few mitochondria- cells are joined by tight junctions.
 Large cells: ~80m.

33
Q

Describe type 2 pneumocytes

A

Surfactant producing cells containing rounded nuclei, their cytoplasm is rich in mitochondria and ER, and microvilli exist on their exposed surface.
TYPE II CELLS SYNTHESISE AND RELEASE SURFACTANT TO PREVENT ALVEOLAR COLLAPSE ON EXPIRATION

34
Q

Describe the shape of type 2 pneumocytes

A

 Cuboidal shaped at ~10microm and positioned in the corners of the alveoli.

35
Q

Where are type 2 pneumocytes found

A

Epithelial type II cells containing lamellar bosies which store surfactant prior to release onto the air-liquid interface (AL). These cells sit in the corners of the alveoli, and embedded in the interstitium with the apices facing the air.
when lung stretches, surfactant is released to replace that which has been used

36
Q

What is the ratio of type 2: type 1 cells

A

 T2:T1 ratio of NUMBERS = 2:1.

 T2:T1 ratio of AREA = 5:95.

37
Q

Summarise type 2 epithelial cells

A

Repair/progenitor cells Precursor of type I cells Secrete surfactant
Cover 5% of the alveolar surface

38
Q

Describe stroll cells in the alveoli

A

Make extracellular matrix – the lung’s cement
Collagen, elastin, to give elasticity and compliance
Divide to repair
[produce interstitial fibrosis if too much deposited - lungs solidify and cannot breathe]

39
Q

Describe alveolar macrophages

A

Derived from circulating blood monocytes
lie on alveolar surface or on alveolar septal tissue
phagocytose foreign material and bacteria
replace cilia in alveoli
migrate to airways along mucociliary escalator or through lymphatic drainage system.

40
Q

What enzymes are released by Clara cells

A

 Contain 2 types of enzymes and other:
o Phase 1 enzymes – Cytochrome p450 oxidases.
 These metabolise foreign compounds but also can activate pro-carcinogens to carcinogens.
o Phase 2 enzymes – Glutathione S-transferase.
 Neutralise BPDE (pro-carcinogens).
o Other: anti-proteinases and lysozyme.

41
Q

Describe the alveolar epithelial-endothelial barrier

A

very thin, hence why diffusion rapid

42
Q

Describe alveolar fibrosis

A

 Classic emphysema = centre-lobular ( pathology starts in acinus- here particles reach)
 Pathway = infection  chronic damage (T1 cell death)  alveolar fibrosis (repair mechanism).
o Results in increased T2 cells, collagen deposition and fibroblasts (make ECM and connective tissue).

43
Q

Describe normal repair

A

 NORMAL repair = T1 cell death triggers growth factor release to increase T2 proliferation and differentiation into type 1 cells

44
Q

Describe abnormal repair

A

 ABNORMAL repair = excess tissue breakdown  elevated growth factor release  fibrotic effect (irreversible).

45
Q

What are the effects of growth factors in fibrosis

A

Type II cell proliferation, Stromal cell proliferation, Connective tissue synthesis

46
Q

What happens in alveolar fibrosis

A

type 2 cells divide in idiopathic or interstitial fibrosis- but they don’t differentiate- severely affecting gas exchange
Cross talk in both directions with fibroblasts:
myofibroblasts induce TII cells to cause fibroblasts to proliferate and release ECM, before fibroblasts cause TII cells to remain as TII not convert to TI
copious amounts of connective tissue

47
Q

Describe how the alveolar epithelium can orchestrate repair

A

Conversion to T1 cells- re-epithelialisation
Conversion to myofibroblasts- more fibrosis- undesirable in excess
MYOFIBROBLASTS CAN TURN TO T2- unsure of mechanism

48
Q

How does smoking damage this repair process

A

 Smoking BLOCKS proliferation and differentiation of T2 into T1 cells. It also blocks communication of T2 cells to myofibroblasts.
More necrosis and apoptosis of T1 and T2 cells
no repair- formation of holes in lung- alveolar damage seen in COPD

49
Q

What are the secretory cells of the epithelia

A

goblet, type 2 cells, club cells

50
Q

What functions do these secretory cells have in common

A

•Secretory epithelial cells have many things in common.
•Secrete protective lining layer to trap deposited particles – surfactant and mucus
•Synthesise and release antioxidants eg glutathione, superoxide dismutase,
•Synthesise and secrete antiproteinases – eg secretory leukoproteinase inhibitor (SLPI)- back up alpha 1 anti-trypsin
•Release lysosyme
•Carry out xenobiotic metabolism (eg process and detoxify
foreign compounds such as carcinogens in cigarette smoke) •Contain cytochrome P450, phase I & II enzymes- lung second to liver in its ability to metabolise xenobiotics

51
Q

What do all smokers have

A

Alveolar inflammaiton- increased number of inflammatory cells (macrophages)
not all macrophages are involved in phagocytosis
increased neutrophils if infection

52
Q

What are the roles of neutrophils and macrophages in the lungs

A

Phagocytosis
Antimicrobial defence
Synthesise antioxidants eg glutathione
Xenobiotic metabolism

53
Q

Quantify the changes in the numbers of neutrophils and macrophages in smokers

A

Increase by up to 10-fold in smokers

54
Q

Describe the proportions of macrophages and neutrophils in the respiratory units

A

Respiratory units –
Mainly macrophages (approx 90%);- no cilia, they remove the particles
Neutrophils up to 10% (may increase to 30% in smokers with respiratory infection)
percentages only go up if infection reaches alveoli

55
Q

Describe the proportions of macrophages and neutrophils in the airways

A

Airways – Macrophage:neutrophil ratio:- 70%:30% in non-smokers 30%:70% in COPD
Still lots of macrophages, but neutrophils have increased by a higher degree
increase due to presence of bacteria, as they are not being cleared by the mucociliary escalator

56
Q

What enzymes are released by neutrophils and macrophages

A 
SERINE PROTEINASES
eg neutrophil elastase (NE)
 METTALLOPROTEINASES
 eg MMP9; Zn/metal at reactive site)
lead to alveolar inflammation
57
Q

What are the substrates for these enzymes

A

Substrates: proteins; connective tissue, elastin, collagen
Activate other proteinases (eg NE degrades and activates MMP), Inactivates antiproteases (eg MMP degrades and inactivates alpha-1 antitrypsin)
Activate cytokines/chemokines and other pro-inflammatory mediators
Will lose lung tissue if more proteinases than antiproteinases

58
Q

What are the roles of oxidants secreted by neutrophils and macrophages

A

oxidants
Generate highly reactive peroxides Interact with proteins and lipids
Inactivate alpha-1 antitrypsin Fragment connective tissue

59
Q

Describe the roles of mediators released by macrophages and neutrophils

A

Chemoattractants/cytokines (eg IL8) attract more inflammatory cells during infection or after toxicant or microbial deposition/inhalation
Growth factors and proteases trigger growth and repair by other cells eg epithelium, stromal fibroblasts

60
Q

Summarise the roles of these mediators

A

cytokines attract more inflammatory cells during infection and growth factors trigger growth and repair

61
Q

What are the roles of phase 1 and 2 enzymes

A

These enzymes are involved in xenobiotic metabolism, ie metabolism of foreign compounds deposited by inhalation
found in club cells, type 2 cells and macrophages

62
Q

Describe what happens to pro carcinogens

A

found in cigarette smoke and are converted to active compounds in lungs by phase I enzymes, before phase II enzymes make them water soluble metabolites that are excreted; if overloaded then DNA binding and mutation occurs (no metabolism)- adduct formation, no repair, mutation

63
Q

Describe Alpha 1- antitrypsin

A

inhibits neutrophil elastase, preventing emphysema

no inhibitor, lungs rot rapidly

64
Q

Summarise the effects of smoking

A

 Smoking BLOCKS proliferation and differentiation of T2 into T1 cells. It also blocks communication of T2 cells to fibroblasts.
 Macrophage and neutrophil numbers increase up to 10-fold.
o Macrophage: Neutrophil ratio = 70:30 but REVERSES in COPD (in UPPER airways).
o Secrete proteases, metalloproteinases (e.g. MMP9)  alveolar inflammation.
o Secrete anti-microbial oxidants and mediators such as growth factors.
 Smoking contains pro-carcinogens which get inadvertently activated by phase 1 enzymes from Clara cells.
o Normally, phase 2 enzymes can metabolise these pro-carcinogens but they may be inactivated by smoking.

65
Q

Summarise alveolar macrophages

A

 Form ~70% of phagocytic cells in the lungs.
 Increase 5-10 fold in a smoker’s lungs.
 Secretes chemokines for chemotaxis of inflammatory/immune cells.
 Secrete proteases to digest foreign bacteria.
 Secrete oxidants and anti-oxidants.

66
Q

Summarise neutrophils

A

 Form ~5% of phagocytic cells in the lungs.
 Increase 5-10 fold in smoker’s lungs and proportionally (up to 30% of phagocytic cells).
 Higher proportion in conducting/large airways.
 Stores high levels of potent proteases.
 Releases very potent oxidative molecules such as hydroxyl anions during activation.

Respiratory System (23 decks)

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