Lung cell biology Flashcards
What are the external insults to the lungs
Smoking, pollution
What is the effect of tobacco on the lungs
COPD- puts holes in the lung- can lead to emphysema
What are the knock on effects of things that affect the airways
May have knock on effects on the CVS- systemic effects
What can respiratory bronchioles have
Alveoli
Describe the shape of the lungs
The lungs have a funnel shape, the respiratory bronchioles and alveoli have the largest surface area
What happens to the cross-sectional area of the lungs
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
Describe the surface area of the lungs relative to the lung lining liquid
surface area of lungs equal to the area of a tennis court, but lining liquid volume equal to a wine glass
Describe lung surfactant
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.
What happens in babies delivered before the 24th week
No surfactant- thus they need respiratory support to keep the lungs open and to perform gas exchange
What happens to gas exchange in COPD
Lungs rot away, see holes- less gas exchange
Describe the basic functions of the respiratory epithelium
- 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
What is key to remember about mediators
they are important- but can go out of control in disease
What does the epithelium need to be able to do
Regenerate itself
Describe goblet cells
§ Found in the large, central and small airways.
§ Make up 20% or 1/5th of the epithelium.
§ Synthesise and secrete mucous.
What is different about goblet cells in smokers
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)
What happens to mucous production in patients with COPD
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
Describe ciliated cells
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”
What is different about ciliated cells in smokers
- 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.
Describe the roles of the alveolar walls
intact walls hold airways open (elastic walls) Alveolar attachemts (septa) creates tensile forces on the airways (positive pressure upon exhalation to prevent collapse)
What is the diameter of small, bronchiolar airways
2mm
What happens to the small, bronchiolar airways in COPD
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
What is the consequences of this damage to the bronchiolar airways in COPD
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.
What causes alveolar destruction (emphysema) in COPD
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
Why does fibrosis occur
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
Summarise the causes of small airway obstruction
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
Describe club (Clara) cells
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
Describe ciliated bronchiolar epithelium
BRONCHIOLAR CILIATED CELLS – increased in smokers and COPD
Beat synchronously to move mucus up to epiglottis and clear trapped debris, cells etc
What does smoking cause in susceptible subjects (i.e those with COPD)
many holes form in the alveoli
Emphysematous alveoli in COPD
Summarise COPD
COPD = bronchitis + emphysema + small airways disease. Affects 10-20% smokers.
Describe alveoli
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
Summarise the alveolar unit
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!
Describe type 1 pneumocytes
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: ~80m.
Describe type 2 pneumocytes
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
Describe the shape of type 2 pneumocytes
Cuboidal shaped at ~10microm and positioned in the corners of the alveoli.
Where are type 2 pneumocytes found
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
What is the ratio of type 2: type 1 cells
T2:T1 ratio of NUMBERS = 2:1.
T2:T1 ratio of AREA = 5:95.
Summarise type 2 epithelial cells
Repair/progenitor cells Precursor of type I cells Secrete surfactant
Cover 5% of the alveolar surface
Describe stroll cells in the alveoli
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]
Describe alveolar macrophages
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.
What enzymes are released by Clara cells
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.
Describe the alveolar epithelial-endothelial barrier
very thin, hence why diffusion rapid
Describe alveolar fibrosis
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).
Describe normal repair
NORMAL repair = T1 cell death triggers growth factor release to increase T2 proliferation and differentiation into type 1 cells
Describe abnormal repair
ABNORMAL repair = excess tissue breakdown elevated growth factor release fibrotic effect (irreversible).
What are the effects of growth factors in fibrosis
Type II cell proliferation, Stromal cell proliferation, Connective tissue synthesis
What happens in alveolar fibrosis
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
Describe how the alveolar epithelium can orchestrate repair
Conversion to T1 cells- re-epithelialisation
Conversion to myofibroblasts- more fibrosis- undesirable in excess
MYOFIBROBLASTS CAN TURN TO T2- unsure of mechanism
How does smoking damage this repair process
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
What are the secretory cells of the epithelia
goblet, type 2 cells, club cells
What functions do these secretory cells have in common
•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
What do all smokers have
Alveolar inflammaiton- increased number of inflammatory cells (macrophages)
not all macrophages are involved in phagocytosis
increased neutrophils if infection
What are the roles of neutrophils and macrophages in the lungs
Phagocytosis
Antimicrobial defence
Synthesise antioxidants eg glutathione
Xenobiotic metabolism
Quantify the changes in the numbers of neutrophils and macrophages in smokers
Increase by up to 10-fold in smokers
Describe the proportions of macrophages and neutrophils in the respiratory units
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
Describe the proportions of macrophages and neutrophils in the airways
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
What enzymes are released by neutrophils and macrophages
SERINE PROTEINASES eg neutrophil elastase (NE) METTALLOPROTEINASES eg MMP9; Zn/metal at reactive site) lead to alveolar inflammation
What are the substrates for these enzymes
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
What are the roles of oxidants secreted by neutrophils and macrophages
oxidants
Generate highly reactive peroxides Interact with proteins and lipids
Inactivate alpha-1 antitrypsin Fragment connective tissue
Describe the roles of mediators released by macrophages and neutrophils
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
Summarise the roles of these mediators
cytokines attract more inflammatory cells during infection and growth factors trigger growth and repair
What are the roles of phase 1 and 2 enzymes
These enzymes are involved in xenobiotic metabolism, ie metabolism of foreign compounds deposited by inhalation
found in club cells, type 2 cells and macrophages
Describe what happens to pro carcinogens
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
Describe Alpha 1- antitrypsin
inhibits neutrophil elastase, preventing emphysema
no inhibitor, lungs rot rapidly
Summarise the effects of smoking
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.
Summarise alveolar macrophages
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.
Summarise neutrophils
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.
