5. Lung Cell Biology Flashcards
Summarise how the structure of the lung is optimised for gaseous exchange
The structure of the lung is optimised for gas exchange – with a surface area of approximately the size of a tennis court
Gas exchange units form a sponge-like structure which are intimately linked with the airways
The cross-sectional area of the lung increases peripherally – with up to 23 generations of gas exchange units
The gas exchange units are lined with a fluid called surfactant; this is secreted in the peripheral link and accounts for ~1 wine glass of fluid – forming a very thin layer covering the respiratory units
Without it, the surface tension of the different gas exchange units will increase, leading to the collapse of the lung
Outline the role of the epithelium in a healthy lung and contrast this with what happens in the lung of a patient with COPD
In a healthy lung, the epithelium forms a continuous barrier, isolating the external environment from the host:
o It produces secretions to facilitate mucociliary clearance
o It protects underlying cells as well as maintain reduced surface tension
o It metabolises foreign and host-derived compounds which may be carcinogenic; this is important for smokers
o It releases mediators; controls the number of inflammatory cells that reach the lung
o It triggers lung repair processes
In COPD, there is an increased number of goblet cells (known as hyperplasia) and increased mucus secretion:
o Between the goblet cells, ciliated cells push the mucus towards the throat
Summarise goblet cells
Normally about 1/5 of the epithelial cells – present in large, central and small airways
Synthesise and secrete mucus
Mucus is complex, with a very ‘thin’ sol phase overlaying cells, and a ‘thick’ gel phase at the air interface
In smokers, goblet cell number at least doubles; secretions increase in quantity and are thicker (more viscoelastic)
Modified gel phase traps cigarette smoke particles but also harbours microorganisms, enhancing chances of infection
What does mucus contain?
Mucin proteins, proteoglycans and gycosaminoglycans, released from goblet cells and seromucouse glands; gives mucus viscoelasticity
Serum-derived proteins, such as albumin and alpha 1-antitrypsin, also called alpha 1-proteinase inhibitor, an inhibitor of polymorphonuclear neutrophil proteases; combats microorganism and phagocyte proteases
Antiproteases synthesised by epithelial cells e.g. secretory leucoprotease inhibitor; combats microorganism and phagocyte proteases
Antioxidants from the blood and synthesised by epithelial cells and phagocytes; uric acid and ascorbic acid (blood), glutathione (cells); combats inhaled oxidants e.g. cigarette smoke, ozone; also counteracts excessive oxidants released by activated phagocytes
Define viscoelasticity
Viscoelasticity is the property of materials that exhibit both viscous and elastic characteristics when undergoing deformation
Viscous materials, like honey, resist shear flow and strain linearly with time when a stress is applied
Elastic materials strain when stretched and quickly return to their original state once the stress is removed
Outline ciliated cells in normal lungs and in a smoker’s lungs
Present in large, central and small airways
Normally approximately 80% of epithelial cells
Cilia beat metasynchronously; imagine a field of corn with wind blowing to form ‘flow waves’:
o This pushes the mucus forward, engaging when vertical; then it circles around to its’ original position in order to prevent the movement of the mucus backward as well as forward
o Tips of cilia in sol phase of mucus pushes mucus towards the epiglottis; this is usually swallowed, but often expectorated
Ciliated cells are severely depleted in smokers with bronchitis; they beat asynchronously; therefore, reduced mucus clearance, bronchitis and respiratory infections occur; however, it extends into the bronchioles of smokers, even though they are reduced in larger airways; airways are thus obstructed by mucus secretions
Bronchitis is much more easily reversed than other illnesses associated with COPD
Define expectorate
To cough or spit out (phlegm) from the throat or lung
Define epiglottis
The epiglottis is a flap made of elastic cartilage covered with a mucous membrane, attached to the entrance of the larynx
It projects obliquely upwards behind the tongue and the hyoid bone, pointing dorsally.
It stands open during breathing, allowing air into the larynx
The main function of the epiglottis is to seal off the windpipe during eating, so that food is not accidentally inhaled
What is the difference between mucus and phlegm?
Phlegm is a form of mucus produced by the lower airways (not the nose and sinuses) in response to inflammation; you may not notice phlegm unless you cough it up as a symptom of bronchitis or pneumonia
Outline small airways
<2mm in diameter
Non-cartilagenous; held open by elastic walls of alveoli pushing on them
In COPD, mucus becomes trapped, the airways narrow and they are broken down by enzymes and inflammatory cells:
o This reduces peripheral gas exchange
Outline Clara cells
Clara cells (a.k.a. ‘club cells’ or ‘bronchiolar exocrine cells’) are non-ciliated secretory bronchiolar epithelial cells
They are present in large, central, small airways, bronchi and bronchioles
One major function they carry out is the synthesis and secretion of the material lining the bronchiolar lumen; this material includes glycosaminoglycans, proteins such as lysozymes, and conjugation of the secretory portion of IgA antibodies
Although found in most conducting and transitional airways, they increase proportionally distally
The bronchi and bronchioles are enriched by these cells
Role: metabolism, detoxification and repair
They contain phase I and phase II enzymes
These cells also make and release high levels of antiproteases, e.g. secretory leukoproteinase inhibitor (SLPI)
They also synthesise and secrete lysozyme; an enzyme that can lyse microorganisms
They synthesis and release antioxidants (e.g. glutathione, superoxide dismutase)
Outline phase I and phase II enzymes and their relevance in the development of lung cancer
A major role of these enzymes is in xenobiotic metabolism, i.e. metabolism of ‘foreign’ compounds deposited by inhalation
Phase I enzymes incude cytochrome P450 oxidases; unfortunately, although these enzymes are designed to metabolise foreign compounds into a format that enables phase II enzymes to react and neutralise the toxic agent, they often activate a precarcinogen to a carcinogen:
o E.g: Benzopyrene (BP) is a precarcinogen in the particulate tar phase of cigarette smoke; one cytochrome P450, labelled CYPIA1 (also called aryl hydrocarbon hydroxylase), oxidases BP to benzopyrene diol epoxide (BPDE) which is a potent carcinogen. Smokers with lung cancer have a polymorphism of CYPIA1 that results in high levels (extensive metabolism leads extensive production of the potent carcinogen)
Phase II enzymes include glutathione S-transferase, which enables conjugation of BPDE to a small molecule that neutralises its activity; some individuals are ‘null’ for glutathione S-transferase (i.e. they do not synthesise glutathione transferase and cannot neutralise BPDE)
Consequently, if an individual who smokes has the CYPIA1 extensive metaboliser gene and the null glutathione gene they are 40 times more likely to get lung cancer
Outline alveoli
In susceptible subject smokers, holes in the alveoli may develop and the alveoli may become larger, leading to a reduction in the surface area available for gas exchange:
o This can be seen as elastic tissue loss, therefore expansion during breathing is reduced which exacerbates dead space
Walls consist of two types of epithelial cells, type I and II
Type II cells are more susceptible to damage than type I, but type I will be damaged more often
Epithelial type II cells (a.k.a. type II pneumocytes) are found only in the alveoli (cover 5% of the alveolar surface); they contain lamellar bodies which store surfactant prior to release onto the air-liquid interface:
o Surfactant is a phosopholipid-rich surface active material that prevents lung collapse upon expiration and has immunological functions
They also synthesise and secrete antiproteases
Positions in the corners of the alveoli, and are embedded in the interstitum with the apical membranes facing the air:
o Type II cells also very close to the capillaries
Type II cells are a precursor of alveolar type I cells; they divide and differentiate to replace damaged type I cells
Contrast type I cells with type II cells
Type I alveolar cells are squamous (giving more surface area to each cell) and cover approximately 90–95% of the alveolar surface; type I cells are involved in the process of gas exchange between the alveoli and blood
Type 1 cells are extremely thin (sometimes only 25 nm); the electron microscope was needed to prove that all alveoli are covered with an epithelial lining; these cells need to be so thin to be readily permeable for enabling an easy gas exchange between the alveoli and the blood
Type II alveolar cells cover a small fraction of the alveolar surface area; their function is of major importance in the secretion of pulmonary surfactant, which decreases the surface tension within the alveoli
Type II cells are also capable of cellular division, giving rise to more type I alveolar cells when the lung tissue is damaged; these cells are granular and roughly cuboidal
Type II alveolar cells are typically found at the blood-air barrier; although they only comprise <5% of the alveolar surface, they are relatively numerous (comprising 60% of alveolar epithelial cells)
Outline the alveolar unit
Consists of type I and II epithelial cells, stromal fibroblasts, alveolar macrophages and capillary endothelium
Ratio of TII: TI epithelial cells = 2:1
Stromal cells make extracellular matrix, which is the ‘cement’ of lung tissue; they also make collagen and elastin to give elasticity and compliance; they divide to repair
The capillary endothelium is in close proximity to alveoli to reduce diffusion distance
Alveolar macrophages are enriched in the lower respiratory tract, but found throughout
