RS Lecture 5 and 6 - Airways function and Lung Cell Biology Flashcards
How do the airways branch?
Dicotomously
Why are the cartilage rings C-shaped?
To allow the oesophagus to move the bolus down into the stomach
What are the basic functions of the airways and how are they facilitated?
Conduits to conduct O2 to alveoli and CO2 out of the lung (gas exchange) -> facilitated by mechanical stability (cartilage), control of calibre (SM) and protection/cleansing
How is the airway organised?
Cartilage rings (offset) > airway SM with some mucus glands > blood vessels > airway epithelium > cilia and mucous
What is the structure of the airway?
What does mucous do?
Traps inhaled particles and absorbs gases -> moved away by the cilia and is swallowed into the oesophagus
What are the different cell types in the airway?
What is inside the goblet cells?
Mucin granules -> mucin is tightly condensed in the vesicles
How does mucin become less condensed in goblet cells?
Upon stimulus, the granules come to the surface of the cell and form a pore, with water filling the pore and when the water can’t enter anymore, it expands out of the vesicle many times bigger
What is the structure of airway submucosal cells?
Mucous producing acinae -> mucous produced and enters the collecting duct, then leaves into the airway via the ciliated duct
What do mucous and serous cells secrete?
Mucous cells secrete mucus and serous cells secrete antibacterials (watery secretion) -> glands also secrete water and salts
What is the structure of cilia?
9+2 -> 9 on outside, 2 inside; dynein slide over each other using energy from mitochondria to move the cilia
How do cilia beat?
Metachromal rhythm -> fields of cilia, with one lot of cilia beat, then the one behind beats after, so the mucus moves down
What are the functions of airway epithelium?
Secretion of mucins, water, electrolytes; movement of mucus by cilia [mucociliary clearance]; physcial barrier; production of regulatory and inflammatory mediators: NO [by NOS], CO [by HO], arachidonic acid metabolites (prostaglandins [by COX]), chemokines (IL-8), cytokines (GM-CSF), proteases
Why is NOS present in the epithelium?
Might be controlling ciliary beat
What is the function of SM in the airways?
Structure, tone (airway calibre) and secretion (mediators, cytokines and chemokines)
What occurs to the SM in asthma?
Due to inflammation: Structure -> hypertrophy and proliferation occurs; tone -> contraction increases; upregulation of secretion of mediators
What occurs to the secretory functions of SM in the airways?
In response to inflammation from bacterial products of cytokines: upregulate NOS -> ^NO; upregulate COX -> ^prostaglandins; Cytokines, chemokines and adhesion molecules brings in inflammatory cells
How is the tracheo-bronchial circulation arranged?
1-5% of CO -> systemic circulation; perfusion is highest in the body as a lot of input and output so can be very highly perfused ->bronchial arteries arise from many sites on aorta, intercostal arteries and other. Blood returns from tracheal circulation via systemic veins and blood from bronchial circulation returns via pulmonary and bronchial veins
What are the functions of the tracheo-bronchial circulation?
Good gas exchange, contributes to warming/humidification of inspired air, clears inflammatory mediators/inhaled drugs, supplies airway tissue and lumen with inflammatory cells/proteinaceous plasma
What is the mechanism of plasma exudation in the airways?
Cells in post-capillary venules can contract, which leaves gaps which lets plasma be released into IF -> sensory nerve causes cells to contract in venule OR inflammatory mediators [histamine/PAF] -> Evans blue dye can be used to see the leakage occurring
How is airway function controlled?
Nerves: PSNS, adrenergic (SNS), sensory. Regulatory and inflammatory mediators: histamine, arachidonic acid metabolites (prostaglandins), cytokines, chemokines. Proteinases (neutrophil elastase). Reactive gas species (O2-, NO)
How is the airway innervated?
Peanut enters airways, which is detected by sensory nerve, which sends PSNS stimulation, which contracts the airways -> SNS relaxes the airways to adrenaline, but there is another relaxation pathway: NO is released from NO-containing nerves [NOS technically], which relaxes the airways
How is the cholinergic reflex carried out?
Irritant detected, sends signal to CNS which is then relayed via vagus to PSNS and effector organs, which are muscarinic receptors and they contract the airway SM, causing mucous release and dilation of vessels
What are the regulatory-inflammatory cells in the airways and the inflammatory mediators that they generally produce and what can mediators affect?
What are the respiratory diseases with loss of airway control?
Asthma, COPD, CF -> cause airway inflammation/obstruction and airway remodelling
What is asthma?
A clinical syndrome charcterised by increased airway responsiveness to a variety of stimuli -> airway obstruction varies of short periods of time and is reversible
What are some symptoms of asthma?
Dyspnoea, wheezing, cough -> airway inflammation and remodelling occurs
What is the pathophysiology of asthma?
Epithelial fragility exposes sensory nerves, setting up a cholinergic reflex, which causes bronchoconstriction and mucus secretion, and the inflammatory cells produce inflammatory mediators, which causes inflammation which causes remodelling, so growth factors cause hypertrophy, more blood vessels, plasma exudation (histamine)
What is the pathology of asthma?
Mucus plug in lumen, basement membrane thickening, epithelial fragility, vasodilation (congested vessels), eosinophils infiltrate tissues; bronchoconstriction (throws airway wall into folds)
What does the epithelium do in the lungs?
Forms a continuous barrier, isolating external env from host. Produces secretions to facilitate clearance via mucociliary escalator and protect underlying cells as well as maintain reduced surface tension. Metabolises foreign and host-derived compounds. Releases mediators. Triggers lung repair processes.
What is the pathology of COPD?
Increased goblet cells (hyperplasia) and increased mucous secretion
What are goblet cells and their functions?
Found in large, central, small airways -> 20% of epithelium. Synthesise and secrete mucus
How do goblet cells change in smokers?
Goblet cell number at least doubles and secretions increase, secretions become more viscoelastic -> modified gel phase traps cigarette smoke particles and harbours MO’s, enhancing chances of infection
What are ciliated cells and their functions?
Found in large, central and small airways -> 80% of epithelium; cilia beat metasynchronously
How are ciliated cells different in smokers w/wout bronchitis?
Ciliated cells are severely depleted, beat asynchronously; ciliated cells found in bronchioles; cilia are unable to transport thickened mucus -> reduced mucus clearance leading to respiratory infection and bronchitis: airways obstructed by mucus secretions
How are small airways held open?
No cartilage -> held open by collagen and elastin fibres to maintain patency -> in COPD elastin/collagen are collapsed, so obstructs
What are the 2 major cell types in respiratory bronchiole?
Bronchiolar ciliated cells and clara cells (club cells)
What are bronchiolar ciliated cells?
Increased in smokers/COPD -> beat synchronously to move mucus up to epiglottis and clear trapped debris/cells
What are clara/club cells?
20% of epithelial cells (lower in smokers), secretory cells, detoxification, repair/progenitor cells -> no cilia and has secretory vesicles in cytoplasm
What are the types of cells in alveolar units?
Type I epithelial cells, Type II epithelial cells, macrophages, capillary endothelium, stromal cells: myofibroblasts
What are Type I epithelial cells?
Large cells and are very thin to allow gas exchange -> cover 95% of surface of alveoli
What are Type II epithelial cells?
Cuboidal, secrete surfactant, repair/progenitor cells and precursor of type I cells -> more abundant than T1EC, but on surface only the apex appears
What are stromal cells?
Make EC matrix (lungs cement) made of collagen, elastin (to give elasticity and compliance) -> divide to repair
What is the ratio of T1 and T2 EC and how can you distinguish them?
T2 have microvilli, so have a ‘ruffled’ appearance -> ratio of 1 (T1):2 (T2)
What are the Pores of Kohn?
Holes made from T2EC -> help regulate pressure through lung, so near alveoli can be ventilated
Where do T2EC sit in the lungs?
In the corners of the alveoli and are embedded in the interstitium with the apices facing the air -> contain lamellar bodies which store surfactant prior to release onto the air-liquid surface
How can the alveolar epithelium be damaged?
Smoking causes holes in the epithelium, as it is very thin and fragile
How can you tell that alveolar repair is occurring?
Increased T2EC, closer together -> increased fibroblasts trying to repair the lung and increased collagen deposition by the fibroblasts
How do fibroblasts act in normal repair?
If T1EC dies, exposed interstitium and basement membrane, which triggers repair response in these cells -> fibroblasts/T2EC release growth factors, which stimulates T2EC to divide, and then they differentiate into T1EC to repair the epithelial layer
How do fibroblasts act in abnormal repair and fibrosis?
Aberrant repair of lung -> Increased T2EC, stromal/fibroblast proliferation (elevated growth factors) and connective tissue synthesis
What antioxidants are released from the epithelium in the lung?
Glutathione, superoxide dismutase
Which antiproteinases are secreted by the epithelium in the lungs?
Secretory leukoproteinase inhibitor
What secretions are secreted by the cells in the lung epithelium?
Lysosymes, cytochrome P450, phase I/II enzymes
What does the secretory epithelium in the lungs carry out?
Xenobiotic metabolism -> process and detoxify foreign compounds such as carcinogens in cigarette smoke
What are the WBC that can be found in the airways?
Macrophages -> police the airways, in the alveolar respiratory tree - long resident time to respond to many different stimuli. Neutrophils -> very rapid, first cell type to proliferate in the lung due to infection
What happens to leukocytes in smokers lungs and what are their actions?
Number increase by up to 10x in smokers -> with neutrophils predominating - actions: phagocytosis, antimicrobial defense, synthesise antioxidants and xenobiotic mechanisms
How does the proportion of macrophages to neutrophils change in different parts of the lungs?
Peripheral lung, macrophages dominate (80/90%); in healthy lungs, macrophages dominate (70:30); in smokers lungs, neutrophils dominate (70:30)
Which proteases are released from leukocytes in the lungs?
Proteases break down MO and ECM -> Neutrophil: serine proteinases (neutrophil elastase) and macrophages: metalloproteinases (MMP-9)
What is the function of the proteases released by the leukocytes in the lungs?
Break down substrates (proteins, connective tissue, elastin, collagen); activate other proteinases (NE degrades and activates MMP), inactivates antiproteinases (MMP degrades and inactivates alpha-1 antitrypsin); activate cytokines/chemokines and other pro-inflammatory mediators
What is the role of oxidants that are released by leukocytes in the lungs?
Antimicrobial -> generate highly reactive peroxides which interact with proteins and lipids; inactivate alpha-1 antitrypsin; fragment connective tissue
Which mediators are secreted by the leukocytes in the lungs?
Chemokines -> IL-8 (neutrophils), MCP-1 (monocytes). Cytokines -> IL-1beta, IL-6, TNFalpha (inflammation). Growth factors -> VEGF, FGF, TGFbeta (cell survival repair and remodelling)
What do neurophils and macrophages release/generate (overview)?
Proteases, cytokines and chemokines, growth factors and oxidants
What are the 2 types of emphysema?
Centriacinar emphysema - air hits the acinus more and then a ripple effect occurs; and Panacinar (alpha-1-antitrypsin deficiency) - complete affect
How does COPD affect the small airways?
Goblet cell hyperplasia, collagen and elastin fibres broken down, so alveoli collapses
What are the 3 components of COPD?
Chronic bronchitis, emphysema and small airways disease
What is the COPD pathophysiology?
SAD pathway is constructive pathology; Emphysema is destructive pathology; Chronic bronchitis is constructive pathology
How does FEV1 change in smokers, non-smokers, COPD?
What are the similarities and differences of COPD and asthma?
