1 2 Key Points: The respiratory system delivers oxygen to the - PDF document

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Key Points: • The respiratory system delivers oxygen to the bloodstream and removes carbon dioxide, a metabolic waste product. It consists of the lungs, the airways, and the diaphragm and other muscles used for breathing 1 • The lungs are surrounded by a pleural membrane that facilitates lung expansion and contraction during respiration. The left lung consists of 2 lobes and is smaller than the right to allow room for the heart. The right lung has 3 lobes 1,2 • The airways begin at the nose and extend through mouth and throat to the trachea, which splits into the left and right primary bronchi. The bronchi enter the lungs and further divide into secondary bronchi, which form channels into the 3 lobes of the right lung and the 2 lobes of the left. Within the lobes, the bronchi continue dividing into tertiary bronchi and then bronchioles, which spread throughout the lungs in smaller and smaller branches until they form terminal bronchioles. These feed air into the alveoli, the capillary-wrapped air sacks where gas exchange takes place 1 References 1. Tu J, et al. IN: Computational fluid and particle dynamics in the human respiratory system . 2013: XVIII, pp. 1-374. www.springer.com 2. Taylor T. Inner body: respiratory system. Available at: https://www.innerbody.com/anatomy/respiratory. Accessed February 12, 2016. 3

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Key Points: • Shown here is the pathophysiologic cascade of CF lung disease, demonstrating the progression from: • CFTR gene mutations; to • Reduced total CFTR channel activity, which is the result of the quantity and/or degree of function of CFTR channels; to • Abnormal chloride transport on the apical epithelial cell membrane • Depletion of the airway surface liquid and, since this liquid is essential to support ciliary stability and functioning, ciliary collapse and defective mucociliary clearance • These pathophysiologic changes result in mucus obstruction, chronic lung infections and inflammation • This destructive cycle leads to scarring and progressive lung disease, ultimately culminating in end-stage lung disease Reference Ratjen FA. Respir Care 2009;54:595–605 5

Key Points: • Ion transport through CFTR channels regulates fluid and electrolyte balance in many organ systems, including the lung, pancreas, gastrointestinal tract, sinuses, liver, reproductive tract, and sweat glands. In the normal airway, as exemplified in this animation, the ability to regulate airway surface liquid (ASL) volume depends on coordination of sodium (Na + ) absorption and Cl- secretion via CFTR • Under normal circumstances, the outward flow of negatively charged Cl- ions is opposed by Na + reabsorption – Na + absorption activity is down-regulated by CFTR function • In an epithelium that lacks functional CFTR, failure of Cl- secretion and unregulated Na + absorption results in dehydration of the ASL Supporting Information • The CFTR protein is responsible for directing the activity of other ion channels in the cells (such as those responsible for Na + absorption from the luminal membrane surface) and cells with defective CFTR exhibit excessive Na + absorption • Airway dehydration results in mucus adhesion – promoting bacterial infection and inflammation References • MacDonald KD, et al. Paediatr Drugs 2007;9:1–10 • Goralsk JL, et al. Curr Opin Pharmacol 2010;10:294–9 • Rowe SM, et al. N Engl J Med 2005;352:1992–2001 6

Key Point: • CFTR mutations can be grouped based on the type of molecular defect in the CFTR protein. There are 6 mutation classes, which generally speaking, can be grouped into 2 main categories: • Mutations that reduce the function of CFTR protein • Mutations that reduce the quantity of CFTR protein Additional Information • Different CFTR mutations cause disruptions at various stages of CFTR protein synthesis or in several aspects of function. Mutations have been grouped in 6 classes based on the molecular consequences • The nonsense or frameshift mutations comprising Class I produce a premature stop (or termination) codon. This results in either truncated non-functional CFTR or the prevention of full translation of mRNA so that no CFTR protein is expressed • Class II CFTR mutations affect post-translational folding and transport of the CFTR protein to the cell surface. These misfolded proteins are recognised as misfolded and targeted for degradation, and so fail to reach the Golgi apparatus. As a result, no CFTR protein or only a very small quantity of dysfunctional CFTR protein reaches the cell surface • Other mutations result in CFTR protein that does reach the apical membrane (Classes III–IV). With some mutations, the CFTR protein channel does not open properly, which is known as a gating defect (Class III), or it has impaired chloride movement, or a conductance defect (Class IV). Both of these defects result in diminished chloride transport across the cell membrane • Class V mutations result in a gene-splicing defect in CFTR mRNA that is not properly processed. Although some functional protein is produced, the amount of CFTR at the cell surface is decreased in comparison with normal levels • Finally, with Class VI mutations, functional protein is produced but is very unstable at the cell surface and undergoes accelerated turnover • As we have described, these CF-associated mutations in the CFTR gene can result in little or no CFTR protein reaching the cell surface or CFTR protein at the cell surface that is dysfunctional References • Wilschanski M & Durie PR. Gut 2007;56:1153–63 • Rowe SM et al. N Engl J Med 2005;352:1992–2001 • MacDonald KD et al. Paediatr Drugs 2007;9:1–10 7

Key Points: • Lung health depends on the concerted action of the lung clearance mechanisms shown here. • First, the airway surface liquid (ASL), which is maintained through ionic secretion of chloride (Cl - ) and bicarbonate (HCO 3- ) through cystic fibrosis transmembrane conductance regulator (CFTR) channels, contains endogenous antimicrobial agents that kill bacteria. • CFTR channels also control mucus secretion from submucosal glands and goblet cells and help maintain appropriate mucous viscosity. Bacteria and other contaminants are trapped in mucus and swept out of airways by the action of motile cilia. 1 Reference Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med . 2015;372(4):351-362. 8

Key Points: • Under normal circumstances in the airway, the balance of fluid and electrolytes is necessary to maintain the airway surface liquid (ASL), a layer of fluid that allows the cilia to efficiently beat and clear mucus, particles and pathogens to maintain airway health In CF disease, dysfunction of CFTR channels can disrupt Cl – transport balance • Lack of ENaC regulation results in Na + hyper-absorption – note a significant increase in • Na + absorption in the lower panel, this is due an reduced amount (quantity) and/or activity (function) of CFTR in the apical membrane The change in the concentration gradient of Cl – is thought to affect fluid balance, • contributing to the dehydration of the ASL. As a result, mucus builds up on the cilia, and pathogens and particles become trapped Additional Information In the epithelial cells, Na + absorption is mediated by the ENaC channels and the Na + /K + -ATPase • pump, while the Cl - transport is mediated via the CFTR and Ca 2+ -activated Cl - channels • In the airways, excess liquid removal from airway surfaces is mediated by transepithelial Na + transport; ENaC channels are highly active when ASL volume is large and inhibited when normal. When ENaC channels are inhibited, Cl - secretion is initiated and this transport is mediated by CFTR In the absence of CFTR, Na + absorption is thus upregulated and Cl - secretion is not initiated • References • Rowe SM et al. N Engl J Med 2005;352:1992–2001 • Proesmans M et al. Eur J Pediatr 2008;167:839–49 • Boucher RC. Eur Respir J 2004;23:146–58 9