Cystic Fibrosis: Multisystem Disorder and Therapies Flashcards
What is the acinus?
An acinus refers to any cluster of cells that resembles a many-lobed “berry,”
Describe the timeline of lung development.
Describe the embryonic stage of lung development.
Describe the pseudoglandular stage of lung development.
Describe the canalicular stage of lung development.
Describe the sacular/alveolar stage of lung development.
Recall the functions of the lung.
Recall the lung defence mechanisms
Describe the mucociliary escalator.
Recall the cells of the lungs.
Describe the FEV test.
Forced expiratory volume (FEV) measures how much air a person can exhale during a forced breath. Forced vital capacity (FVC) is the total amount of air exhaled during the FEV test.
Forced expiratory volume and forced vital capacity are lung function tests that are measured during spirometry. Forced expiratory volume is the most important measurement of lung function. It is used to:
- Diagnose obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). A person who has asthma or COPD has a lower FEV1 result than a healthy person.
- See how well medicines used to improve breathing are working.
- Check if lung disease is getting worse. Decreases in the FEV1 value may mean the lung disease is getting worse.
Recall normal flow-volume curve.
Describe the extent of pulmonary disease in CF.
Recall the pathophysiology of CF.
Recall the cell types that express CFTR.
Recall the ion transport in normal lung.
Recall the ion transport in CF lung.
Recall the effect of ASL volume hyperabsorption in CF.
Recall the mechanism of reduced pH of ASL and its effects.
- Loss of CFTR-dependent bicarb secretion
- pH of airway-surface liquid decreases resulting in impaired antibacterial activity
Describe abnormal mucus in CF.
Describe the abnormal airway microenvironment due to CF.
Recall inflammation due to CF.
Recall the dysregulation immune pathways in CF.
- Activee NF-kB => ↑ secretion of proinflammatory cytokines eg IL-8, IL-6 TNFα, IL-1β
- CF ASL contains high levels of ROS
- Neutrophils major contributor
- Airway epithelium
- Exacerbated by ↓antioxidant defense – ↓ glutathione metabolism => invigorates proinflammatory environment
- Accumulation of abnormally folded CFTR in ER results in responses that trigger ‘cell stress’ and apoptosis
- Ceramide accumulation => inducing apoptosis
- breakdown product of sphingomyelin found in plasma membrane and in endolysosome
- Abnormal basal lipid metabolism - skewed towards
- ↑ production of arachidonic acid (AA) & leukotriene B4
- ↓docosahexaenoic acid (DHA) and lipoxin A4 (LXA4).
- Blunting of interferon signaling – interferes with eradication of bacteria – ↑susceptibility to viral infections
TLR4 senses __________. TLR5 senses ____________________. ______ poorly displayed on surface of CF cells and fails to respond well to stimulation.
Describe neutrophils in regards to CF response.
- Neutrophils are first and main inflammatory cell found in CF airways
- Neutrophils have 3 main anti-bacterial weapons
- Phagocytosis
- Granule release (protease rich)
- NET formation (DNA fibres that entangle, immobilise and kill pathogens)
Recall roles of other immune cells in CF.
- Macrophages
- Increased numbers
- Altered function: impaired efferocytosis
- Intrinsic defects
- Dendritic cells
- T cells
- skewed towards Th2/Th17 immune response
- Counter-regulatory T cells (Tregs) may be reduced in CF
- Invariant natural killer T cells
- Dysregulated in CF
- Upregulated in absence of CFTR
Recall the pathology of bronchiectasis in CF.
Recall the Sweat Test.
Recall the role of CFTR in sweat gland.
Recall the clinical features of high salt sweat
Recall the two functions of the pancreas.
Recall the clinical presentation of CF on the pancreas and possible treatments
Recall the pathophysiology of the pancreatic disease
- CFTR in the apical membrane of the pancreatic ductal epithelial cell
- Regulation of chloride secretion – Reduced luminal liquid •
- Regulation of bicarbonate secretion
- Acidic pH of luminal liquid
- key buffer for pancreatic fluid
- Neutralises gastric acid
- Optimal pH for digestive enzyme function
- Viscous pancreatic secretions
- Pancreatic duct obstruction
- Progressive fibrosis and fatty infiltration
- Premature activation of proteolytic enzymes
- inflammation and destruction
Describe pancreatitis.
Recall the genetics of pancreatitis in CF patients.
Recall modifiers that likely results in pancreatitis development in CF patients.
Recall clinical presentation of pancreatitis.
- May be initial or only clinical manifestation of CF
- Affects 20% of PS patients of which – Only 18% have single episode
- Acute pancreatitis: 2 of 3
- Upper abdominal pain +/- emesis
- Amylase or lipase >3 x uln
- Consistent abdominal imaging (CT, MRI, u/s)
- Acute recurrent pancreatitis – >2 episodes of AP with return to baseline between
- Chronic pancreatitis
- Chronic abdominal pain or exocrine or endocrine insufficiency
- Plus characteristic imaging
Recall management of pancreatitis.
Recall the effects of CF on endocrine pancreas.
Recall the pathogenesis of CFLD.
Recall the clinical features of CFLD.
Recall clinical significance of CFLD.
Recall diagnosis of CFLD.
Recall the treatment of CFLD.
Recall the effects of CF in the GIT.
Recall meconium ileus.
Recall Distal Intestinal Obstruction Syndrome
Recall gastro-oesophageal reflux.
Recall other GI complications caused by CF.
Recall osteoporosis caused by CF.
Recall effects of CF on the genito-urinary system.
Recall the effects of CF in the renal system.
Recall the effects of CF in ENT, CVS, and skin
- ENT
- Nasal polyps in 10-30%
- Sinus involvement
- Aminoglycosides are ototoxic
- CVS – Corpulmonale
- Skin – Aquagenic wrinkling of palms – Acrodermatitis enteropathica like rash – Vasculitis – Nutritional
Recall the goals of CF treatment
Recall physiotherapy techniques for CF.
- Active Cycle of Breathing Techniques (ACBT) – introduced as blowing games
- Autogenic Drainage (AD)
- Assisted AD
- Positive Expiratory Pressure (PEP)
- Mask
- Mouthpiece (MoPEP)
- Combination
- Bubble
- Activity and exercise
Recall the role of antimicrobials for CF.
- prophylaxis
- exarcebations
Majority of CF patients eventually acquire _____________.
Describe mucolytics and anti-inflammatory agents for CF.
Recall the nutrition requirements for CF patients.
- Energy requirements 120-150% normal
- Wide variation
- Increased expenditure
- Increased losses
- Reduced intake
- High fat (35-40%) high protein diet
- Supplemental feeds
- Oral
- nasogastric
- gastrostomy (PEG)
- Improved growth improves lung function
Recall pancreatic enzymes supplements used for CF patients.
Describe briefly about protein rescue therapy
- Modulators
- Overcome basic CFTR defect
- Mutation (class) specific
Recall protein rescue therapy for Class II mutations.
- Can be combined with potentiator, Ivacaftor
- In-vitro studies of lumacaftor-ivacaftor in Phe508del respiratory epithelia
- Lumacaftor alone increases CFTR-mediated chloride transport to roughly 15% of wild type,
- addition of Ivacaftor increases transport to nearly 30% of wild type
Describe Ivacaftor
- Significant improvement in lung function
- Significant ↑ in weight
- Significant ↑ in time to exacerbation
- Significant ↓ symptoms
Describe Orkambi
- Lumacaftor-ivacaftor combination
- used for phe508del homozygous patients
- Patients from 6 years
- Patients from 2 years from Dec 19
- Recall:
- Lumacaftor - small molecular compounds – shown to increase amount of Phe508del–CFTR trafficked to cell surface
- Ivacaftor - potentiator
Describe Symdeko.
- Tezacaftor + ivacaftor combination
- For patients >12 years
- For homozygous phe508del or residual function mutation
Describe Trikafta.
- Elexacaftor- tezacaftor- ivacaftor combination
- Phase 3 open label study in progress
- for patietns > 12 years
- At least one phe508del mutation
- Phase 3 open label study in progress
- Recall:
- Elexacaftor (VX-445) - In vitro demonstrated significant increased mature CFTR protein and activity when added to Symdeko
Recall future CF therapies.
Recall Phase 1-3 of Clinical trials
Recall Amplifier ELX-02.
Recall Amplifier MRT5005.
Recall novel antibacterials for CF.
- Vancomycin inhalation powder
- treatment of MRSA
- Phase 2 study demonstrated significant ↓ in MRSA density in sputum. Phase 3 study underway
- AP-PA02: inhaled phage therapy
- In lab tests AP-PA02 killed >80% of PsA strains
- Phase 1&2 trials planned
- Inhaled Nitric oxide: phase 2 study
- i.v.Gallium
- Similar to iron - disrupts iron-dependent biological processes
- In vitro kills antibiotic-resistant Pseudomonas
- Phase 2 study in chronically infected adults
- No difference in FEV1 or Psa in sputum
- Phase 1 study in adults with NTM
- Molgamostim
- Form of granulocyte macrophage-colony stimulating factor (GM-CSF)
- Phase 2 study in progress to treat NTM in adults
Recall anti-inflammatory drugs for CF.
Describe the difficulty of gene therapy for CF.
- Introduce a normal copy of the CFTR gene into the cells of the conducting airways
- Likely to need repeated application
- Lung efficient barrier to foreign material.
- avoid being cleared from lungs by mucociliary escalator
- penetrate mucus and then cell membrane
- cross cytoplasm and DNA must enter nucleus
- Avoid host immune response
Majority of CF gene therapy trials used delivery of GTA to _______ and _______________ of CF patient volunteers as a surrogate tissue
Majority of CF gene therapy trials used delivery of GTA to nasal and maxillary sinus epithelia of CF patient volunteers as a surrogate tissue
Recall the vectors of gene therapy for CF.
- Viral vectors
- Adenovirus
- Retrovirus
- Adeno-associated virus
- Non-viral vectors
- cationic liposomes complexed with plasmid DNA.
- GL67A/pGM169 is the combination of cationic liposome (GL67A) and plasmid DNA expressing CFTR (pGM169)
- Short duration of efficacy – viral promoter exchanged for humanized promoter capable of sustaining prolonged gene expression
- Mild flu-like symptoms – presence of unmethylated CpGgroups on bacterially derived DNA
Describe LPC.
