Flashcards in L59 – Proteases in Chronic Obstructive Pulmonary Disease Deck (42):
What is a genetic cause of COPD?
alpha 1- antitrypsin deficiency
During general* examination, what are the cardinal signs of COPD?
Diffuse wheezing to auscultation
Regular HR with no murmur
"barrel" chest (emphysema)
Moderate nail clubbing
Weight loss (emphysema)
What are the oximetry readings for nomal, significantly low O2 and hypoxia?
Normal = 95%
<92% = significantly low
90% = hypoxemia
What are the CXR signs of COPD?
Lungs are hyperlucent, hyperinflated (low-set diaphragm), with blebs (vascularization on
What are the normal and COPD FEV1/FVC readings?
Normal: FEV1/FVC = 0.8
COPD = FEV1/FVC < 0.7
What are the corresponding FEV1 for 4 different diseases stages in COPD?
I = mild: FEV1 >= 80%
II = moderate: 50% < FEV1 < 80%
III = severe: 30% < FEV1 <
IV = very severe: FEV1:
<30% predicted; or
<50% predicted + chronic respiratory failure
What are the corresponding FEV1/FVC for different stages of COPD severity?
All predicted to FEV1/FVC < 0.70
Outline the structural changes to the lungs in COPD?
All caused by chronic inflammation:
- parenchymal destruction
- loss of alveolar attachments
- Peri-bronchial fibrosis
- Mucus hyper-secretion
- Loss of elastic recoil
- small airway chronic inflammation
a-1 antitrypsin deficiency can lead to emphysema? How?
a1 antitrypsin deficiency > lack of anti-protease > protease causes abnormal breakdown of elastin in connective tissue of lungs > emphysema
2 types of proteases?
What are the differences between the 2 types of proteases?
Exopeptidases = (e.g. aminopeptidases,
carboxypeptidases): terminal amino acids, non-specific
Endoproteinases (e.g. endopeptidases): internal
How are proteases classified?
What is the role of neutrophil elastase?
Innate immunity, complement activation
Name some Metalloproteinases?
How does MMP12 act on bacteria?
destroy phagocytosed bacteria by hydrolysis
What causes peri-bronchial fibrosis?
Excessive ECM collagen deposition in bronchial walls
Cigarette smoke can trigger which two cells for mediating inflammation?
Macrophages and neutrophils mainly
What is the pathway of cigarette smoke inducing production of IL-8? Which cell?
Smoke > Activated alveolar macrophage produces tumor necrosis factor (TNF-α) > activate NF-κB transcription factor > express IL-8 gene > IL-8
Cigarette smoke can also activate epithelial cells. What is triggered in epithelial cells?
PDE4 in epithelial cells activates inflammatory cells (CD8+ lymphocyte, neutrophil)
What are the other cytokines released by activated alveolar macrophage to attract inflammatory cells?
Neutrophil chemotactic factors
How does inflammatory cells cause imbalance in proteases?
Inflammatory cells are rich in proteases and oxidants
>> imbalance of proteases /anti-proteases
+ imbalance of oxidants / antioxidants in cytoplasm of lung cells
How is protease imbalance normally resolved (aka not in chronic inflammation)?
Solved by exporting or degrading certain proteases
What are some proteases secreted by inflammatory cells that can cause local parenchymal tissue damage?
What are some tissue inhibitors/ protectors secreted to combat the imbalance of proteases?
-Tissue inhibitors of metaloproteinase: TIMPs, SLPI
-alpha-1 antitrypsin coating protects lung surface from proteases
What do neutrophils release to breakdown lung tissue? What is the state of neutrophils (intact or not)?
Activated and disintegrating neutrophils release azurophil granules containing serine proteinase (neutrophil elastase)
During chronic inflammation, what are the levels of protease inhibitors?
Cannot work against proteases
Why is alpha 1 antitrypsin not able to coat the lung surface in genetic defect?
Alpha-1 antitrypsin is produced but is trapped in liver >>> causes liver damage
Cannot reach lungs for protective coating
What are MMPs? Which cells make MMPs?
Produced by epithelial cells, alveolar macrophages and neutrophils
What is the composition of MMPs? What is the location of MMPs?
calcium-dependent zinc-containing endopeptidases (specific)
What are some MMPs released in COPD?
What are some important matrix proteins targeted in COPD?
What are the roles of fibronectin and laminin?
fibronectin >> binds to integrins, extracellular
laminin >> promotes the attachment of epithelial cells to the basal lamina
MMPs, apart from damaging ECM matrix proteins, can activate what other substrates?
Other proteases (e.g. cathepsin)
Growth factors (e.g TGFb, amphiregulin)
Cell surface receptors (e.g. ADAM, NOTCH)
What is the relationship between Cigarette smoke, MMP-12, a1-AT and TIMP-1?
Cigarette smoke>> MMP-12 secreted by alveolar macrophages >> inhibit a1-AT >> loss of inhibition on neutrophil elastase
>> increased activity of neutrophil elastase inhibits TIMP-1 >> further loss of inhibition on MMP-12 (Vicious cycle)
What is the result of Lack of MMP-12 in a COPD patient?
PROTECTS from emphysema and peribronchial fibrosis (less deposition) caused by long-term cigarette smoke exposure
What is the role of TGF-B?
Induce apoptosis and fibrogenesis >> chronic bronchitis
What is the role of Elastin fragments?
recruit more monocytes to differentiate into
alveolar macrophages > exacerbate situation in COPD
What is the chemical pathway of TGT-B activation? Which MMPs are involved and what is the final result?
Cigarette smoke > activate MMP2 and MMP9 > turns pro-TGTb into activated TGT-B (cleaves binding protein off pro-TGTb)
TGFR signalling > activate myofibroblast, deposit excessive ECM (collagen, fibronectin) in bronchial walls > PERI-BRONCHIAL FIBROSIS
When EGFR is activated, how do epithelial basal cells differentiate?
Epithelial basal cells differentiate into
nongranulated secretory cells
How does neutrophils mediate mucus PRODUCTION (not secretion)?
Mucin production occurs when neutrophils:
Secrete TNF-α > express* EGFR
Release O2 free radicals > activate* EGFR
Secrete elastase > stabilize mRNA
How does neutrophils mediate mucus secretion (not production)?
Mucin secretion occurs when neutrophils release:
Cathepsin G proteinase 3