Remodelling in the Lung Flashcards
Describe the histopathology of an asthmatic patients airway (7)
- Mucus plug in lumen made of mucus, plasma proteins and eosinophils (neutrophils in severe asthma)
- Epithelial fragility
- Thickened Reticular Basement Membrane
- Smooth Muscle Hypertrophy
- Submucosal gland hypertrophy leading to increased goblet cells
- Vasodilation due to cytokines and histamine
- Cellular Infiltration (eosinophils and neutrophils)
Compare the bronchial epithelial cells in an asthmatic (normal, mild, severe)
Normal: Healthy cilia, with no gaps in between cells. Presence of ciliated cells, goblet cells and basal cells
Mild: Some disruption of ciia. There s also disruption of the cell junctions in the airway.
Severe: Almost absent cilia with non-functioning tissue
A thickened reticular basement membrane is associated with which of the following:
a. ↑airway hyperresponsiveness
b. ↑mortality
c. ↑asthma attacks
d. number of surrounding fibroblasts/myofibroblasts
e. ↑cellular infiltration
a. ↑airway hyperresponsiveness
c. ↑asthma attacks
d. number of surrounding fibroblasts/myofibroblasts
The reticular basement membrane consists of connective tissue including (4):
reticulin
glycosaminoglycan
fibronectin
tenascin
Explain the function of the reticular basement membrane.
Acts as a reservoir for inflammatory mediators, water, growth factors (e.g. heparin sulphate)
Myofibroblasts are activated forms of fibroblasts. Describe function and features.
Lay down collagen in tissue remodelling. (type I and III)
Contractile like myocytes as they have actin. Contraction pulls wound tissue together.
Release other connective tissue, growth factors, cytokines and up-regulating integrins. TGF-B stimulates (myo)fibroblast proliferation through paracrine and autocrine stimulation
Describe how the epithelial-mesenchymal trophic unit (EMTU) is involved in the repair of epithelial injury:
- Epithelial Injury
- Fibroblast Activation
- Myofibroblast Effects
- Remodelling
Epithelial Injury
- Damaged epithelial cells release growth factors (TGF-B, FGF, EGF, PDGF, CTGF) and chemokines (CXCL1, CXCL8)
- ↓PGE2 and ↑MMPs (MMPs can cleave latent GF and activate them)
Describe how the epithelial-mesenchymal trophic unit (EMTU) is involved in the repair of epithelial injury:
- Epithelial Injury
- Fibroblast Activation
- Myofibroblast Effects
- Remodelling
Fibroblast Activation
- Fibroblasts differentiate into activated myofibroblasts through the GFs.
- Fibrocytes and stem cells recruited from the blood - activation and differentiation
- Activated myofibroblasts have a-SMA expression)
Describe how the epithelial-mesenchymal trophic unit (EMTU) is involved in the repair of epithelial injury: (5)
- Epithelial Injury
- Fibroblast Activation
- Myofibroblast Effects
- Remodelling
Myofibroblast Effects
- Collagen (I and III)/connective tissue synthesis and secretion
- Secretion of its own GF, MMPs and cytokines
- Myofibroblast TGF-B activates more fibroblasts in an autocrine manner
- Myofibroblast TGF-B blocks epithelial repair - ensures the underlying tissue heals before the epithelial surface does.
- Angiotensin II induces epithelial apoptosis
Describe how the epithelial-mesenchymal trophic unit (EMTU) is involved in the repair of epithelial injury:
- Epithelial Injury
- Fibroblast Activation
- Myofibroblast Effects
- Remodelling
Remodelling
- Thickened reticular BM (epithelial chemotactic factors attract SMC and fibroblasts towards epithelium)
- Myofibroblasts secrete VEGF and ET1 to stimulate SMC and vascular endothelium
- Increased vasculature meaning there is increased vascularity and therfore easier transport for mediators and leukocytes. Increased hyperplasia
Describe the relevance of the epithelial-mesenchymal trophic unit (EMTU) in chronic inflammation (like asthma or COPD)
Chronic inflammation leads to abberant re-activation of the EMTU in asthma - once chronic pathology is present, it’s difficult to reverse (cycle of EMTU activation -> remodelling)
- EMTU can be activated independent of inflammation, but operating parallel to inflammation*
- Has importance in normal/fetal lung development*
Describe the histopathology of COPD (5)
- Mucus plugging
- Goblet cell hyperplasia
- Fibrosis
- Alveolar wall degradation
- Some ASMC thickening
- Cellular infiltrates
- CD68+ macrophages and CD8+ lympohcytes - both cytotoxic
Where do CS particles accumulate in the lungs and what are its effects on the lung airways
Particles accumulate in small airways.
Macrophages also accumulate here to clear the particles.
Release of cytokines attract neutrophils which release proteases (elastin) and ROS which damages interstitial tissue and epithelium
Damage found in the centre o the acinus
Presence of CD8+ lympohcytes too but reasons unclear. Cytotoxic and causes damage.
a-1-antitrypsin: A deficiency of this protein leads to increased _____ activity and therefore more ______ ______. The damage is found _______ the acinus as supposed to in the centre of the acinus as seen in COPD caused by CS particles.
a-1-antitrypsin: A deficiency of this protein leads to increased protease activity and therefore more alveolar damage. The damage is found througout the acinus as supposed to in the centre of the acinus as seen in COPD caused by CS particles.
Describe the homeostasis of protease activity
Extracellular proteases are involved in remodelling and are regulated by anti-proteases.
A balance between the two is needed for controlled regulation of tissue remodelling.
- Serine proteases irreversibly inhibited by a-1-antitrypsin and irreversibly by SLPI and Elafin*
- MMPs inhibited by TIMPS*
- Cystein proteases inhibited by cystatins*
