Lecture 21 - Fibrosing Disease of the Lung Flashcards
What is fibrosis?
When does it occur?
Fibrosis: abnormal deposition of ECM
Occurs in:
• Chronic obstructive diseases (Asthma, COPD: emphysema, bronchitis)
• Fibrosing disease of the lung
What is the most common fibrosing disease of the lung?
What are some other aetiologies?
- IPF: Idiopathic pulmonary fibrosis
• most common
Known causes:
2. Iatrogenic • antibiotics • anti-inflammatories • radiotherapy • chemotherapy
- Inhaled dust particles
• Silicates
• Asbestos
etc.
Describe IPF: • Major features • Median age of diagnosis • Location of pathology • Risk factors • Epidemiology • Prognosis • Symptoms
- Chronic & irreversible
- Usually lethal
- Unknown cause
Median age of diagnosis:
• 66 years
• Limited to the lungs
Risk factors:
• Cigarette smoking
• Wood & metal dust exposure
• Genetic transmission
Epidemiology:
• Men (predominantly)
• Rising incidence
Prognosis:
• about 3 year survival after diagnosis
Symptoms:
• Cough
• Progressive dyspnea
Describe the progression of IPF
What are the different clinical phenotypes?
Progression:
- Asymptomatic period
• Lasts years
• Progressive degeneration of lung function - Onset of symptoms
3a. Rapid progressive course
3b. Slow progressive course
+ acute exacerbations which speed up the progression
How is IPF diagnosed?
What are the major and minor criteria
- High resolution computed tomography
• Heterogeneous gaps in tissue
• Thickened septa between lobes (interstitial tissue) - Surgical biopsy & high power histology
Fibroblastic loci:
• Observed as pale foci
• Full of fibroblasts
Histopathologic hallmark: Heterogenous appearance: • Areas of fibrosis • Scarring • Honeycomb change alternating with regions that are less affected.
Major criteria:
- Exclusion of other known causes if interstitial lung disease
- Abnormal lung function tests
- Abnormalities in chest radiographs
Minor criteria: • > 50 years • Insidious onset • Duration of more than 3 months • Crackles: breathing causes a crackling sound
What is the histological and radiological pattern of IPF?
Usual interstitial pneumonia
Describe the gross appearance
Cobblestone:
• enlarged airspaces
Gross honeycombing
Describe the microscopic appearance
“Usual interstitial pneumonia”
• Patchy fibrotic reaction
• Spatial heterogeneity
Fibrotic foci
• Epithelial cells still present, but they have become cuboidal
- Paucity of inflammation
- Lack of uniform involvement
Describe acute exacerbations in IPF
What are the pathological features?
What does it lead to in terms of clinical presentation?
Leads to rapid decline in lung function
Diffuse alveolar damage
Pathological features: • Type II pneumocyte hyperplasia • Oedematous alveolar septa • Hyaline membranes • Squamous cell metaplasia (in alveoli) • Thrmobi in pulmonary arteries
How may IPF be studied?
- Biopsies from patients
• Dead tissue
• Only can do observational studies or immunohistochemistry - Cell line studies
• However, the cell lines are not typical and representative of the disease
• Different micro-environment - Primary cell culture
• Cells taken directly from the person
• Cells retain the phenotype
• More useful and representative - Animal models
• Bleomycin in mice
What was Bleomycin originally?
A cancer drug
Describe the Bleomycin model of IPF
Pros / cons
Bleomycin causes pulmonary fibrosis in the lung similar to IPF
The drug administered to mice
Mice get IPF
Drawbacks:
• Mouse lifespan & anatomy are different
• Lacks human chronicity
• Bleomycin releases free radicals and causes DNA damage
What is the paradigm of IPF?
Formerly: Chronic inflammation
Now: Aberrant wound healing (disease starting at epithelial level)
- Injury of alveolar epithelial cells
– TGF-B induction –
- Activation of fibroblasts and myofibroblasts
– ECM deposition –
- Pulmonary fibrosis
What is the genetic component of IPF?
Specific genes expressed in alveolar epithelial cells involved:
- MUC5B: codes for mucin
- TERT/TERC: telomere length
- SPA & SPC: surfactant protein
Changes in these genes are observed in disease
Describe the observation of ER stress
Alveolar epithelial cells observed to have ER stress
Unfolded protein response:
- Environmental insults or genetic predisposition (MUC5B etc.) → unfolded proteins
- Stress detected in cell
- Apoptosis and / or fibrosis
What are some environmental insults that lead to the UPR?
Viral infection
Smoking
What is TGF-β?
How does it become activated?
What is the major source of it?
What processes does it bring about?
Key fibrotic cytokine
Inactive form:
• LAP (latency associated peptide) bound
During fibrosis, an integrin binds to the LAP and the TGF-β is released and becomes activated
Source:
• Epithelial cells
Function: • Increased collagen synthesis • Differentiation & stimulation of fibroblasts into myofibroblasts • Epithelial cell proliferation • EMT
What is EMT?
What is the role in IPF?
Epithelial-mesenchymal transition
Transition:
Epithelial cell → fibroblast
Controversy:
• only demonstrated in vitro
→ not representative of the body
List the profibrotic attributes of epithelial cells in IPF
• ER stress • Genetic mutations: - SPC & SPA - MUC5B - TERT • TGF-β
Describe the role of external stressors in IPF
Give a specific example
Not solely genetic component, but also external insults
KO mice for the particular genes do not spontaneously develop pulmonary fibrosis, but can develop it with external stimuli
Examples: • Gastrointestinal reflux - proteolytic enzymes, acid & food enter lungs - damage to epithelial cells • Treatment: proton pump inhibitors
What is the role of the mesenchyme in IPF?
Important role of mesenchyme & fibroblasts
Fibrocytes:
• secrete collagen
Increased presence of fibrocytes in circulation associated with poor prognosis and exacerbation
What are myofibroblasts?
How are they produced?
Derived from common progenitor fibrocytes (from bone marrow)
Three paths of differentiation:
1. EMT: Epithelial cell → fibroblast → myofibroblast
- Fibrocyte in blood → fibroblast → myofibroblast
- Resident fibroblast → myofibroblast
TGF-β:
• Fibroblasts differentiate into myofibroblasts under TGF-β signalling
• Need constant signalling, otherwise they go away
What are fibrocytes?
From the bone marrow
Present in the blood
Recruited to sites of injury
Precursor for fibroblasts and myofibroblasts
How are fibrocytes recruited by the alveolar epithelium?
Fibrocyte: CXCR4
Alveolar epithelium: CXCL12
What is special about the fibroblasts in IPF?
- Resistant to apoptosis (pro-survival genes FoxO3a)
- Remain in the lung for a long time
- Hyper-proliferative
Describe the similarity of IPF to cancer
- Pro-survival genes
- Invasive
- Down regulation of apoptosis
- Foci of fibroblasts are like little tumours
Describe epithelial-mesenchymal cross-talk
Communication between epithelial cell and fibroblast
• Normally in close contact
• Epithelial cell releases products that stimulate fibroblasts:
- TGF-β
- GFs
- Mesenchyme interacts with ECM
- Aberrant ECM drives changes in fibroblast as well as epithelial cells
What is the role of inflammation in IPF?
Macrophages:
• make most of the active TGF-β
• responsible for activating latent TGF-beta
• predominantly M2 macrophages
What are the two types of macrophages?
- M1: Inflammatory
• collagen turn over - M2: Profibrotic
• produces TGF-β
• collagen production etc.
Describe propagation of lung fibrosis
- Predisposition
• Genetic factors
• External stressors
• Ageing - Initiation
• TGF-β activation
• UPR activation
• Fibrocyte recruitment - Progression
• Fibroblast differentiation
• ECM remodelling
• Epigenetic change
- Still don’t know why IPF is so relentless, is controversial
- External stressors may be important in propagation
- ECM contains molecules that signal mesenchymal cells to secrete more ECM (vicious cycle)
- “Feed forward auto amplified loop of matrix remodelling”
- There may be a role of epigenetics
What are some therapeutic strategies for IPF?
- Combination therapy of antioxidants & anti-inflammatories:
• Prednisolone etc.
• Slower decline in lung function - Antifibrotic agents
• IFN-gamma - Endothelin receptor antagonists
- Lung transplant
• only proven treatment
What are the therapeutic challenges in IPF?
There is much redundancy in the pathways leading to the fibrosis
Simply knocking out one is not sufficient
Each pathway needs to be targeted
