L28- Fibrosis

Question 1

what is fibrosis

Answer 1

An excessive deposition of matrix
components that results in a destruction of normal tissue architecture and a compromise in tissue function

Question 2

examples of fibrosis

Answer 2

keloids, post-op adhesions, Duputreyn’s contracture, Liver fibrosis, Scleroderma, Systemic sclerosis, Myocardial infarction, Idiopathic pulmonary fibrosis, CI induced
fibrosis

Question 3

what stain is used to identify collagen build up

Answer 3

massons trichrome - stains blue

Question 4

Tissue repair vs Fibrosis

Answer 4

Single injury vs Repeated injury

Acute inflammation (resol) vs chronic inflammation (cont)

Cytokine/GF real vs Cytokine GF release

Innate/immune response vs Innate /immune response

Re-epithelialisation vs impaired re-epithelialisation

Fibroblast to myofibroblast differen → apoptosis vs Multiple cell type to myofibroblast differen → senescence

MMP/TIMP balanced vs MMP/TIMP unbalanced

ECM deposition regulated vs ECM deposition unregulated

Question 5

common mechanisms of fibrosis

Answer 5

leukocyte infiltration, release of cytokines, cytokine polarization, TGFb, WNT, hedgehog, PDGF signalling pathways, soluble guanylate cyclase, nuclear receptor signalling, coagulation cascade, 5-HT signalling

Question 6

distinct mechanisms of fibrosis

Answer 6

disease specific triggers, cellular site of injury, composition of infiltrate, sources of myofibroblasts

Question 7

TGFb profibrotic properties

Answer 7

promotes matrix synthesis, induce fibroblast proliferation, differentiation of fibroblasts into myofibroblasts, promotes myofibroblast survival, prevents matrix degradation

promotes mesenchymal transition of epithelial cells

Question 8

TGFb siganlling

Answer 8

1. Ligands and receptors: TGF-β ligands bind to TβRII and dimerises with TβRI (s/t kinase receptor)
2. Signal transduction: activated receptor complex phosphorylates SMADs (SMAD2/3), recruits SMAD4
   and translocates to the nucleus
3. Gene regulation: SMAD complex interacts with transcription factors to regulate target genes
4. Non-canonical pathways: TGF-β can also activate non-canonical pathways e.g. MAPK, PI3K/AKT etc

Question 9

causes of pulmonary fibrosis

Answer 9

drug induced - methotrexate, chemo
radiation induced - chest radiation
environmental - mold, animal exposure
autoimmune - joint inflammation, skin
occupational - prior of current exposure to fumes, asbestos, silica
idiopathic - unknown cause

Question 10

what is another name for environmentally induced pulmonary fibrosis

Answer 10

hypersensitivity pneumonitis

Question 11

what is another name for autoimmune induced pulmonary fibrosis

Answer 11

connective tissue disease-related

Question 12

what is another name for occupationally induced pulomary fibrosis

Answer 12

pneumoconiosis

Question 13

examples of fibrotic diseases

Answer 13

Idiopathic pulmonary fibrosis (IPF) Asbestosis
Collagen
Vascular disorders
Sarcoidosis
Acute respiratory distress syndrome (ARDS)

Question 14

characteristics of pulmonary fibrosis

Answer 14

↑fibroblasts & myofibroblasts

↑remodelling/angiogenesis

↓PGE2 & ↑TGF-β, ↑collagen

Question 15

characterisation of IPF

Answer 15

Poor prognosis
50% 3-year survival
chronic use of steroids associated with
significant side effects
current treatment limited (pirfenidone & nintedanib)

Question 16

mechanism of action of nintedanib

Answer 16

Tyrosine-kinase inhibitor, targeting VEGFR, FGFR and PDGF
- blocks growth factor receptors preventing signalling and fibroblast proliferation

unknown additional mechanisms

Question 17

mechanism of action of perfenidone

Answer 17

targeting fibroblast proliferation and TGF-β-induced collagen production
- blocks TGFb signalling pathway (SMADs)

unknown additional mechanisms - Antifibrotic/anti-inflammatory

Question 18

side effects of pirfenidone

Answer 18

headache, insomnia, diarrhea, dizziness, weight loss, upper resp infect, sinus inflamm

Question 19

side effects of nintedanib

Answer 19

nausea, diarrhea, abnormal liver function, abdom pain

Question 20

Pathogenesis of IPF

Answer 20

1. Tissue injury
2. Inflammation of lung parenchyma
3. Aberrant wound healing
4. Collagenous fibrosis
5. Pulmonary interstitium remodelling

Question 21

senolytics

Answer 21

• Class of small molecules
• Selectively induce death of senescent
  cells (cessation of cell division)
• Prevents, alleviates, or reverses age related diseases
• Elimination of senescent cells
  pharmacologically or genetically in
  mice attenuates lung fibrosis and
  restores lung function

Question 22

what are some things cellular senescence causes

Answer 22

stem cell exhaustion, myofibroblast apoptosis resistance, increase SASP

Question 23

examples of senolytics

Answer 23

dasatinib + quercetin
o TKI targets BCR/Abl, Src, c-kit, ephrin receptors etc
o anti-cancer drug for certain leukemias

o anti-oxidant, inhibits PI3K/AKT, reduces anti-apoptotic Bcl-w
and nonspecific PKI. Anti-inflammatory, anti-cancer

Question 24

T cell immunotherapy and examples

Answer 24

targets the overactive immune system that causes IPF
- Checkpoint inhibitors (anti-PD-1/PD L1, CTLA-4, LAG3)
- Vaccines to Adam 12 targeting fibroblasts/myofibroblasts
- CAR-T cells to fibroblast activation factor (FAP)

Question 25

B cell therapy example

Answer 25

rituxumab - monoclonal antibody that targets CD20 on B-lymphocytes - has been reported to induce acute lung injury - improve lung function in IPF patients with acute exacerbations - improves lung function in ILD patients