L10.3 Inflammation and tissues remodelling in diseased lung

Question 1

Catabasis

Answer 1

Inflammation resolve

Question 2

Inflammation mechanism

Answer 2

1. Recognise
2. Kill/contain (putting scar tissue around)
3. Resolve/tissue remodelling (if insult persists)
   
   • Anti-inflammatory agents are poor at treating remodelling

Question 3

Molecular inflammatory responses

Answer 3

• Inflammation draws cell to the environment
• Endothelium cells moves from blood into tissues → produce inflammatory response
• Fibroblasts activated with inflammatory response (lay down scar tissue & contracts to close wound)
• Macrophage/APC → communicates with Th (helper T-cells)
  
  • Uses PRR to understand pathogen
  • Sends coactivtaion signals → expand WBC, and produce activating cytokines
  • Th cells expand and exert effects in response to inflammation

Question 4

Important cytokines

Answer 4

• TNF α → important in arthritis
• IL4/IL13 → important in asthma
• EMT → Epithelium into mesenchymal tissue during inflammation
  
  • Important for wound healing → cells able to migrate and close its wounds
  • Epithelium doesn’t regress back to original phenotype → chronic inflam and disease arise

Question 5

Consequences of prolonged macrophages

Answer 5

• Macrophage accumulation → persistent inflammatory response:
  
  • ↑GF → fibrosis & remodelling
  • ↑Protease
    
    • May degrade smaller airways → emphysema + GF → fibrosis around tubes

Question 6

Significance of LTs

Answer 6

• LTB4 makes neutrophils come into tissue
• LTC/D/E4 causes SM contraction in asthma

Question 7

Tuberculosis mechanism

Answer 7

• Macrophage normally slash and kill pathogen
• TB pathogens invade macrophage and live in macrophage
  
  1. Immune system cannot kill
  2. Macrophage produce GF
  3. Fibrous tissue and chemokines surround the invaded TB → contained
  • TNF drugs introduced for arthritis causes TB relapse

Question 8

Features of asthma

Answer 8

• Example of tissue pathology caused by chronic inflammation

1. Epithelial transdifferentiation: Ciliated cells → becomes goblet secretory cells
2. EMT: Myofibroblasts invading from epithelium
   
   • Epithelial cells transition into myofibroblasts (contractile)
3. Neuronal sprouting
4. Angiogenesis and vascular remodelling
5. Hypertrophy + Hyperplasia of ASM
6. Scarring (ECM deposit collagen) & extends deep into airway walls

Question 9

Epithelial-mesochymal transition (EMT)

Answer 9

• Central process in wound healing
• Epithelium loses normal phenotype → transdifferentiate into myofibroblasts
  
  • Able to make connective tissues and contract strongly
  • Hypercontracts in asthma

Question 10

EMT regulation

Answer 10

• EMT regulated by E-cadherin and β-catenin
  
  • E-cadherin → expressed b/w epithelial cells normally
    
    • Contact inhibition → epithelial cells stop growing when they contact each other
    • Wound sustained → E-cadherin must be lost → allow growth of cells
  • If E-cadherin and β-catenin blocked → cell goes into EMT
    
    • May lead to cancers

Question 11

Idiopathic pulmonary fibrosis (IPF)

Answer 11

• Interstistum normally thin for gas exchange
  
  • Fibrosis in interstistum → thickens space → unable to do gas exchange
• Excessive angiogensis, TGFβ
  
  • Sustained TGFβ → maintains EMT → transition into fibrotic stage
    
    • Causes Honey comb lung (many small holes in lungs)
      
      • Scar tissue contracts → rips lung and produces small holes
• Recruits further fibrotic agents from bone-marrow

Question 12

Failed treatment of IPF

Answer 12

• Anti-inflammatory agents are not useful in the treatment of IPF

Question 13

Treatment of IPF: Pirfenidone

Answer 13

• Inhibits TGFb stimluated collagen production
• Reduce fibrogenic and inflam mediate including TGF-b and IL1
• Slows rate of decline of lung function

Question 14

Treatment of IPF: Nintedanib

Answer 14

• Inhibit 4 GF kinases
• Slow rate of decline of lung function

Question 15

Lecture summary

Answer 15