Trigger 6: Mechanism of IPF

Question 1

causes and risk factors of IPF

Answer 1

• Smoking
• Metal dust inhalation
• Agricultural and livestock
• Silica
• Sand
• Stone
• Wood dust
  Microbial agents (virus’, fungi and bacteria)

Question 2

mutations

Answer 2

some studies have shown that IPF patient with mutations in the SFTPC gene are at higher risk of

Question 3

SFTPC gene

Answer 3

encodes for surfactant protein C

Question 4

mutation in SFTPC gene

Answer 4

stops production of surfactant protein C- induces induces the unfolded protein response.

Question 5

unfolded proteins response

Answer 5

a response by the ER to the accumulation of misfolded proteins- which aims to restor normal function by halting protein translation, degrading misfolded proteins.

Question 6

what starts IPF

Answer 6

epithelial injury

Question 7

what occurs after epithelial injury

Answer 7

Activation of coagulation cascade and inflammation

Question 8

1. Activation of coagulation cascade and inflammation

Answer 8

a. The damage to alveolar structure and the loss of AECs, with disruption of basement membrane, involves alveolar vessels and leads to increased vascular permeability. This early phase of wound healing response is characterized by the formation of wound clot; consequently, new vessels should be formed and endothelial cells should proliferate, involving endothelial progenitor cells (EPCs).
b. The pro-coagulation environment reduces the degradation of extracellular matrix(ECM), resulting in a profibrotic effect, and inducing differentiation of fibroblasts into myofibroblasts via proteinase-activated receptors

Question 9

during IPF development what is established

Answer 9

chemokine networks

Question 10

chemokine networks

Answer 10

a. Macrophages immediately produce cytokines that stimulate an inflammatory response, and later participate to the transition to a reparative environment, recruiting fibroblasts, epithelial and endothelial cells.
b. When injury persists, neutrophils and monocytes are recruited.
c. The production of reactive oxygen species (ROS) worsens epithelial damages, and an imbalance between antioxidants and pro-oxidants may lead to epithelial cells apoptosis and dysfunctional pathways activation
d. The role of lymphocytes is still debated; certain lymphocytic cytokines are considered profibrotic, with direct effects on fibroblasts and myofibroblasts activity. Th-1, Th-2 and Th-17T-cells have been linked to IPF pathogenesis.

Question 11

what occurs after coagulation, inflammation and chemokine network development

Answer 11

1. Leukocyte infiltration

2. Activation of AEC proliferation

Question 12

after activation of AEC proliferation

Answer 12

fibroblast recruitment, proliferation and differentiation

Question 13

fibroblast recruitment, proliferation and differentiation

Answer 13

a. Fibroblasts are tissue mesenchymal cells committed to re-establish a normal and well-structured ECM in wound healing repair process. During IPF pathogenesis both lung and fibrocytes-derived fibroblasts are persistently exposed to profibrotic mediators secreted by activated fibroblasts, leading to ECM production and trans-differentiation to myofibroblasts.
b. The most important stimulating factor for trans-differentiation is TGF-β1, but also PDGF plays a significant role.

Question 14

what causes the loss of organ function experienced in IPF

Answer 14

a. Myofibroblasts have contractile properties due to αSMA, similarly to smooth muscle cells (SMCs); the main difference between these cells is the irreversibility of contraction of myofibroblasts, that may regulate collagen remodelling, inducing a spatial re-organization of collagen fibrils, increasing mechanical stress and leading to a stiffer ECM.

Question 15

which pro-inflammatory cytokine is most implicated

Answer 15

TGF-B