Fibrotic tissue formation and resolution

Question 1

How does fibrosis start?

Answer 1

When processes in wound healing are dysregulated, the result is chronic injury. (excessive) ECM production will lead to a fibrotic lesion. Fibrosis goes hand in hand with chronic inflammation, which will worsen the situation.

Question 2

Is fibrosis reversible?

Answer 2

Fibrosis is reversible under certain circumstances. Keep in mind that resolution of fibrosis is based on animal research and is not yet applicable to people.

Question 3

What are theraputic options for fibrosis?

Answer 3

What are theraputic option for fibrosis?

• Removal of the cause of injury
• Degradation of excessive ECM
• Elimination of fibrogenic myofibroblasts

Question 4

Theraputic option: Removal of the cause of injury

Answer 4

The underlying issue should be resolved. This is however only possible if the disease is well known.

Question 5

Theraputic option: Degradation of excessive ECM

Answer 5

ECM can be broken down by using (for example) matix metallo proteases (MMPs). Degradation is harder when the ECM is crosslinked. Macrophages are importent for this process because they produce both growth factors and MMPs depending on the phase of wound healing

Question 6

Crosslinked ECM

Answer 6

Lysyl oxidase (LOX) can create links between collagen fibers and/or elastin fibers.

Question 7

Theraputic option: Elimination of (fibrogenic) myofibroblasts(4 ways)

Answer 7

4 possible ways of removal/deactivation:

a. Apoptosis: induce self-destruction of the cell. Mind that myofibroblasts in fibrotic tissue seem to have resistance to apoptosis due to anti-apoptotic and pro-survival genes.
b. Senescence: inducing an irreversible type of cell cycle arrest. Cells in this senescence state are quickly destroyed by immune cells.
c. Dedifferentiation: differentiate the myofibroblasts back into an inactive form/state
d. Reprogramming: dedifferentiate or transdifferentiate into other cell types which are less harmful (like hepatocytes or cardiomyocytes).