Current anti-fibrotic therapies

Question 1

BMP7

Answer 1

A factor involved in development and bone formation. BMP7 is part of the TGF-β superfamily (pro-fibrogenic) and might be important as anti-fibrotic agent.

Question 2

micro-RNAs(miRNA)

Answer 2

Short non-coding RNA, that regulate target mRNA through post-transcriptional repression mechanisms.

Question 3

Peroxisome proliferator-activated receptors (PPARs)

Answer 3

These are nuclear transcription factors that form a dimer with RXR. It has 3 subtypes: α, β-δ and γ.

Question 4

Relaxin

Answer 4

A polypeptide hormone needed to control fibrosis by stimulating MMPs (ECM degradation) and inhibiting TGF-β.

Question 5

TGF-b pathway

Answer 5

Inhibition of TGF-β is dangerous since it is important in a lot of other processes (cause side-effects!). Therefore target lower in the signaling pathway.

Question 6

What does the LPA1 receptor do?(4 things)

Answer 6

LPA1 promotes:
- fibroblast migration,
- vascular leak,
- eptithelial apoptosis and
- resistance to myofibroblast apoptosis.
These are the related to the pathogenesis ideopathic pulminairy fibrosis.

Question 7

IL-4 and IL-13

Answer 7

Both are mediators of immune reaction and are more highly expressed in fibrotic diseases.

Question 8

Pentraxin-2

Answer 8

An endogenous protein that regulates the immune response. It promotes repair and inhibits fibrosis by inhibiting the differentiation of monocytes into fibrocytes and macrophages can only differentiate into pro-resolution macrophages.

Question 9

What it the difference between BMP7 and TGF-β?

Answer 9

The BMP7 receptor phosphorylates SMADs 1/5/8 instead of Smad 2/3.

Question 10

What is the role of BMP7 in fibrosis?

Answer 10

In fibrosis BMP7 is downregulated, but it can be used as an antagonist to TGF-β. This has antifibrotic effects.

Question 11

What are 3 downsides to BMP7?

Answer 11

• High doses are needed
• Low bioavalability
• High chance of off target effects

Question 12

What is the role of miRNAs in fibrosis?

Answer 12

There are many miRNAs which are over- or under expressed in fibrosis, which can lead to pro- or anti- fibrotic effects.

Question 13

When is mi-RNA effective treatment for fibrosis?

Answer 13

Mi-RNAs have shown promising effect in treatment of cardiac fibrosis and CF.

Question 14

What is the role of PPARα in fibrosis?

Answer 14

PPAR α agonists prevent lipid oxidation (liver) and has anti-fibrotic effects in different types of fibrosis

Question 15

What is the role of PPARγ in fibrosis?

Answer 15

PPAR γ agonists plays a role in fibrosis control (focus on liver again)

Question 16

What is the role of PPARβ-δ in fibrosis?

Answer 16

PPAR β-δ agonists not very well known

Question 17

What is the receptor for Relaxin?

Answer 17

RXFP1

Question 18

How can LPA1 be used to combat fibrosis?

Answer 18

Small-molecule antagonists are promising as therapeutic to reduce its pathogenic role in injury and fibrosis.

Question 19

How can IL-4 and IL-13 be used to combat fibrosis?

Answer 19

Antibodies can target these cytokines or the IL-receptor.

Question 20

Why is pentraxin-2 an attractive therapeutic option?(3 reasons)

Answer 20

• localizes to the site of injury
• inhibits fibrosis
• promotes repair

Question 21

LoxL2

Answer 21

Promotes crosslinking.

Question 22

GS-6624

Answer 22

Non compaditive allosteric anti-body Inhibitor of LoxL2. This antibody leads to less myofibroblasts, less ECM production and less expression of TGF-beta. The positive feedback loop that leads to fibrosis is broken by this molecule.