So today I am going to give you a further glimpse into my research. I am going to tell you about diseases, that I am trying to understand. But first lets consider asking a question.

When the wound heals normally, in worst case scenario you get a scar in the end. But what if the scarring never stopped?

Tip of the iceberg - examples of some fibrotic diseases
Adapted from an image by Виталий Смолыгин | Public Domain.

The burden of fibrotic diseases

If the skin wound did not stop scarring, you will get a disease called keloids. But these overscarring or fibrotic diseases are not only limited to skin. Fibrosis can be a cause or consequence of many chronic disease. No organ is spared. An epithelial or vascular injury in any organ or signals that mimic injury in absence of actual injury cause fibrotic disease of any organ you can name. In lungs you have pulmonary fibrosis. You can have fibrosis start in skin of limbs and spread to lungs - scleroderma. You can have scarring in the heart, or cardiac fibrosis, following an ischemic injury after a heart attack (Talman et al., 2016). This further leads to heart failure. If you drink too much alcohol, you are at risk of liver cirrhosis. If you don't drink alcohol, you can still have liver fibrosis in non alcoholic fatty liver disease (NAFLD). If you have diabetes you are at high risk of diabetic nephropathy or renal fibrosis (Kanasaki et al., 2013). You are also at high risk of having fibrosis in retina (diabetic retinopathy). We also have fibrotic cysts in PCOS (Zhou et al., 2017). Then there is vascular fibrosis in atherosclerosis (Lan et al., 2013). Well, even stroma of solid tumor is a fibrotic tissue (more on that later). To sum it up about 45% of deaths in the world can be attributed to one or the other fibrotic condition (Wynn, 2008).

When fibroblasts make their work an obsession

Wound healing vs fibrosis - the difference of persistent fibroblast activation
Illustrated by @scienceblocks

Fibrosis, can be thought of as an overscarring wound. At the core of all the fibrotic diseases are activated fibroblasts. In the previous article, I told you about these construction workers called fibroblasts. The fibroblasts are cells that live in connective tissue of the organ - such as dermis in skin. Their job is to secrete and maintain architecture of extracellular matrix (ECM), in the tissue. In a normal wound healing scenario the fibroblasts get activated on sensing the wound signal. The activated fibroblasts - multiply, migrate towards wound site, gains contractile property which helps in wound contraction, and overproduce extracellular matrix which seals the would. But once the wound is healed these fibroblasts need to be deactivated or die via apoptosis. However, some of these fibroblasts remain in wounded region remodeling the matrix for years. But what if fibroblasts fail to deactivate or die?

Well, in that case, you will have these activated fibroblasts secreting excessive ECM and also perturbed mechanical properties of the tissue. It would eventually lead to hardening of the tissue and loss of organ function as a result. This non stop scarring of organ, it's hardening and failure is referred to as fibrosis. (Wynn, 2008).

Why are fibroblasts chronically activated?

If you think of fibroblasts are the effector cells for causing fibrosis, then comes the question that why do these effectors die or deactivate during normal wound healing but not during fibrogenesis? What is it that is fueling the chronic activation of fibroblasts? There can be multiple factors contributing contributing to it. It is regulation by immune cells, signals secreted by epithelial cells and even mechanical and immunological feedback from fibroblasts themselves. All of these are vast topics and I would discuss them in upcoming posts dedicated to pathology of fibrosis. But let's have a brief look at them.

The role of epithelial cells

In the previous post I mentioned that epithelial cells are the first to sense the injury. They secrete signalling molecules which cause fibroblasts proliferation, migration and their differentiation into myofibroblasts. For instance epithelial cells secrete TGF-beta, angiotensin II and reactive oxygen species (ROS) (Sakai and Tager, 2013). While these signals are acute in case of wound, they are chronic in case of fibrosis The chronic nature can be due to a chronic injury to the organ, a repetitive injury or because of some gene being mutated or overexpressed that mimics a wound signal. One example of chronic signal is when epithelial cells express snail. Snail is a transcription factor known to cause epithelial to mesemchymal (fibroblast) transition (EMT) during embryonic development. Whether EMT is source of activated fibroblast or not is a debatable topic. Nevertheless, Snail overexpression is associated with many fibrotic diseases (Nakasaki et al., 2015, Bhattacharya et al., 2011).

Role of immune cells and inflammation.

A chronic injury is also site of chronic inflammation. If you remember from previous article then inflammation caused by invading neutrophil, macrophages and lymphocytes at wound site is acute. It lasts for few days. But, unresolved inflammation is known to cause overscarring of wound and fibrosis. Chronic wound signals from epithelial cells or positive feedback from fibroblasts can both cause chronic inflammation. Other causes of chronic inflammation could be an autoimmune condition or even injury induced due to graft rejection after organ transplant. The key here is inability to say goodbye to immune cells once the work is done (Desai et al., 2018, Wynn, 2008).

Positive feedback from mechanical cues

Another reason for chronically active fibroblast is response of fibroblast to mechanical tension around them. High mechanical tension activates fibroblast(Tschumperlin et al., 2014). Fibroblast in turn respond to this by increasing mechanical tension further. In this paper published by our lab you will see a protein called Fibuln5. Fibulin5 regulates the mechanical properties of extracellular matrix. In the mice model used in this paper, the epithelial cells constantly produce fibulin5, which increases the tension in collagen fibers (Nakasaki et al., 2015). And it just spirals down from there.

A remark on current treatments for fibrosis

Even though we understand some of the mechanisms for fibroblast activation and pathology of fibrosis, most of them clinical trials so far have been disappointing. For instance, TGF-beta is one of the strongest candidate in pathology of fibrosis(Walton et al., 2017). But, TGF-beta inhibitors have not proved so effective in clinical trials. Same holds for another pro-fibrotic factor endothelin. This could be because wound healing is so intimately related to survival of the organism that there are more than one signalling pathways for achieving the same result. Amd same might be true for fibrosis. We need to find a common link to break the loop. The future strategy hence include targeting proteins that might be responsible for producing the chronic wound signal. For instance targeting snail and targets downstream of snail sounds like a good idea. Targeting non receptor tyrosine kinases in fibroblasts and it's upstream activators is another promising approach (Distler et al., 2010). In yet another strategy, the researchers targeted mitochondria of activated fibroblasts to cause kill these cells via apoptosis (Lagares et al., 2017).

Which strategy would prove more efficient is something we will know with time. But I will like to end the article by saying, that finding a way to resolve fibrosis seems to hold the key to further improve average lifespan of our species. In future articles we will have a closer look at tumor stroma and then physical forces in wound, before coming back to fibrosis.

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References

1. Keloids

2. pulmonary fibrosis

3. scleroderma

4. Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res. 2016 Sep;365(3):563-81. doi:10.1007/s00441-016-2431-9. Epub 2016 Jun 21. Review. PubMed PMID: 27324127; PubMed Central PMCID: PMC5010608.

5. Liver cirrhosis

6. NAFLD

7. Kanasaki K, Taduri G, Koya D. Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne). 2013;4:7. Published 2013 Feb 6. doi:10.3389/fendo.2013.00007

8. Zhou F, Shi LB, Zhang SY. Ovarian Fibrosis: A Phenomenon of Concern. Chin Med J (Engl). 2017;130(3):365-371.

9. Lan TH, Huang XQ, Tan HM. Vascular fibrosis in atherosclerosis.

10. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199-210.

11. The biology and physics of wound healing (part 1 - the cellular players and dynamics of healing).

12. Sakai N, Tager AM. Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis. Biochim Biophys Acta. 2013;1832(7):911-21.

13. Nakasaki et al., 2015, The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis

14. Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2011;8(1):42-54. Published 2011 Oct 25. doi:10.1038/nrrheum.2011.149

15. Desai O, Winkler J, Minasyan M, Herzog EL. The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Front Med (Lausanne). 2018;5:43. Published 2018 Mar 20. doi:10.3389/fmed.2018.00043

16. YAP and TAZ drive matrix stiffness-dependent fibroblast activation (1180.6). Daniel Tschumperlin, Xaralabos Varelas, and Fei Liu, 2014.

17. Walton KL, Johnson KE, Harrison CA. Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis. Front Pharmacol. 2017;8:461. Published 2017 Jul 14. doi:10.3389/fphar.2017.00461

18. Distler JH, Distler O. Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis. 2010 Jan;69 Suppl 1:i48-51. doi: 10.1136/ard.2009.120196. Review. PubMed PMID: 19995744.

19. Lagares D, Santos A, Grasberger PE, Liu F, Probst CK, Rahimi RA, Sakai N, Kuehl T, Ryan J, Bhola P, Montero J, Kapoor M, Baron M, Varelas X, Tschumperlin DJ, Letai A, Tager AM. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci Transl Med. 2017 Dec 13;9(420). pii:eaal3765. doi: 10.1126/scitranslmed.aal3765. PubMed PMID: 29237758.