By Conor Sugden, University of Liverpool
Inflammatory mechanisms and processes contribute to the pathogenesis of a number of conditions – one of which is fibrosis. Inflammation and fibrosis are intrinsically linked, and much about their complex relationship is still unknown.
Whereas a healthy inflammatory response is necessary for successful wound healing, a prolonged response often precedes tissue fibrosis. Complicating this, anti-inflammatory molecules such as TGF-β exhibit a pro-fibrotic effect, highlighting the need to achieve a greater understanding of the link between inflammation and fibrosis.
An Umbrella Term
Fibrosis is a part of many diseases; including idiopathic pulmonary fibrosis (IPF), liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis, and it is estimated that fibrosis contributes to ~45% of deaths in the developed world. In the UK, over 32,000 people suffer from IPF alone, and prevalence of the disease is increasing.
Fibrosis is the abnormal or excessive accumulation of extracellular matrix (ECM). The ECM has traditionally been viewed as a scaffold to support cell adhesion and migration, although it is being realised that it is indeed is much more complex than this. An incredible variety of stimuli cause the ECM to undergo remodelling in fibrotic diseases, and although understanding of the mechanisms of fibrosis is increasing at an exciting rate, there is still much to learn. Intensified ECM deposition is a normal response to injury, however sustained deposition leads to its thickening, which can affect normal tissue properties and may lead to eventual organ failure.
A Delicate Balance
At the moment, it is difficult to predict if injuries will heal without fibrosis, as some wounds heal without scarring, as with foetal wounds. In adults, inflammatory cells respond to the initial insult by cleaning up the wound and producing signalling proteins and growth factors. It is with the release of these molecules that the remodelling of the ECM is orchestrated. Whereas overproduction of ECM of course leads to fibrosis, chronic wounds can develop if remodelling is not completed; another serious problem.
The potential role that the ECM has in regulating inflammation is now being recognised. Evidence is accumulating that the ECM has a significant role in immune cell recruitment and activation; a growing research area. Of the cells involved in both inflammation and fibrosis, macrophages may be seen as the ‘master regulators’, playing different roles at different stages of inflammation. More work is needed to uncover the exact roles and activation pathways of macrophages, and all cells involved in the inflammatory response, as (although very important) macrophages are by no means solely responsible for fibrosis following inflammation. ECM research is moving at an exciting pace, and as we improve the tools needed to properly investigate the ECM, the field will continue to expand.
The relationship between inflammation and fibrosis is complex, and our understanding of the intricacies of this relationship is still in its infancy. Targeting inflammation should be investigated when searching for therapies for fibrosis, moreover, fibrosis must remain in the minds of those targeting inflammation as a potential downstream consequence.
Furthermore, we must strive to develop a greater understanding of the direct interactions between the ECM and the inflammatory response.
- Wynn, T. (2008). Cellular and molecular mechanisms of fibrosis. The Journal of Pathology, 214(2), pp.199-210.
- Friedman, S., Sheppard, D., Duffield, J. and Violette, S. (2013). Therapy for Fibrotic Diseases: Nearing the Starting Line. Science Translational Medicine, 5(167), pp.167sr1-167sr1.
- British Lung Foundation. (2017). Idiopathic pulmonary fibrosis statistics. [online] [Accessed 12 Feb. 2017]
- Sorokin, L. (2010). The impact of the extracellular matrix on inflammation. Nature Reviews Immunology, 10(10), pp.712-723.
- Wynn, T. and Barron, L. (2010). Macrophages: Master Regulators of Inflammation and Fibrosis. Seminars in Liver Disease, 30(03), pp.245-257.
This post is the first in our inflammation series. If you are interested in reading more on this topic, you can also check out the August issue of The Biochemist magazine.