Fibrosis is associated with 45% of all deaths in the developed world and yet no effective treatments exist to prevent or reverse it (Wynn, 2007). Fibrosis is where healthy tissue is replaced by scar tissue. Fibrosis can affect all major tissues in the body including the lungs, heart and skin.

The scar tissue, which is thick and rigid, is formed by a dysregulated accumulation of collagen, which is the most abundant protein in the human body and is found mostly in connective tissues.

Idiopathic pulmonary fibrosis (IPF), which is a type of chronic lung fibrosis, is one of the most common types of fibrosis in humans. As the lung is 25% connective tissue, fibrosis can cause great damage to lung function (Pyeritz, 2017). The exact cause of IPF is unknown. The current theory is that it is triggered by damage to the cells lining the lung alveoli, caused by viruses or exposure to toxic substance, such as tobacco smoke (Mostafaei et al., 2021).

IPF is characterised by progressive scarring of lung tissue and the accumulation of collagen fibres in the alveolar spaces (air sacs) of the lungs, making gaseous exchange inefficient and reducing pulmonary function (Todd et al., 2015). The walls in the lungs become stiff and inflexible, which makes the physical act of breathing difficult for people with IPF as their lungs do not expand easily to let air enter (Swigris et al., 2005).

In a healthy lung, a lung injury, such as a lung infection, leads to activation and recruitment of fibroblasts, which are the predominant collagen producing cell (Wynn, 2008). Fibroblasts deposit the appropriate amount of collagen and the lung injury is healed. Collagen also provides great strength to tissue and is particularly prevalent in tissues that must resist stress and pressure, such a tendons (Rozario and Desimone, 2011). Collagen is deposited after wounding to repair internal injury and close wounds (Mathew-Steiner, Roy and Sen, 2021).

Conversely, in an IPF lung, a lung injury results in an overproduction of collagen by fibroblasts and scar tissue is formed. Studies have shown that a type of immune cell, called a macrophage, can also deposit collagen directly at a wound site, whereas previously it was thought that only fibroblasts possessed this function (Simões et al., 2020). These studies guided the hypothesis that macrophages and fibroblasts communicate in wound sites to manage collagen deposition and in IPF they may communicate incorrectly to deposit excess collagen.

I study the interaction between fibroblasts and macrophages, and how their inappropriate communication may lead to collagen dysregulation.

Experimental Methods

To study the interaction between fibroblasts and macrophages, co-culture experiments were conducted. These experiments involve culturing (growing) fibroblasts with or without macrophages to see what affect macrophages have on collagen deposition by fibroblasts.

When the fibroblasts are cultured with macrophages, the amount of fibroblast-derived collagen increases, compared to when fibroblasts are grown on their own. This suggests the two cell types communicate and macrophages provide fibroblasts with some kind of signal, to produce more collagen. This signal is likely beneficial in homeostasis. For example, after a viral lung infection, macrophages help to repair damage by promoting the migration and proliferation of fibroblasts, resulting in tissue repair. But if macrophage-fibrosis signal is inappropriate, macrophages may not stop signalling to fibroblasts and collagen accumulation and eventual production of fibrotic tissue will occur.

It is also thought that circadian clocks, which are the body’s natural timing device, may have an effect on collagen regulation. Circadian clocks function as a self-sustained oscillator to ‘keep time’, as biological processes must be turned on and off at different points throughout a 24-hour cycle to achieve homeostasis.

Some genes responsible for regulating collagen synthesis are clock controlled and it has been shown that collagen synthesis occurs during the night. This means that, in a healthy person, any collagen degradation that occurs during the day, due to general wear and tear, is offset by collagen replenishment at night (Chang et al., 2020). We therefore hypothesise that perturbations in clock genes can alter when, and how much, collagen is made.

Experiments to record the circadian clock of fibroblasts were conducted. The results showed that macrophages can restart the circadian clock in fibroblasts. As the clock is needed for proper collagen regulation (collagen is regulated by clock genes), these results suggest that macrophages can influence when collagen is made by fibroblasts, simply by altering the circadian clock in fibroblasts.

Taken together, data shows that although fibroblasts are the predominant collagen producing cell, macrophages play a significant role in regulating its production.

Chang, J. et al. (2020) ‘Circadian control of the secretory pathway maintains collagen homeostasis’, Nature Cell Biology, 22(1), pp. 74–86. doi: 10.1038/s41556-019-0441-z.

Mathew-Steiner, S. S., Roy, S. and Sen, C. K. (2021) ‘Collagen in wound healing’, Bioengineering, 8(5). doi: 10.3390/bioengineering8050063.

Mostafaei, S. et al. (2021) ‘The role of viral and bacterial infections in the pathogenesis of IPF: a systematic review and meta-analysis’, Respiratory Research, 22(1). doi: 10.1186/s12931-021-01650-x.

Pyeritz, R. E. (2017) ‘Connective Tissue in the Lung: Lessons from the Marfan Syndrome’, Annals of Internal Medicine, 102(2), pp. 289–290.

Rozario, T. and Desimone, D. W. (2011) ‘Dynamic View’, Regenerative Medicine, 341(1), pp. 126–140. doi: 10.1016/j.ydbio.2009.10.026.The.

Simões, F. C. et al. (2020) ‘Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair’, Nature Communications, 11(1). doi: 10.1038/s41467-019-14263-2.

Swigris, J. J. et al. (2005) ‘Patients’ perspectives on how idiopathic pulmonary fibrosis affects the quality of their lives’, Health and Quality of Life Outcomes, 3, pp. 1–9. doi: 10.1186/1477-7525-3-61.

Todd, N. W. et al. (2015) ‘Permanent alveolar collapse is the predominant mechanism in idiopathic pulmonary fibrosis’, Expert Review of Respiratory Medicine, 9(4), pp. 411–418. doi: 10.1586/17476348.2015.1067609.

Wynn, T. A. (2008) ‘Cellular and molecular mechanisms of fibrosis’, Journal of Pathology, pp. 199–210. doi: 10.1002/path.2277.

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