From Inflammation to Fibrosis: Mechanisms of Pathological Transition

Introduction: Why Does Inflammation Beget Fibrosis?

Acute inflammation is a normal physiological response to protect the body from infection and injury. However, if inflammation fails to resolve appropriately and becomes chronic, the tissue repair process runs out of control, transitioning into an irreversible pathological state called "fibrosis." This "Inflammation-to-Fibrosis Transition" is a pathological phenomenon common across organs and is gaining attention as a target for drug discovery. Based on findings from top journals like Nature, this article explains the cellular and molecular mechanisms driving this transition.

1. The "Face Change" of Macrophages: From M1 to M2

The most important cell in the transition from inflammation to fibrosis is the Macrophage. Macrophages undergo Polarization into "M1 type (Pro-inflammatory)" and "M2 type (Pro-reparative)" depending on the environment.

M1 Macrophages: The Igniters of Inflammation

• Activators: LPS, IFN-γ
• Secretions: TNF-α, IL-1β, IL-6 (Pro-inflammatory cytokines)
• Role: Elimination of pathogens, tissue destruction (necessary in the acute phase)

M2 Macrophages: Promoters of Repair and Fibrosis

• Activators: IL-4, IL-13 (Th2 cytokines)
• Secretions: TGF-β, IL-10 (Anti-inflammatory), PDGF (Growth factor)
• Role: Promotion of tissue repair, but accelerates fibrosis when excessive

The "M1 to M2 Shift" in Chronic Inflammation

In the acute phase, M1 type is dominant, but as inflammation becomes chronic, it gradually shifts to M2 type. This M2 type continuously secretes TGF-β, causing fibroblasts to differentiate into myofibroblasts and accelerating fibrosis (Frontiers in Immunology 2020).

2. TGF-β: The Key Cytokine Linking Inflammation and Fibrosis

TGF-β (Transforming Growth Factor-beta) is the "Master Regulator" governing the transition from inflammation to fibrosis.

The Duality of TGF-β

• Anti-inflammatory Action: Suppresses excessive inflammation in the acute phase (in coordination with IL-10).
• Pro-fibrotic Action: Activates fibroblasts and promotes collagen production.

In chronic inflammation, TGF-β is continuously released from damaged epithelial cells and M2 macrophages, shifting the process from the "termination" of inflammation to the "initiation of fibrosis."

3. EMT (Epithelial-Mesenchymal Transition): Epithelial Cells Turning into Fibroblasts

Another important mechanism is EMT (Epithelial-Mesenchymal Transition).

• Triggered by chronic inflammation and TGF-β stimulation, epithelial cells change into "Mesenchymal cells," i.e., fibroblast-like cells.
• This phenomenon is observed in many organs, including the lungs, kidneys, and liver.
• Cells undergoing EMT lose their original epithelial functions and conversely begin to produce ECM such as collagen.

4. Missing the "Stop Sign" of Inflammation: Runaway to Fibrosis

Why does inflammation transition to fibrosis? The key lies in the failure of inflammation resolution mechanisms.

• Lack of SPMs (Specialized Pro-resolving Mediators): Reduced production of lipid mediators (resolvins, maresins, etc.) that actively resolve inflammation.
• Impaired Efferocytosis (Phagocytosis of Dead Cells): Apoptotic neutrophils are not properly processed, leading to necrosis and exacerbating inflammation.
• Persistent Stimuli: Factors that cannot be eliminated, such as viral infection, autoimmunity, or exposure to chemicals.

When these overlap, the normal pathway of "Acute Inflammation → Resolution" is blocked, deviating into the pathological pathway of "Chronic Inflammation → Fibrosis" (Nature 2020).

Conclusion

Inflammation and fibrosis are two ends of a continuous spectrum. The reason why anti-inflammatory drugs alone cannot stop fibrosis is that fibrosis is driven by unique mechanisms distinct from inflammation. Approaches that not only "stop inflammation quickly" but also "prevent the transition to fibrosis" or "reverse already formed fibrosis" are required as next-generation therapeutic strategies.

Our disease models are the optimal platform to evaluate this complex transition process in stages and multilaterally verify the potential of novel therapeutics.

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References

1. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016;44(3):450-462.
2. Distler JHW, et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol. 2019;15(12):705-730.
3. Henderson NC, et al. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-566.