Fibrotic tissue deposition is a normal response to tissue injury. Fibrosis is the result of dysregulation of the tissue repair response, where there is excessive accumulation of the extracellular matrix (ECM) components such as collagen and fibronectin ® disruption of tissue architecture ® repetitive injury/assault results in further fibrosis (1)

Cytokines IL-1, IL-6, TNF and TGF-β promote IL-17 secreting cells ® IL-17A was identified as a key inducer of fibrosis in several different organ systems, including the lung, liver, kidney, heart, and skin (see Figure 1)

Figure 1: Divergent cytokine pathways drive fibrosis (Image source Henderson, Rieder & Wynn 2020) (1)

Chronic inflammation, recurring physical/mechanical/chemical damage, radiation, autoimmune dysfunction and pathogens are all implicated in the initiation of organ fibrosis. (2)

Organ Fibrosis is degenerative and effects multiple sites (2)

Fibrosis occurs as a disruption of ECM homeostasis

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These proteins and molecules are therefore potential therapeutic targets e.g. PI3K/Akt and TGF β inhibitors

Figure 2: Development of collagen linearisation, stiffness and cross linking (Image source Cox and Erler 2014) (2)

FIBROSIS AND CANCER

“The epithelial to mesenchymal transition (EMT) now takes centre stage as the convergence point between inflammation and the progression of degenerative fibrotic diseases and cancer.” (4)

Chronic inflammation leads to fibrosis ® predisposes tissues to cancer initiation (5)

Up to 20% of cancers are linked to chronic inflammation-related fibrosis. Pathogenesis of fibrosis may be infectious or autoimmune aetiologies including gastric, head and neck, breast, hepatocellular, oesophageal, colon, pancreatic, cervix, and vulvar cancers (5)

In early stages of some tumour development, thickening of the ECM and stromal cells act to restrain tumour development ® over time stromal cells undergo ‘metabolic reprogramming’ to support cancer growth ® may lead to metastasis (5) (see Figure 2)

Tissue fibrosis, notably pulmonary fibrosis is a by-product of chemotherapy agents such as methotrexate, bleomycin and gemcitabine. (5)

Breast cancer is directly associated with secondary issues such as hepatic inflammation and fibrosis. (6)

Primary tumour fibrosis is driven by the tumour cells via recruitment of fibroblasts, macrophages and leukocytes leads to stroma expansion / desmoplasia (7)

Tumour cells are found in circulation/TME but do not always lead to metastatic disease ® therefore the microenvironment of the secondary sites must have tumour supporting factors to support metastatic colonisation. (2)

TGF β expression is implicated in multiple modes of proinflammatory expression to induce elevated fibronection and type1 collagen ® excess fibrillar collagen ® fibrosis (8, 9)

ACTIVE COMPONENT

PHARMACOLOGY & MECHANISMS

Quercetin

·       Modulates AKT activation in senescent normal lung and idiopathic pulmonary fibroblast ® disruption of cell survival pathway (10)

·       Reverses bleomycin induced pulmonary fibrosis (10)

·       Suppresses protein expression of collagen I (10)

Baicalein

·       Inhibits ECM / Fibroblast activation of TGF β1 and PDFG-induced human dermal fibroblasts in systemic sclerosis (11)

·       Suppresses IL-6 and TNF-α ®  inhibits hepatic stellate cell activation / reduces ALT, AS, Laminin, collagens and hyaluronic acid ® ameliorates liver fibrosis (12)

Baicalin

·       Mediates the CaMKII and PI3K/AKT signalling pathways to inhibit histopathological damage and lung fibroblast proliferation (13)

·       Decreases collagen deposition, lung coefficient and hydroxyproline via ERK1/2 pathway ® antifibrotic effect via adenosine A2A receptor (12)

·       Inhibits inflammation through NF-κB and inflammasome pathway (12)

Salvianolic Acid B

·       Increases and regulates expression of HO-1, OSD and GSH-Px; inhibits NOX-2 and NOX-4 etc ® inhibits ROS and lipid peroxidation; Inhibits TNF-α/NF-κB and TLR4/ NF-κ-B signalling pathways ® reduction of myofibroblast proliferation ® ameliorates fibrosis (liver) (14)

·       Mechanisms of action in chronic inflammatory diseases, including pulmonary fibrosis can be seen in Figure 4

Emodin

·       Decreases HMGB1 and IKKγ protein expression ® inhibits expression of p-IκBα and p65 in cells ® interfering with p65, NF-κB expression in the nucleus ® reduces pulmonary fibrosis (15)

·       Regulates apoptosis and collagen production in hepatic stellate cells ®inhibits fibrosis formation (15)

·       Mechanisms and signalling pathways of Emodin can be seen in Figures 5-7

Artemisinin

·       Suppresses expression of  a-SMA and type IV collagen in lungs ®suppression of notch signalling in lung fibrobalsts ® decreased fibroblast activation ®reduced pulmonary insult (bleomycin) induced fibrotic response (3)

·       Reduces VEGF and VEGF2 expression in tumour and endothelial cells within the tumour body ® reduces blood vessel density within tumour ®reduces fibrosis development and progression (3)

Oridonin

·       Inhibits NLRP3 inflammasome ® ameliorates carbon tetrachloride-induced liver fibrosis (16)

·       Promotes Nrf2-depenent antioxidative and Nrf2-independent anti-inflammatory effects on LPS induced acute lung injury (16)

·       Suppresses α-SMA and COL1A1 in TGF-b1-induced MRC-5 cells in pulmonary fibrosis (16)

REFERENCES

Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-66.

Cox TR, Erler JT. Molecular Pathways: Connecting Fibrosis and Solid Tumor Metastasis. Clinical Cancer Research. 2014;20(14):3637-43.

Dolivo D, Weathers P, Dominko T. Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics. Acta Pharm Sin B. 2021;11(2):322-39.

López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1(6-7):303-14.

Chandler C, Liu T, Buckanovich R, Coffman LG. The double edge sword of fibrosis in cancer. Translational Research. 2019;209:55-67.

Sannappa Gowda NG, Shiragannavar VD, Puttahanumantharayappa LD, Shivakumar AT, Dallavalasa S, Basavaraju CG, et al. Quercetin activates vitamin D receptor and ameliorates breast cancer induced hepatic inflammation and fibrosis. Frontiers in Nutrition. 2023;10.

Shekhar MP, Pauley R, Heppner G. Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 2003;5(3):130-5.

Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJD, Morris D, et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proceedings of the National Academy of Sciences. 2000;97(4):1778-83.

Finkelstein JN, Johnston CJ, Baggs R, Rubin P. Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis. Int J Radiat Oncol Biol Phys. 1994;28(3):621-31.

Hohmann MS, Habiel DM, Coelho AL, Verri WA, Jr., Hogaboam CM. Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo. Am J Respir Cell Mol Biol. 2019;60(1):28-40.

Peng B, Hu Q, He R, Hou H, Chen Y, Li H, et al. Baicalein alleviates fibrosis and inflammation in systemic sclerosis by regulating B-cell abnormalities. BMC Complementary Medicine and Therapies. 2023;23.

Hu Z, Guan Y, Hu W, Xu Z, Ishfaq M. An overview of pharmacological activities of baicalin and its aglycone baicalein: New insights into molecular mechanisms and signaling pathways. Iran J Basic Med Sci. 2022;25(1):14-26.

Zhao H, Li C, Li L, Liu J, Gao Y, Mu K, et al. Baicalin alleviates bleomycin‑induced pulmonary fibrosis and fibroblast proliferation in rats via the PI3K/AKT signaling pathway. Mol Med Rep. 2020;21(6):2321-34.

Xiao Z, Liu W, Mu Y-p, Zhang H, Wang X-n, Zhao C-q, et al. Pharmacological Effects of Salvianolic Acid B Against Oxidative Damage. Frontiers in Pharmacology. 2020;11.

HaoShang, Jia X, Liu H, Zhang X, Shao Y. A comprehensive review of emodin in fibrosis treatment. Fitoterapia. 2023;165:105358.

Li X, Zhang C-T, Ma W, Xie X, Huang Q. Oridonin: A Review of Its Pharmacology, Pharmacokinetics and Toxicity. Frontiers in Pharmacology. 2021;12.