Claudia Serrano

Introduction. Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown cause in which extracellular matrix deposition replaces healthy lung tissue leaving the architecture of alveoli irreparably damaged.¹ It is known that IPF usually occurs in patients over the age of 65 and is associated with exertional, labored breathing and chronic dry cough.^1,2 Susceptibility to IPF is exacerbated by environmental factors such as cigarette smoke, dust, and viral infections. In addition, pre-existing genetic factors are present in one third of IPF patients such as variants in the promotor region of MUC5B, which normally aids in defense against airway pathogens.³ After being diagnosed, prognosis for patients is only 2-5 years. Current leading treatments, which act through tyrosine kinase inhibition, have prohibitive costs of over $100,000 annually and have been found to only marginally slow disease progression. ¹ Therefore, the underlying mechanism of fibrosis development is currently being researched in order to discover a viable, therapeutic target for the prevention of original fibrotic formation in IPF. Methods Under light isoflurane anesthesia, subcutaneous bleomycin (BLM) has been been administered in mice in order to model pulmonary fibrosis.^4,5 In vitro and in vivo, extracellular matrix synthesis and myofibroblast differentiation have then been quantified by measuring the production of alpha-smooth muscle actin (α-SMA). The effects of 5-HT_2B receptor antagonists EXT5 and EXT9 have thus been examined according to their effects on serum cytokine levels, tissue density, as well as the presence of fibrosis biomarkers such as collagen producing cells, and myofibroblasts.⁴ Results BLM induced fibrotic mice exhibited elevated total proteoglycan production (P < 0.01) and α -SMA (P < 0.05). Following treatment with 5-HT_2B receptor antagonists EXT 5 or EXT 9 resulted in decreased levels of collagen-producing cells, myofibroblasts, TNF- α, and IL-1B in the modeled fibrosis. In regard to gene expression,  5-HT_2B receptor antagonism also significantly decreased levels of Cdkn1α (p < 0.05) which encodes p21, a protein associated with cell damage and cell cycle regulation. ⁵ Overall p21 levels were significantly reduced (p = 0.0024) as a result of 5-HT_2B antagonism. Conclusions These results indicate that 5-HT_2B receptor antagonism prevents fibrotic development in IPF through inhibition of extracellular matrix deposition and decreased myofibroblast differentiation. Suppressed levels of TNF- α and IL-1B indicate that 5-HT_2B receptors have an additional role in the inflammatory process of IPF. 5-HT_2B receptors are therefore promising pharmaceutical targets in the prevention of idiopathic pulmonary fibrosis^4,5

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4. Löfdahl A, Rydell-Törmänen K, Müller C, et al. 5-HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo. Physiol Rep. 2016;4(15): e12873. doi:10.14814/phy2.12873
5. Löfdahl A, Rydell-Törmänen K, Larsson-Callerfelt AK, et al. Pulmonary fibrosis in vivo displays increased p21 expression reduced by 5-HT2B receptor antagonists in vitro – a potential pathway affecting proliferation. Sci Rep 2018;8(1):1927. Published 2018 Jan 31. doi:10.1038/s41598-018-20430-0