Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite

Abstract

Tissue fibrosis causes debilitating human diseases such as liver cirrhosis, heart failure, chronic kidney disease and pulmonary insufficiency. It is a dynamic process orchestrated by specific subsets of monocyte-macrophages, fibroblasts, pericytes and hepatic stellate cells. Fibrosis is linked to tissue inflammation. Pro-inflammatory macrophages promote fibrosis by driving myofibroblast differentiation and macrophage myofibroblast transition. Myofibroblasts express α-smooth muscle cell actin (α-SMA) and secrete extracellular matrix (ECM) proteins notably collagen I and III. Deposition of ECM proteins at injury sites and interstitial tissues distorts normal structure and impairs vital functions. Despite advances in the mechanisms of fibrosis at cellular, molecular and genetic levels, prevention and treatment of fibrotic diseases remain poorly developed. Recent reports suggest that 5-methoxytryptophan (5-MTP) is effective in attenuating injury-induced liver, kidney, cardiac and pulmonary fibrosis. It inhibits macrophage activation and blocks fibroblast differentiation to myofibroblasts. Furthermore, it inhibits hepatic stellate cell differentiation into myofibroblasts. As 5-MTP is an endogenous molecule derived from tryptophan catabolism via tryptophan hydroxylase pathway, it is well-suited as a lead compound for developing new anti-fibrotic drugs. This article provides an overview of 5-MTP synthesis, and a critical review of its anti-fibrotic activities. Its mechanisms of actions and potential therapeutic value will be discussed.

Astragaloside IV Ameliorates Isoprenaline-Induced Cardiac Fibrosis in Mice via Modulating Gut Microbiota and Fecal Metabolites

“…Cardiac fibrosis (CF) is characterized by cardiac fibroblasts hyperproliferation and extracellular matrix accumulation, which ultimately becomes an irreversible contributor to heart failure (HF) ( Travers et al., 2016 ; Wu, 2021 ). CF is an inevitable pathological process of HF.…”

Predictive Value of 5-Methoxytryptophan on Long-Term Clinical Outcome after PCI in Patients with Acute Myocardial Infarction-a Prospective Cohort Study

“…Through their interactions, they stimulate fibroblasts to differentiate into myofibroblasts, which release collagen and ECM proteins to cause myocardial fibrosis (MF). Thus, macrophage-mediated inflammatory tissue injury and MF are the primary pathophysiological processes that lead to LVR and HF after MI [9,23].…”

“…Additionally, 5-MTP can inhibit the proliferation and migration of tumor cells by hampering the p38-MAPK/ NF-kB pathway, stenosis caused by the vascular injuryinduced proliferation of endothelial and smooth muscle cells, chronic kidney disease (CKD) progression as well as renal and liver fibrosis as seen in various studies on tumorigenesis [8], inflammation inhibition [9], peripheral artery disease [10], CKD [11], and liver fibrosis [12].…”

5-Methoxytryptophan alleviates atrial structural remodeling in ibrutinib-associated atrial fibrillation

“…Emerging evidence indicates that the decrease in 5-MTP levels in ischemic heart tissue may be associated with the inhibition of tryptophan hydroxylase-1 by proinflammatory mediators [ 19 ]. Additionally, 5-MTP has been shown to effectively prevent injury-induced liver, kidney, heart, and lungs, by inhibiting macrophage activation and preventing fibroblast differentiation [ 20 ]. Our study confirmed that 5-MTP significantly inhibited inflammation, decreased LA fibrosis, and reduced AF vulnerability in rats treated with ibrutinib-treated.…”