The role of tryptophan metabolism in pulmonary fibrosis

The National Heart, Lung, and Blood Institute awarded $207,488 to the Regents of the University of Michigan on September 30, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct research into the role of tryptophan metabolism in idiopathic pulmonary fibrosis.

The research investigates how tryptophan metabolites, particularly those produced through the kynurenine pathway, activate immune signaling mechanisms that contribute to pulmonary fibrosis progression. The project examines tryptophan degradation enzyme (TDO) inhibition as a potential therapeutic target and determines whether downstream kynurenine pathway metabolites signal to dendritic cells to stimulate pro-inflammatory responses that drive fibrosis. Preliminary data from the research team's murine bleomycin-induced lung fibrosis model demonstrate that TDO inhibition provides significant protection against fibrosis, and human IPF patient samples show that TDO is uniquely expressed in alveolar fibroblasts of IPF patients but absent in healthy controls. The work aims to identify novel therapeutic approaches for idiopathic pulmonary fibrosis, a progressive fibrotic lung disease with median survival of 2–5 years following diagnosis.

The award is a Project Grant that supports this investigator-initiated research at the University of Michigan's Ann Arbor campus. Performance of work extends through September 29, 2027. The assistance type is a Project Grant.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lungs that is more common in aging and men, with 1 in 200 adults over age of 70 diagnosed. Patients have an estimated 2-5 years mean survival time following diagnosis, and only lung transplant is considered curative. Understanding the causes and immunological environment of the fibrotic lung could provide new targets for therapeutic or prophylactic treatment. Tryptophan metabolism is associated with increased inflammation in the lungs of IPF patients, as well as in our bleomycin-induced murine lung fibrosis model, producing several metabolites, such as kynurenine (KYN) that are recognized by the aryl-hydrocarbon receptor (AHR). AHR has been well-characterized as affecting the immune system through several mechanisms both pro- and anti-inflammatory. Preliminary data from our lab show that inhibiting one of the early enzymes in the kynurenine pathway (KP) of tryptophan metabolism, TDO, results in significant protection from fibrosis in our murine bleomycin (BLM) model. Data from human IPF patients support that TDO is uniquely expressed in alveolar fibroblasts of IPF patients, but not healthy controls. Furthermore, AHR is mostly highly expressed in dendritic cells (DCS) which play a critical role in fibrosis. We hypothesize that KP metabolites from fibroblasts are activating AHR in DCS to stimulate pro-inflammatory signals which in turn drive pulmonary fibrosis. The long term goal of this proposal is to understand how tryptophan metabolism impacts lung fibrosis in order to identify novel therapies for IPF. The objectives of this project are to determine how TDO inhibition affects downstream metabolites, and whether those metabolites are signaling to relevant immune cells which are important for fibrosis, specifically DCS, in a pro-inflammatory way. The specific aims of my proposal are: 1) to determine the in vivo effects of TDO inhibition on the KYN pathway and dendritic cells, and 2) to evaluate the mechanism of fibroblast-dendritic cell cross talk through EX vivo CO-culture and conditioned media experiments. Under the first aim, i will perform metabolomics on healthy mice and on mice with BLM-induced fibrosis with or without treatment with a TDO inhibitor in order to understand how fibrosis alters the metabolome of the lung and to establish the effect of TDO inhibition on downstream immunomodulatory metabolites. I will also perform rnaseq on primary DCS from the same conditions to determine how their maturation and pro-inflammatory pathways are altered, as well as evaluate their functional capacity to polarize naïve t-cells. Under the second aim, i will test primary fibroblasts, DCS, and t-cells of both our murine BLM model and human IPF patients to determine the specific mechanism of anti-fibrotic activity by both directly treating cells with TDO-inhibitors and tryptophan metabolites of interest, as well as using conditioned media experiments to evaluate signaling.