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Hung Nguyen, PhD







Pulmonary and Critical Care Medicine; and Rheumatology


Hung N. Nguyen*, Yunju Jeong, Yunhye Kim, Hyunbum Kim, Merriam T. Louis, Yaunghyun H Kim, Aidan Cullen, Humra Athar, Patrick Gavin, Muhammad D. Sheikh, Reshmi Manandhar, Ke Yuan, Michael B. Brenner, Edy Y. Kim

Principal Investigator

Edy Y. Kim


Autocrine LIF/LIFR loop amplifies multiple pro-fibrotic programs in lung fibroblasts and LIFR blockade reduces fibrosis in human IPF PCLS


Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD) with a high mortality rate. Current treatment options are limited in efficacy and have broad mechanisms. Highly targeted therapies for IPF have failed in part due to the diversity of pro-fibrotic stimuli upstream of fibroblasts. Here, we demonstrate that leukemia inhibitory factor (LIF), via its receptor (LIFR), is a “master amplifier” of multiple upstream pro-fibrotic activators, including IL-4, IL-13 and TGFb. We observed higher expression of LIF in bulk tissue RNAseq of human IPF lung explant vs. control as well as in single cell RNAseq of IPF vs. healthy fibroblasts from lung tissues. Also, following TGFb stimulation of human lung fibroblasts derived from ILD donors, LIF was strongly upregulated along with key fibrotic gene markers including COL1A1, COL1A2, POSTN and ACTA2. Using LIFR siRNA or blocking antibody, we found that blockade of LIF-LIFR signaling reduced the induction of pro-fibrotic program by TGFb. Moreover, blockade of LIFR signaling also reduced the pro-fibrotic effects of IL-4 or IL-13. This suggested that LIF acts via LIFR as an autocrine amplification loop in fibroblasts downstream of multiple pro-fibrotic stimuli. Notably, this loop operates independently of IL-11. Using small molecular inhibitors or siRNA against JAK kinases, JAK2 was found to act downstream of LIFR. To demonstrate that targeting LIFR was beneficial for treating fibrosis, we blocked LIFR in human IPF precision cut lung slice (PCLS) and observed significant reduction in fibrotic gene expression. As a master amplifier that integrates several upstream profibrotic or proinflammatory stimuli, LIF/LIFR may serve as a single target to address an unmet therapeutic need for treatment of a wide range of fibrotic and inflammatory disorders, including IPF or autoimmune diseases.

Clinical Implications

Diseases characterized by fibrosis include idiopathic pulmonary fibrosis (IPF),cirrhosis, systemic sclerosis, scleroderma, hypertrophic cardiomyopathy, dilated cardiomyopathy, atrial fibrillation, ventricular fibrillation, and other interstitial lung diseases.
Fibrosis is a leading cause of morbidity and mortality. Yet, there are only limited therapeutic options available. Currently, fibrosis-specific therapies are approved only for pulmonary fibrosis, and these therapies, at best, slow but do not stop the progressive fibrosis, morbidity and mortality.
LIFR can be an attractive therapeutic target as it is a “common downstream pathway” in fibroblasts in diseased contexts. In addition, we found that this mechanism regulates fibroblasts derived from multiple tissues including lung, heart, skin, and cancer. This implies that targeting LIFR will benefit fibrotic diseases from many organs such as the heart, skin, liver, and lung.