Breaking a Novel Feedback Loop to Inhibit Fibrosis Grant uri icon


  • Fibrosing diseases such as pulmonary fibrosis are associated with up to 45% of the deaths in the US.In these diseases, inappropriate scar tissue called fibrotic lesions forms in internal organs. There are no FDA-approved therapies that reverse fibrosis, and much remains to be known about mechanisms driving fibrosis. Infibrotic lesions in mouse and human lungs, there is an increase in the levels of sialidases, enzymes thatremove sialic acids from the distal tips of extracellular glycoproteins and other glycoconjugates. Sialidasesappear to potentiate fibrosis at least in part by increasing levels of the pro-fibrotic cytokine TGF-β1 producedby some immune system cells. Conversely, TGF-β1 causes lung epithelial cells, lung fibroblasts, and someimmune system cells to upregulate sialidases. Our hypothesis is that fibrosis is driven in part by a runawaypositive feedback loop where sialidase potentiates fibrosis and fibrosis potentiates sialidase. In support of thishypothesis, we found that injections of two different sialidase inhibitors reduce pulmonary fibrosis in the mousebleomycin model. To gain insight into what appears to be a fundamental mechanism linking the immunesystem to lung epithelial cells and fibroblasts, as well as a mechanism that helps drive fibrosis, we proposethree specific aims. Since identifying the key sialidase(s) that is/are upregulated in fibrosis will identify potentialtargets to inhibit fibrosis, our first aim is to test the hypothesis that a sialidase called NEU3 is the majorsialidase that potentiates fibrosis. Our second aim is to determine which immune system cells respond tosialidases and elucidate the receptor(s) whereby immune system cells sense the upregulated sialidases, andthus identify potential targets to block the feedback loop. Our third aim is to determine how sialidases cause anupregulation of TGF-β1, thus essentially working backwards on the sialidase sensing pathway toward the Aim2 work. Together, this work will help to elucidate a novel mechanism that regulates the innate immune systemand fibrosis, and may lead to new therapies for fibrosing diseases.

date/time interval

  • 2018 - 2022