Inflammatory cell recruitment to LAM nodules drives tissue destruction in TSC lung disease: opportunities for drug repurposing

Grant holder: Professor Simon Johnson
: University of Nottingham 

Project status: Ongoing – due to finish 2 Oct 2018

Lymphangioleiomyomatosis (LAM) is a lung and lymphatic problem which occurs as part of tuberous sclerosis in adult women. As the prognosis of those with TSC improves, LAM is becoming a significant problem for some adults with the disease. Most women with TSC are mildly affected by LAM but for some it can become a serious problem causing collapsed lungs and breathlessness and eventually respiratory failure. Although drugs like rapamycin and Everolimus can slow the progression of LAM, some still progress despite treatment and new therapies are needed. The lungs of women with LAM contain abnormal cells with TSC gene mutations called LAM cells. Our research team has recently shown that LAM cells attract other cells called fibroblasts, which together can produce proteins that damage the lungs and attract inflammatory cells. This study will examine the mechanisms by which LAM cells and fibroblasts together attract mast cells, a specific type of inflammatory cell and how these mast cells contribute to lung damage in LAM. As mast cells are known to cause the growth of fibroblasts and the activation of lung damaging proteins and we will determine whether this occurs in LAM and importantly if existing drugs can block these processes. We will examine if the number of mast cells in the lungs of women with LAM is related to the severity of their lung disease and their clinical outcome. This work will determine the how mast cells are attracted to LAM lungs, the significance of this finding and whether drugs which affect mast cells could improve current treatments to reduce lung damage in those with TSC and LAM.

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