Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis.
| Autor: | Babaei-Jadidi, Roya, Dongre, Arundhati, Miller, Suzanne, Uribe, Marcos Castellanos, Stewart, Ian D., Thompson, Zoe M., Nateri, Abdolrahman S., Bradding, Peter, May, Sean T., Clements, Debbie, Johnson, Simon R., Castellanos Uribe, Marcos, Stewart, Iain D |
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| Předmět: |
TRYPTASE
DISEASE progression LYMPHANGIOMYOMATOSIS LUNG diseases DISEASES in women CANCER cell culture RESEARCH FIBROBLASTS ANIMAL experimentation RESEARCH methodology LUNG tumors MEDICAL cooperation EVALUATION research LYMPHATIC tumors HYDROLASES COMPARATIVE studies MAST cells GENES CELLS CHEMOKINES MICE |
| Zdroj: | American Journal of Respiratory & Critical Care Medicine; 8/15/2021, Vol. 204 Issue 4, p431-444, 14p |
| Abstrakt: | Rationale: Lymphangioleiomyomatosis (LAM) is a multisystem disease that causes lung cysts and respiratory failure. Loss of TSC (tuberous sclerosis complex) gene function results in a clone of "LAM cells" with dysregulated mTOR (mechanistic target of rapamycin) activity. LAM cells and fibroblasts form lung nodules that also contain mast cells, although their significance is unknown. Objectives: To understand the mechanism of mast-cell accumulation and the role of mast cells in the pathogenesis of LAM. Methods: Gene expression was examined using transcriptional profiling and qRT-PCR. Mast cell/LAM nodule interactions were examined in vitro using spheroid TSC2-null cell/fibroblast cocultures and in vivo using an immunocompetent Tsc2-null murine homograft model. Measurements and Main Results: LAM-derived cell/fibroblast cocultures induced multiple CXC chemokines in fibroblasts. LAM lungs had increased tryptase-positive mast cells expressing CXCRs (CXC chemokine receptors) (P < 0.05). Mast cells located around the periphery of LAM nodules were positively associated with the rate of lung function loss (P = 0.016). LAM spheroids attracted mast cells, and this process was inhibited by pharmacologic and CRISPR/cas9 inhibition of CXCR1 and CXCR2. LAM spheroids caused mast-cell tryptase release, which induced fibroblast proliferation and increased LAM-spheroid size (1.36 ± 0.24-fold; P = 0.0019). The tryptase inhibitor APC366 and sodium cromoglycate (SCG) inhibited mast cell-induced spheroid growth. In vivo, SCG reduced mast-cell activation and Tsc2-null lung tumor burden (vehicle: 32.5.3% ± 23.6%; SCG: 5.5% ± 4.3%; P = 0.0035). Conclusions: LAM-cell/fibroblast interactions attract mast cells where tryptase release contributes to disease progression. Repurposing SCG for use in LAM should be studied as an alternative or adjunct to mTOR inhibitor therapy. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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