Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis
نویسندگان
چکیده
Rationale: Lymphangioleiomyomatosis (LAM) is a multisystem disease that causes lung cysts and respiratory failure. Loss of TSC (tuberous sclerosis complex) gene function results in clone “LAM cells” with dysregulated mTOR (mechanistic target rapamycin) activity. LAM cells fibroblasts form nodules also contain mast cells, although their significance unknown. Objectives: To understand the mechanism mast-cell accumulation role pathogenesis LAM. Methods: Gene expression was examined using transcriptional profiling qRT-PCR. Mast cell/LAM nodule interactions were vitro spheroid TSC2-null cell/fibroblast cocultures vivo an immunocompetent Tsc2-null murine homograft model. Measurements Main Results: LAM-derived induced multiple CXC chemokines fibroblasts. lungs had increased tryptase-positive expressing CXCRs (CXC chemokine receptors) (P < 0.05). located around periphery positively associated rate loss = 0.016). spheroids attracted this process inhibited by pharmacologic CRISPR/cas9 inhibition CXCR1 CXCR2. caused tryptase release, which fibroblast proliferation LAM-spheroid size (1.36 ± 0.24–fold; P 0.0019). The inhibitor APC366 sodium cromoglycate (SCG) cell–induced growth. In vivo, SCG reduced activation tumor burden (vehicle: 32.5.3% 23.6%; SCG: 5.5% 4.3%; 0.0035). Conclusions: LAM-cell/fibroblast attract where release contributes to progression. Repurposing for use should be studied as alternative or adjunct therapy.
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ژورنال
عنوان ژورنال: American Journal of Respiratory and Critical Care Medicine
سال: 2021
ISSN: ['1073-449X', '1535-4970']
DOI: https://doi.org/10.1164/rccm.202007-2854oc