Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Immunology

Background:

• Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease characterized by lung cysts and progressive respiratory failure.
• LAM pathogenesis involves tuberous sclerosis complex (TSC) gene mutations leading to dysregulated mechanistic target of rapamycin (mTOR) activity in LAM cells.
• Lung nodules in LAM, composed of LAM cells and fibroblasts, contain mast cells, whose role in the disease remains unclear.

Purpose of the Study:

• To elucidate the mechanism of mast cell accumulation in LAM lung nodules.
• To investigate the functional role of mast cells in the pathogenesis of LAM.

Main Methods:

• Gene expression analysis using transcriptional profiling and qRT-PCR.
• In vitro studies using spheroid TSC2-null cell/fibroblast cocultures to model LAM nodule formation and mast cell interactions.
• In vivo studies utilizing an immunocompetent Tsc2-null murine homograft model.

Main Results:

• LAM cell/fibroblast cocultures induced CXC chemokine expression, attracting mast cells expressing CXCR1 and CXCR2.
• Mast cell presence around LAM nodules correlated with accelerated lung function decline.
• Mast cell tryptase release stimulated fibroblast proliferation and LAM spheroid growth, effects inhibited by tryptase inhibitors and sodium cromoglycate (SCG); SCG also reduced tumor burden in vivo.

Conclusions:

• Interactions between LAM cells and fibroblasts attract mast cells, and mast cell-derived tryptase contributes significantly to LAM progression.
• Sodium cromoglycate (SCG) demonstrates potential in inhibiting mast cell activation and reducing disease burden.
• Repurposing SCG warrants investigation as a potential adjunctive or alternative therapy to mTOR inhibitors for LAM patients.