Vitamin A levels are associated with a decrease in lymphangioleiomyomatosis progression and MITF-mediated cell growth

Background Lymphangioleiomyomatosis (LAM) is a metastatic cystic lung disease characterized by cysts lined with nodules exhibiting cellular heterogeneity. These nodules contain smooth muscle–like LAM cells with melanosomal features (e.g., Pmel17) and mutations in the tuberous sclerosis complex (TSC) genes, TSC1 and/or TSC2 . Loss of TSC function leads to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway, and sirolimus, an mTOR inhibitor, is used to slow disease progression. Proteins involved in melanosome structure are regulated by the microphthalmia-associated transcription factor (MITF). Because vitamin A plays a critical role in lung development and deficiency leads to lung destruction, and because MITF is regulated by vitamin A metabolites, we hypothesized that vitamin A influences LAM disease progression. Methods Serum vitamin A (retinol) levels were measured in 653 patients with LAM over 4,502 clinical visits. Clinical phenotyping and pulmonary function testing were performed longitudinally. The effects of retinol metabolites on cultured lung-derived and circulating LAM cells were evaluated. Gene expression profiling was conducted on laser-capture microdissected (LCM) LAM nodules. Circulating LAM cells were characterized phenotypically and genotypically. Results Higher blood retinol levels were associated with higher percent-predicted FEV₁ and DLCO (both P < 0.001) in multivariate analyses adjusting for baseline pulmonary function, TSC status, mTOR inhibitor use, and time of visit. Patients with higher retinol levels exhibited a significantly slower annual decline in percent-predicted FEV₁ compared with those with lower levels ( P = 0.003). Approximately 80% of upregulated genes in LAM nodules were retinoic acid–dependent, including MITF . Retinol metabolites increased proliferation in heterogeneous cell cultures derived from LAM lungs, supporting a role for the microenvironment in regulating LAM cell behavior. Consistent with a role for vitamin A in LAM, circulating LAM cells expressed the prometastatic marker CD44v6, the retinoic acid receptor STRA6, and CD38, a gene upregulated by retinoic acid. Conclusion Retinol influences both lung-resident and circulating LAM cells, affecting normal lung tissue and MITF-dependent signaling pathways that may regulate cell proliferation, invasion, and disease progression. These findings suggest that vitamin A plays an important role in LAM pathobiology and may contribute to modulation of disease progression.