Molecular Pathogenesis of Lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.Keywords: tuberous sclerosis; TSC1; TSC2; mTOR; signal transduction; estrogen Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease of uncertain etiology that affects young women. LAM cysts are formed as a result of the proliferation of an abnormal smooth muscle-like cell, the LAM cell. The mechanism by which LAM cells cause this architectural distortion of the lung is unknown. The clinical course of LAM is frequently inexorable, leading to death or lung transplantation in 10 to 15 years, although recent studies indicate that there is much variability in the natural history of the disorder (1, 2). The most common clinical manifestation is the insidious onset of exertional dyspnea; patients may also experience a nonproductive cough. Other common features include spontaneous pneumothorax, which results from cyst rupture, and chylothorax, which results from obstruction of pulmonary lymphatics and hilar lymph nodes by the slowly proliferating LAM cells. Less frequently, hemoptysis or chyloptysis may occur (1, 2).Most of the current therapies for LAM are supportive in nature. Bronchodilators are offered because many patients have obstructive physiology, often with some degree of reversibility, on pulmonary function testing. Oxygen is provided to patients with significant hypoxia. Current recommendations stipulate

Serum Vascular Endothelial Growth Factor-D Prospectively Distinguishes Lymphangioleiomyomatosis From Other Diseases

“…The median serum VEGF-D level was elevated in S-LAM subjects without AMLs (1,142 [IQR 659-1,912] pg/mL) and not signifi cantly different from S-LAM subjects with AMLs (1,191 [IQR 878-2,243] pg/mL). There was a trend toward greater VEGF-D elevation in subjects with S-LAM with a history of chylous effusions compared with those without this disease manifestation, but the difference did not reach statistical signifi cance (1,855 [IQR 917-3,014] pg/mL vs 1,142 [IQR 691-1,885] pg/mL, P 5 .086).…”

“…Median serum VEGF-D levels were elevated in S-LAM compared with healthy volunteers (1,175 [IQR 780-2,013] pg/mL vs 309 [IQR 211-433] pg/mL, P , .001) ( Fig 4 ). Furthermore, serum VEGF-D levels were normal in emphysema, PLCH, Sjögren with cystic lung disease, and BHD.…”

A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis

“…LAM cells produce proteolytic enzymes, which may contribute to lung cyst formation [8,9]. Matrix metalloproteinases (MMPs), can degrade extracellular matrix, and can affect cell growth, invasion, angiogenesis and inflammation [10].…”

Sporadic lymphangioleiomyomatosis with bloody sputum as an initial symptom: A case report and review of the literature

“…In addition, chylothorax may be the first symptom of LAM, occurring as a primary manifestation in ~25% of patients (11,12). The obstruction of the lymphatic system is the most important mechanism underlying the establishment of chylothorax, while the obstruction of blood vessels leads to the formation of focal areas of hemorrhage and hemoptysis (13). The present study reported a sporadic case of LAM, in which the onset symptom was bloody sputum, and the diagnosis of LAM was confirmed 5 years after the initial presentation.…”