Pathophysiology of Lymphangioleiomyomatosis

Abstract

Pulmonary lymphangioleiomyomatosis (LAM) is a progressive, destructive, cystic lung disease caused by the diffuse proliferation of smooth muscle like LAM cells that carry bi-allelic loss-of-function mutations in the TSC1 or TSC2 gene. LAM affects almost exclusively women. LAM occurs in women with tuberous sclerosis complex (TSC) and in women who do not have TSC, which is referred to as sporadic LAM. LAM can result in pneumothorax and oxygen dependency, and also has non-pulmonary manifestations, including renal angiomyolipomas and retroperitoneal lymphangioleiomyomas. Recent progress in LAM has led to FDA approval of sirolimus (rapamycin) for the therapy of LAM and the development of VEGF-D as a diagnostic biomarker in the setting of a characteristic chest computed tomography (CT) scan. Here, we review the clinical and genetic features of LAM, the pathophysiology of LAM, and animal models of LAM, highlighting key clinical and translational unknowns.KeywordsTuberous sclerosis complex (TSC)Lymphangioleiomyomatosis (LAM)Angiomyolipoma (AML)Vascular endothelial growth factor-D (VEGF-D)Forced expiratory volume in one-second (FEV1)MosaicismEstrogenPneumothoraxTuberinHamartinMechanistic target of rapamycin (mTOR)Rheb