Interstitial Lung Disease: Pathophysiology and Genetic Predisposition

Penelope A. Lympany, PhD, and Roland M. du Bois, MD, Imperial College of Science, Technology and Medicine, London, UK

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Lymphangioleiomyomatosis

Lymphangioleiomyomatosis is a rare disease that affects only women and occurs at a frequency of 1 per million in the UK and France,[85] with a mean age of onset of 34 years.[86,87,88] The most frequently affected organ is the lungs, which present with numerous cysts. The lymphatic vessels, blood vessels, and airways are surrounded by smooth muscle proliferation. Generally, the course of the disease results in respiratory failure.[87,89] The lymph nodes in the abdomen and pelvis may also be involved, and up to 50% of patients have renal angiomyolipomas.

This disease has no known etiology, although it can occur in patients with tuberous sclerosis.[90] The tuberous sclerosis complex (TSC) is an autosomal dominant condition associated with a germline mutation in 1 of 2 genes, TSC-1 and TSC-2, on chromosomes 9 and 16, respectively.[91,92,93] This results in heterozygosity at either the TSC-1 or TSC-2 locus. Subsequent loss of heterozygosity in individual tissues through somatic mutation allows manifestation of the defect.

The presence of smooth muscle proliferation in the lungs of subjects with lymphangioleiomyomatosis and the recurrence of the disease in donor lungs following transplantation into affected individuals implicates circulating mediators. Normal airway smooth muscle cells are capable of producing large numbers of growth factors and other mitogens. Various abnormalities in growth and transcription factors have been described in cells taken from patients with lymphangioleiomyomatosis, including increased expression of basic fibroblast growth factor and platelet-derived growth factor[94,95] and increased production of angiotensin II.[96]

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