Genetic and morphologic determinants of pneumothorax in lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis, a multisystem disease affecting women, is characterized by proliferation of abnormal smooth muscle-like cells in the lungs, leading to cystic destruction of the parenchyma and recurrent pneumothoraces. Clinical characteristics of lymphangioleiomyomatosis patients were analyzed to determine the relationship of pneumothoraces to disease progression. Patients were genotyped for polymorphisms in genes of extracellular matrix proteins collagen, elastin, and matrix metalloproteinase-1 to assess their association with pneumothoraces. Clinical data and polymorphisms in the genes for types I and III collagen, elastin, and matrix metalloproteinase-1 were compared with the prevalence of pneumothorax. Of 227 patients, 57% reported having had at least one pneumothorax. Cyst size on high-resolution computed tomography scans was associated with pneumothorax; patients with a history of pneumothorax were more likely to have larger cysts than patients who had no pneumothoraces. In patients with mild disease, those with a history of pneumothorax had a faster rate of decline in forced expiratory volume in 1 s (FEV(1); P = 0.001, adjusted for age) than those without. Genotype frequencies differed between patients with and without pneumothorax for polymorphisms in the types I and III collagen and matrix metalloproteinase-1 genes. Larger cysts may predispose lymphangioleiomyomatosis patients to pneumothorax, which, in early stages of disease, correlates with a more rapid rate of decline in FEV(1). Polymorphisms in types I and III collagen and matrix metalloproteinase-1 genes may cause differences in lung extracellular matrix that result in greater susceptibility to pneumothorax.

Pneumothorax After Air Travel in Lymphangioleiomyomatosis, Idiopathic Pulmonary Fibrosis, and Sarcoidosis

“…In agreement with prior observations, 9 we found that LAM patients who had pneumothoraces tend to have lower FEV 1 , and a CT scan pattern consisting of larger cysts scattered throughout relatively normal lung parenchyma. This suggests that the presence of larger cysts predisposes patients both to pneumothorax and greater rates of FEV 1 decline.…”

“…For LAM and IPF patients, the severity of lung disease and cyst size were graded semiquantitatively by CT scans, as previously described. 8,9 Patients who had 1 to 10 cysts were placed in the category of minimal disease (grade 0). If Ͼ 10 cysts were identified, the lungs were divided in three zones (upper, middle, and lower).…”

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

“…Levels of different MMPs were elevated in urine and lung nodules of LAM patients [150], and analysis of LAM tissue from lung biopsies indicated elevated reactivity of MMP2 and MMP9, but not of TIMP1 and TIMP2 [151]. MMP1 was suggested as a modifier gene affecting changes in the ECM that result in greater susceptibility to pneumothorax and rate of decline in lung function [152]. Consequently, MT1-MMP, an activator of MMP1, was also associated with proliferating LAM cells [153].…”

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

“…Lung cysts are the hallmark lesion in LAM and are present in all patients ( fig. 2) [29,30]. Their appearance, size and contour vary considerably typically ranging from 2-5 mm in diameter but occasionally as large as 30 mm [31,32].…”