Reversible Airflow Obstruction, Proliferation of Abnormal Smooth Muscle Cells, and Impairment of Gas Exchange as Predictors of Outcome in Lymphangioleiomyomatosis

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease, occurring in women, characterized by cystic degeneration of the lungs, abdominal tumors, and proliferation of abnormal smooth muscle cells. Lung function abnormalities consist of impairment of the diffusion capacity (DL(CO)) and airflow obstruction. The objective of this study was to correlate the functional impairment with histologic measures of disease severity to identify predictors of disease outcome. Lung function of 143 patients and lung biopsies of 74 of these patients were reviewed for evidence of airway disease and scoring of disease severity. A positive response to bronchodilators was associated with more severe airflow obstruction, a predominantly solid pattern of LAM lesions in the lung biopsy, and greater rate of decline in expiratory flow. Airway inflammation, present in 61% of the lung specimens, was not associated with reversible airway obstruction and did not correlate with the severity of airflow obstruction. DL(CO) correlated best with the LAM histologic score (LHS), a demonstrated predictor of outcome. We conclude that reversible airway obstruction is found in LAM patients with accelerated loss of lung function and a predominantly solid pattern of LAM lesions. Impairment of DL(CO) correlates with LHS, a predictor of survival and time to lung transplantation.

Reversible Airflow Obstruction in Lymphangioleiomyomatosis

“…Further, a positive response to bronchodilators was a predictor of decline in Dlco after adjusting for FEV 1 /FVC ratio. This finding differs from those reported in our previous study 9 in which we found a relationship between a positive bronchodilator response to albuterol, the predominance of LAM cell proliferation, and an accelerated decline in FEV 1 but not in Dlco. However, the fact that a response to bronchodilators is now shown to be associated with a greater rate of Dlco decline is not surprising.…”

“…In agreement, 9 the proportion of positive responses to ␤-adrenergic bronchodilators was found to be greater in patients whose lung biopsy specimens showed a predominantly proliferative pattern of LAM lesions. Further, although airways inflammation (ie, bronchiolitis) was found in airways surrounded by heavy infiltrates of LAM cells, 9 there was no pathologic evidence of bronchial asthma, smooth-muscle hypertrophy, or any other condition that could be associated with airways disease. One must conclude that airflow obstruction in patients with LAM is related to LAM cell proliferation.…”

“…Physiologic data from 21 of the 106 NIH patients participating in the prospective study were reported previously. 9 The study was approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute, NIH; Office of Human Subjects Research, NIH; and Ospedale San Giuseppe, which had a Federal-Wide Assurance with the US Office of Human Research Protections. Written consent was obtained from all patients.…”

“…In addition, we questioned whether the type of bronchodilator used could affect the frequency of a positive response. To address these issues, we first expanded our retrospective analysis 9 to 235 patients. Then, we conducted a prospective study in 130 patients to determine the prevalence of positive responses to both ␤-adrenergic and anticholinergic agents.…”

Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

“…These lesions promote cystic destruction of the lung and lead to loss of pulmonary function, for which there is no therapy (6). The molecular mechanisms promoting LAM cell proliferation remain largely unknown (7).…”