It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (e.g., angiomyolipomas, lymphangioleiomyomas, chylous effusions). Serum VEGF-D, a lymphangiogenic factor, is higher in LAM patients than healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM. Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers. We observed that serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (P<0.001). However, when patient samples were grouped based on extent of lymphatic involvement, (e.g., lymphangioleiomyomas, adenopathy), the statistical difference was maintained only for patients with LAM and lymphatic involvement (P<0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (AUC =0.845 P<0.0001), and a fair predictor for LAM disease (AUC=0.751 P<0.0001). Of note, serum VEGF-D levels correlated as well to CT grade (P=0.033). We conclude that serum VEGF-D is a measure of lymphatic involvement in LAM. Based on our observations in LAM, we questioned whether lymphatics may have a role in the pathogenesis of other pulmonary diseases. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, debilitating respiratory disease, whose pathogenesis is poorly understood. In IPF, the lung parenchyma undergoes extensive remodeling. We hypothesized that lymphangiogenesis is part of lung remodeling, and sought to characterize pathways leading to lymphangiogenesis in IPF. We found lymphatic vessels in alveolar spaces in IPF lung tissue, and their diameter correlated with disease severity, suggesting that the alveolar microenvironment plays a role in the lymphangiogenic process. In bronchoalveolar lavage fluid (BALF) from IPF subjects, short-fragment hyaluronic acid was found, which induced migration and proliferation of lymphatic endothelial cells (LEC), processes required for lymphatic vessel formation. To determine the origin of LECs in IPF, macrophages were isolated from the alveolar spaces;CD11b+ macrophages from IPF subjects and not from healthy volunteers formed lymphatic-like vessels in vitro. Our findings demonstrate that in the alveolar microenvironment of subjects with IPF, soluble factors such as short-fragment hyaluronic acid, and cells such as CD11b+ macrophages, contribute to lymphangiogenesis. These results improve our understanding of lymphangiogenesis and tissue remodeling in IPF and perhaps other fibrotic diseases. Subjective grading of LAM on HRCT is imprecise and can be arduous especially in cases with severe involvement. We proposed a computer-aided evaluation system that grades LAM involvement based on analysis of lung texture patterns. A committee of support vector machines was employed for classification. The system was tested on 36 patients with LAM. The computer grade demonstrated a good correlation with subjective radiologist grade (R=0.91, p<0.0001) and pulmonary functional tests (R=0.85, p<0.0001). The grade also provided precise progression assessment of disease over time. LAM is characterized by cystic lung destruction caused by LAM cells, smooth-muscle like cells, which have mutations in the tumor suppressor genes Tuberous Sclerosis Complex (TSC) 1 or 2, and have the capacity to metastasize. Since chemokines and their receptors function in chemotaxis of metastatic cells, we hypothesized that LAM cells may be recruited by chemokine(s) in the lung. Quantification of 25 chemokines in bronchoalveolar lavage fluid from LAM patients and heealthy volunteers revealed that concentrations of CCL2, CXCL1 and CXCL5 were significantly higher in samples from LAM patients than healthy volunteers. In vitro, CCL2 or MCP-1 induced selective migration of cells showing loss of heterozygosity of TSC2 from a heterogeneous populations of cells grown from explanted LAM lungs. In addition, the frequencies of single-nucleotide polymorphisms in the CCL2 gene promoter region differed significantly in LAM patients and healthy volunteers (p=0.018), and one polymorphism was associated significantly more frequently with the decline of lung function. The presence (i.e., potential functionality) of chemokine receptors was evaluated using immunohistochemistry in lung sections from 30 patients with LAM. Expression of chemokines and these receptors varied among LAM patients and differed from that seen in some cancers (e.g., breast cancer and melanoma cells). These observations are consistent with the notion that chemokines such as CCL2 may serve to determine mobility and specify site of metastasis. We previously reported that approximately one fourth of patients with LAM may respond to bronchodilators. A recent study, however, questioned the validity of those observations.
The aims of our curent study were to determine the prevalence of reversible airflow obstruction in LAM, and to identify associated clinical and physiological parameters. First, clinical and physiologic characteristics of 235 patients were analyzed to determine the frequency of response to albuterol during a total of 2,307 visits. Second, we prospectively evaluated the response to albuterol (2.5 mg) and ipratropium (500 ?g) in 130 patients and correlated responses with their clinical and physiologic characteristics. In the retrospective study, 51% of the patients responded at least once to bronchodilators;of these, 12% responded ? 50% of the time. Higher frequency of positive bronchodilator responses was associated with greater rates of decline in FEV1 and DLCO. In the prospective study, thirty-nine (30%) responded to bronchodilators: 12 to ipratropium, 9 to albuterol, and 18 to both. The prevalence of asthma and smoking in 39 responders was not different from that seen in 91 non-responders. Patients who responded to ipratropium and/or albuterol had significantly (p<0.02) lower FEV1 and DLCO and a greater rate of FEV1 (p=0.044) and DLCO decline (p=0.039). After adjusting for FEV1/FVC ratio, DLCO decline was also greater in responders than nonresponders (p=0.009). Thus, patients with LAM may have partially reversible airflow obstruction. Of note, a positive response to bronchodilators was associated with an accelerated rate of decline in pulmonary function. The prevalence of pneumothorax associated with travel in interstitial lung diseases is unknown. In LAM, where pneumothorax is common, patients are often concerned about the occurrence of a life-threatening event during air travel.
The aim of our current study was to determine the prevalence of pneumothorax associated with air travel in patients with LAM, idiopathic pulmonary fibrosis (IPF), and sarcoidosis. Records and imaging studies of 449 patients traveling to NIH were reviewed. 449 patients traveled 1,232 times: 299 by airplane (816 trips) and 150 by land (416 trips). Sixteen of 281 LAM patients arrived with a pneumothorax. In five, the diagnosis was made by chest roentgenogram, and in 11 by computed tomography scans only. Of the 16 patients, 14 traveled by airplane and two by land. Seven of the 16, one of whom traveled by train, had a new pneumothorax;nine had chronic pneumothoraces. A new pneumothorax was more likely in patients with large cysts and more severe disease. The frequency of a new pneumothorax for LAM patients who traveled by airplane was 2.9 % (1.1 per 100 flights) and by ground transportation, 1.3 %(0.5 per 100 trips). No IPF (n=76) or sarcoidosis (n=92) patients presented with a pneumothorax.
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