Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor gene TSC2.

Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction, resulting from proliferation of smooth-muscle-like cells, which have mutations in the tumor suppressor genes TSC1 or TSC2. Among 277 LAM patients, severe disease was associated with hypoxia and elevated red blood cell indexes that accompanied reduced pulmonary function. Because high red cell indexes could result from hypoxemia-induced erythropoietin (EPO) production, and EPO is a smooth muscle cell mitogen, we investigated effects of EPO in human cells with genetic loss of tuberin function, and we found that EPO increased proliferation of human TSC2-/-, but not of TSC2+/-, cells. A discrete population of cells grown from explanted lungs was characterized by the presence of EPO receptor and loss of heterozygosity for TSC2, consistent with EPO involvement. In LAM cells from lung nodules, EPO was localized to the extracellular matrix, supporting evidence for activation of an EPO-driven signaling pathway. Although the high red cell mass of LAM patients could be related to advanced disease, we propose that EPO, synthesized in response to episodic hypoxia, may increase disease progression by enhancing the proliferation of LAM cells.

The potential anticoagulant property of Caulerpa lentillifera crude extract.

BACKGROUND: Anticoagulants have been used in the treatment of several circulatory diseases and thrombotic disorders, and in the blood sampling for hematologic analysis. Sulfated polysaccharides (SP), which have anticoagulant properties, are found in most seaweeds, including Caulerpa spp. OBJECTIVE: The study generally aimed to evaluate the potential anticoagulant property of Caulerpa lentillifera. METHODOLOGY: The whole plant of fresh C. lentillifera was washed thoroughly with distilled water and manually expressed to obtain the extract. C. lentillifera extract was tested in two phases. Phase one utilized nine male albino rabbits, which were randomly and equally allocated into three groups: (1) negative control (oral distilled water and subsequent in vitro mixing of extracted blood with normal saline solution), (2) positive control (oral aspirin and subsequent in vitro mixing of extracted blood with normal saline solution), and (3) experimental group (oral distilled water and in vitro mixing of extracted blood with C. lentillifera extract). Blood coagulation was evaluated by measuring the clotting time using the slide and tube methods. In phase two, peripheral blood from three apparently healthy adult dogs were used. Blood collection was performed thrice. In each collection, the sample was divided into five aliquots: (1) negative control (normal saline solution), (2) positive control (ethylenediaminetetraacetic acid [EDTA]), and (3-5) experimental treatments at 0.1, 0.15, and 0.2 ml of C. lentillifera extract. Coagulation was evaluated by measuring the clotting time using the tube method. RESULTS: Phase one results revealed significant differences on the clotting time between the negative and the positive and experimental groups (P < 0.05), and no significant differences on the clotting time between the positive and the experimental groups (P > 0.05). In phase two, all blood samples mixed with EDTA did not clot, while the negative control had an average clotting time of 2.01 min. Blood mixed with 0.2 ml of C. lentillifera extract had the longest coagulation time (15.49 min). Simple linear regression revealed a positive significant correlation (multiple R = 0.9450, R2 = 0.8931, P = 0.02) implying dose-dependent anticoagulant potential. The study showed that C. lentillifera extract may have a potential anticoagulant property due to its component SP.

Early interstitial lung disease in familial pulmonary fibrosis.

RATIONALE: Identification of early, asymptomatic interstitial lung disease (ILD) in populations at risk of developing idiopathic pulmonary fibrosis (IPF) may improve the understanding of the natural history of IPF. OBJECTIVES: To determine clinical, radiographic, physiologic, and pathologic features of asymptomatic ILD in family members of patients with familial IPF. METHODS: One hundred sixty-four subjects from 18 kindreds affected with familial IPF were evaluated for ILD. Bronchoalveolar lavage fluid cells were analyzed using flow cytometry. Lung biopsies were performed in six subjects with asymptomatic ILD. MEASUREMENTS AND MAIN RESULTS: High-resolution computed tomography abnormalities suggesting ILD were identified in 31 (22%) of 143 asymptomatic subjects. Subjects with asymptomatic ILD were significantly younger than subjects with known familial IPF (P < 0.001) and significantly older than related subjects without lung disease (P < 0.001). A history of smoking was identified in 45% of subjects with asymptomatic ILD and in 67% of subjects with familial IPF; these percentages were significantly higher than that of related subjects without lung disease (23%) (P = 0.02 and P < 0.001, respectively). Percentages of activated CD4(+) lymphocytes were significantly higher in bronchoalveolar lavage fluid cells from subjects with asymptomatic ILD compared with related subjects without lung disease (P < 0.001). Lung biopsies performed in subjects with asymptomatic ILD revealed diverse histologic subtypes. CONCLUSIONS: Asymptomatic ILD in individuals at risk of developing familial IPF can be identified using high-resolution computed tomography scan of the chest, especially in those with a history of smoking. Lung biopsies from individuals in this cohort with early asymptomatic lung disease demonstrate various histologic subtypes of ILD.