Cigarette smoke induces genetic instability in airway epithelial cells by suppressing FANCD2 expression

Chromosomal abnormalities are commonly found in bronchogenic carcinoma cells, but the molecular causes of chromosomal instability (CIN) and their relationship to cigarette smoke has not been defined. Because the Fanconi anaemia (FA)/BRCA pathway is essential for maintenance of chromosomal stability, we tested the hypothesis that cigarette smoke suppresses that activity of this pathway. Here, we show that cigarette smoke condensate (CSC) inhibited translation of FANCD2 mRNA (but not FANCC or FANCG) in normal airway epithelial cells and that this suppression of FANCD2 expression was sufficient to induce both genetic instability and programmed cell death in the exposed cell population. Cigarette smoke condensate also suppressed FANCD2 function and induced CIN in bronchogenic carcinoma cells, but these cells were resistant to CSC-induced apoptosis relative to normal airway epithelial cells. We, therefore, suggest that CSC exerts pressure on airway epithelial cells that results in selection and emergence of genetically unstable somatic mutant clones that may have lost the capacity to effectively execute an apoptotic programme. Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis

Hypoxic Pulmonary Vasoconstriction in Humans:Tale or Myth

Hypoxic Pulmonary vasoconstriction (HPV) describes the physiological adaptive process of lungs to preserves systemic oxygenation. It has clinical implications in the development of pulmonary hypertension which impacts on outcomes of patients undergoing cardiothoracic surgery. This review examines both acute and chronic hypoxic vasoconstriction focusing on the distinct clinical implications and highlights the role of calcium and mitochondria in acute versus the role of reactive oxygen species and Rho GTPases in chronic HPV. Furthermore it identifies gaps of knowledge and need for further research in humans to clearly define this phenomenon and the underlying mechanism

Birefringence measurements of structural inhomogeneities in Rana pipiens rod outer segments.

The birefringence (deltan) of Rana pipiens rod outer segments (ROS) reveals microstructure inhomogeneities not seen with other techniques. In the basal 20-30-micron length of the ROS there is a nearly linear axial gradient in deltan of approximately equal to -2 x 10(-5)/micron. No consistent deltan gradients are found in the distal 20-30 micron of the ROS. Using glycerol imbibition to separate the intrinsic and form birefringence components, we found that the basal deltan gradient was principally due to a gradient of the intrinsic birefringence component. The disk membrane volume fraction decreases uniformly from the basal end to the distal end, while the disk membrane refractive index increases. The contributions of these changes to the form birefringence approximately cancel, so that the form component is fairly uniform along the ROS axis. Because its axial distance from the inner segment is a measure of the time since a disk membrane was formed, these gradients may reflect a disk membrane aging process. Occasionally a highly birefringent, 2-micron-wide band is seen at the basal end ot the ROS, possibly where the envelope membrane folds to form new disk membranes

Pulmonary artery infusion of prostacyclin increases lobar bronchial blood flow

Intrapulmonary systemic to pulmonary bronchial blood flow [Qbr (s-p)] decreases with administration of cyclooxygenase inhibitors. This effect may be due to a decrease in the production of vasodilating prostaglandins and reflect either a decrease in the total intrapulmonary bronchial blood flow (Qbr), or a redistribution of the intrapulmonary systemic venous return. In nine open chested dogs the left lower lobe (LLL) was isolated and perfused in situ. Blood flow to the extrapulmonary airways (Qep), and Qbr were measured by the reference flow technique. Qbr (s-p) was measured as the overflow from the closed LLL perfusion circuit. After ibuprofen, PG-I2 was infused into the LLL PA and the Qbr (s-p) was continuously monitored. Qbr, and Qep were measured before and after ibuprofen, and during and after the PG-I2 infusion. The upstream pressure for Qbr (s-p) was estimated with and without PG-I2 infusion. After ibuprofen the Qep, Qbr, and Qbr (s-p) fell to 45, 22, and 17%, respectively, of the pre-ibuprofen values (P less than 0.05). PG-I2 increased the Qbr (s-p) and Qbr (P less than 0.05), while Qep was unchanged. During all experimental conditions the simultaneous measurements of Qbr and Qbr (s-p) were not different from each other (P less than 0.001). The upstream pressure for Qbr (s-p) increased from 30 to 50 cm H2O (P less than 0.05). Intralobar bronchial blood flow is drained almost entirely through the pulmonary circulation, and PG-I2 in the LLL pulmonary circulation increases systemic blood flow to the LLL, probably acting at the level of a systemic arteriole

Temperature dependence of intraparenchymal bronchial blood flow

Previous studies suggested that bronchial vascular resistance, like that of the skin, changes with the temperature of the surrounding tissue. To investigate this phenomenon, we recorded anastomotic (systemic to pulmonary) (Qbrs-p) and total (Qbr) bronchial blood flow over a temperature range centered on normal. In 7 open-chested dogs the in situ left lower lobe (LLL) was separately ventilated (30 degrees C, 5% CO2 in humidified air) and was suspended in a fabric net from a strain gauge for continuous recording of weight. The pulmonary circulation of the LLL was pump-perfused at 255 +/- 69 ml/min in a closed circuit with temperature set at 30, 33, 36, 39 and 42 degrees C. Qbrs-p was measured as overflow from the LLL vascular circuit corrected for LLL weight changes. Qbr, tracheal, mid-esophageal and coronary flow were measured with 15 mu radiolabelled microspheres injected in the left atrium. The animal's core temperature and that of the humidified air around the LLL were held constant. Qbr and Qbrs-p were equal and reached a peak at 36 degrees C with lower levels of flow at higher and lower temperatures. Esophageal, tracheal and coronary flow and cardiac output did not change nor did pressures in the systemic and LLL pulmonary artery and in the LLL airways. An intralobar change in temperature above or below 36 degrees C decreases only the lobar bronchial blood flow and does not influence blood flow to other nearby tissues including those vascularized by the bronchial circulation