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Pulmonary Microvasculature (pulmonary + microvasculature)
Selected AbstractsKATP Channels Are an Important Component of the Shear-Sensing Mechanism in the Pulmonary MicrovasculatureMICROCIRCULATION, Issue 8 2006S. CHATTERJEE ABSTRACT Objective: To investigate the role of a KATP channel in sensing shear, specifically its cessation, in the endothelial cells of the pulmonary microvasculature. Methods: Endothelial cells isolated from the pulmonary microvasculature of wild-type and KATP channel knockout (KIR6.2,/,) mice were either statically cultured (non-flow-adapted) or kept under flow (flow-adapted) and the KIR currents in these cells were monitored by whole-cell patch-clamp technique during flow and its cessation. Membrane potential changes, generation of reactive oxygen species (ROS), and Ca2+ influx with flow cessation were evaluated by the use of fluorescent dyes. Lungs isolated from wild-type mice were imaged to visualize ROS generation in the subpleural endothelium. Results: By patch-clamp analysis, reduction in the KIR current with cessation of flow occurred only in wild-type cells that were flow-adapted and not in flow-adapted KIR6.2,/, cells. Similar observations were made using changes in bisoxonol fluorescence as an index of cell membrane potential. Generation of ROS and Ca2+ influx that follow membrane depolarization were significantly lower in statically cultured and in KIR6.2,/, cells as compared to flow-adapted wild-type cells. Imaging of subpleural endothelial cells of the whole lung showed that the KATP antagonist glyburide caused the production of ROS in the absence of flow cessation. Conclusions: The responses to stop of flow (viz. membrane depolarization, KIR currents, ROS, Ca2+) were significantly altered with knockout of KATP channels, which indicates that this channel is an important component of the pulmonary endothelial response to abrupt loss of shear stress. [source] Experimental metastasis and primary tumor growth in mice with hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2006F. LANGER Summary., During experimental lung metastasis, tumor cells adhere to the pulmonary microvasculature and activate coagulation via surface-expressed tissue factor (TF), leading to local fibrin deposition and platelet aggregation. While interventional studies have demonstrated great efficacy of anticoagulants and antiplatelet agents in inhibiting metastasis, no information is available on how tumor biology may be affected by congenital bleeding disorders such as hemophilia A. We therefore used a syngeneic model to study experimental metastasis and primary tumor growth in factor VIII (FVIII)-deficient mice. By conventional reverse transcription-polymerase chain reaction, flow cytometry, and one-stage clotting assays, we demonstrated constitutive expression of TF mRNA, antigen, and procoagulant activity in the murine B16F10 melanoma cell line. In hemophilic mice, B16F10 lung metastasis was significantly (P < 0.001) enhanced by a single dose of human FVIII (100 U kg,1), suggesting that FVIII played a critical role during the early blood-borne phase of the metastatic cascade. In contrast, lung seeding was significantly (P < 0.05) reduced by lepirudin, a direct thrombin inhibitor, suggesting that thrombin generation contributed to pulmonary metastasis even in the absence of FVIII. Consistent with this finding, intravenous injection of B16F10 cell-evoked laboratory changes of a hemolytic thrombotic microangiopathy and consumptive coagulopathy in both hemophilic and non-hemophilic mice. Subcutaneous implantation of B16F10 cells into mice with hemophilia A gave rise to primary tumors in an exponential growth pattern similar to that observed in non-hemophilic mice. Although TF expression by B16F10 cells may promote thrombin-dependent metastasis in mice with hemophilia A, amplification of coagulation by host FVIII appears to be necessary for maximum lung seeding. [source] KATP Channels Are an Important Component of the Shear-Sensing Mechanism in the Pulmonary MicrovasculatureMICROCIRCULATION, Issue 8 2006S. CHATTERJEE ABSTRACT Objective: To investigate the role of a KATP channel in sensing shear, specifically its cessation, in the endothelial cells of the pulmonary microvasculature. Methods: Endothelial cells isolated from the pulmonary microvasculature of wild-type and KATP channel knockout (KIR6.2,/,) mice were either statically cultured (non-flow-adapted) or kept under flow (flow-adapted) and the KIR currents in these cells were monitored by whole-cell patch-clamp technique during flow and its cessation. Membrane potential changes, generation of reactive oxygen species (ROS), and Ca2+ influx with flow cessation were evaluated by the use of fluorescent dyes. Lungs isolated from wild-type mice were imaged to visualize ROS generation in the subpleural endothelium. Results: By patch-clamp analysis, reduction in the KIR current with cessation of flow occurred only in wild-type cells that were flow-adapted and not in flow-adapted KIR6.2,/, cells. Similar observations were made using changes in bisoxonol fluorescence as an index of cell membrane potential. Generation of ROS and Ca2+ influx that follow membrane depolarization were significantly lower in statically cultured and in KIR6.2,/, cells as compared to flow-adapted wild-type cells. Imaging of subpleural endothelial cells of the whole lung showed that the KATP antagonist glyburide caused the production of ROS in the absence of flow cessation. Conclusions: The responses to stop of flow (viz. membrane depolarization, KIR currents, ROS, Ca2+) were significantly altered with knockout of KATP channels, which indicates that this channel is an important component of the pulmonary endothelial response to abrupt loss of shear stress. [source] The Lung Is The Major Site That Produces Nitric Oxide To Induce Acute Pulmonary Oedema In Endotoxin ShockCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2001Ru Ping Lee SUMMARY 1. The present study was undertaken to determine the locus of nitric oxide (NO) production that is toxic to the lung and produces acute pulmonary oedema in endotoxin shock, to examine and compare the effects of changes in lung perfusate on endotoxin-induced pulmonary oedema (EPE) and to evaluate the involvement of constitutive and inducible NO synthase (cNOS and iNOS, respectively). 2. Experiments were designed to induce septic shock in anaesthetized rats with the administration of Escherichia coli lipopolysaccharide (LPS). Exhaled NO, lung weight (LW)/bodyweight (BW) ratio, LW gain (LWG) and lung histology were measured and observed to determine the degree of EPE 4 h following LPS. The EPE was compared between groups in which LPS had been injected either into the systemic circulation or into the isolated perfused lung. The lung perfusate was altered from whole blood to physiological saline solution (PSS) with 6% albumin to test whether different lung perfusions affected EPE. Pretreatment with various NOS inhibitors was undertaken 10 min before LPS to investigate the contribution of cNOS and iNOS to the observed effects. 3. Endotoxin caused profound systemic hypotension, but little change in pulmonary arterial pressure. The extent of EPE was not different between that induced by systemic injection and that following administration to isolated lungs preparations. Replacement of whole blood with PSS greatly attenuated (P < 0.05) EPE. In blood-perfused lungs, pretreatment with NOS inhibitors, such as N, -nitro- L -arginine methyl ester, aminoguanidine and dexamethasone, significantly prevented EPE (P < 0.05). 4. The major site of NO production through the whole blood is in the lung. The NO production mediated by the iNOS system is toxic to the endothelium in the pulmonary microvasculature. Inhalation of NO for patients with sepsis may be used with clinical caution. Therapeutic consideration of lung extracorporeal perfusion with PSS and pharmacological pretreatment with iNOS inhibitors may be warranted. [source] | ||||||||||