American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · Oct 2009
ReviewMeasurement of extravascular lung water using the single indicator method in patients: research and potential clinical value.
Extravascular lung water includes all of the fluid within the lung but outside of the vasculature. Lung water increases as a result of increased hydrostatic vascular pressure or from an increase in lung endothelial and epithelial permeability or both. ⋯ Bedside measurement of extravascular lung water in patients is now possible using a single indicator thermodilution method. This review critically evaluates the experimental and clinical evidence supporting the potential value of measuring extravascular lung water in patients using the single indicator method.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Oct 2009
Comparative StudyGolgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques.
Golgi dysfunction has been previously investigated as a mechanism involved in monocrotaline-induced pulmonary hypertension (PAH). In the present study, we addressed whether Golgi dysfunction might occur in pulmonary vascular cells in idiopathic PAH (IPAH) and whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH. Quantitative immunostaining for the Golgi tethers giantin and p115 on human lung tissue from patients with IPAH (n = 6) compared with controls demonstrated a marked cytoplasmic dispersal of giantin- and p115-bearing vesicular elements in vascular cells in the proliferative, obliterative, and plexiform lesions in IPAH and an increase in the amounts of these Golgi tethers/matrix proteins per cell. ⋯ Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and an increase in giantin and p115. Specifically, the HIV-Nef-positive cells showed increased giantin, p115, and the activated transcription factor PY-STAT3. These data represent the first test of the Golgi dysfunction hypothesis in IPAH and place trafficking and Golgi disruption in the chain of causality of pulmonary vasculopathies in the macaque model.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Oct 2009
Regulation of intrapleural fibrinolysis by urokinase-alpha-macroglobulin complexes in tetracycline-induced pleural injury in rabbits.
The proenzyme single-chain urokinase plasminogen activator (scuPA) more effectively resolved intrapleural loculations in rabbits with tetracycline (TCN)-induced loculation than a range of clinical doses of two-chain uPA (Abbokinase) and demonstrated a trend toward greater efficacy than single-chain tPA (Activase) (Idell S et al., Exp Lung Res 33: 419, 2007.). scuPA more slowly generates durable intrapleural fibrinolytic activity than Abbokinase or Activase, but the interactions of these agents with inhibitors in pleural fluids (PFs) have been poorly understood. PFs from rabbits with TCN-induced pleural injury treated with intrapleural scuPA, its inactive Ser195Ala mutant, Abbokinase, Activase, or vehicle, were analyzed to define the mechanism by which scuPA induces durable fibrinolysis. uPA activity was elevated in PFs of animals treated with scuPA, correlated with the ability to clear pleural loculations, and resisted (70-80%) inhibition by PAI-1. Alpha-macroglobulin (alphaM) but not urokinase receptor complexes immunoprecipitated from PFs of scuPA-treated rabbits retained uPA activity that resists PAI-1 and activates plasminogen. ⋯ An equilibrium between active and inactive scuPA (k(on) = 4.3 h(-1)) limits the rate of its inactivation by PAI-1, favoring formation of complexes with alphaM. These observations define a newly recognized mechanism that promotes durable intrapleural fibrinolysis via formation of alphaM/uPA complexes. These complexes promote uPA-mediated plasminogen activation in scuPA-treated rabbits with TCN-induced pleural injury.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Oct 2009
The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice.
Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dose-dependently inhibited the pressor response of acute hypoxia. ⋯ Treatment with HMR1766 (10 mg x kg(-1) x day(-1)), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH.