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Werner Seeger - One of the best experts on this subject based on the ideXlab platform.
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subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Ralph T Schermuly, Axel Roehl, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christian Schudt, Herrmann Tenor, Friedrich Grimminger, Werner Seeger, D WalmrathAbstract:Aerosolized prostacyclin (PGI 2 ) has been suggested for selective pulmonary vasodilation, but its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition may offer a new strategy for amplification of the vasodilative response to nebulized PGI 2 . In perfused rabbit Lungs, continuous infusion of the thromboxane mimetic U46619 was used to establish stable pulmonary hypertension [increase in pulmonary arterial pressure (pPA) from ∼7 to ∼32 mm Hg], which is accompanied by progressive Edema formation and severe disturbances in gas exchange with a predominance of shunt flow (increase from 2 , dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibitor motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor tolafentrine on pulmonary hemodynamics were established (potency rank order: rolipram > tolafentrine ∼ motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI 2 was chosen to effect a moderate pPA decrease (∼4 mm Hg; rapidly returning to prenebulization values within 10–15 min) with only a slight reduction in shunt flow (∼49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmonary hemodynamics, caused prolongation of the post-PGI 2 decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI 2 to ∼9 to 10 mm Hg, prolonged the post-PGI 2 vasorelaxation to >60 min, reduced the extent of Lung Edema formation by 50%, and decreased the shunt flow to ∼19% (i.v. rolipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude that Lung PDE3/4 inhibition, achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplifies the pulmonary vasodilatory response to inhaled PGI 2 , concomitant with an improvement in ventilation-perfusion matching and a reduction in Lung Edema formation. The combination of nebulized PGI 2 and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension.
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surfactant alterations in severe pneumonia acute respiratory distress syndrome and cardiogenic Lung Edema
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Andreas Gunther, Friedrich Grimminger, D Walmrath, C Siebert, R E Schmidt, S Ziegler, M Yabut, Bettina Temmesfeld, H Morr, Werner SeegerAbstract:Bronchoalveolar lavage fluids (BALF) were analyzed for surfactant abnormalities in 153 patients with acute respiratory failure necessitating mechanical ventilation. Diagnoses were acute respiratory distress syndrome (ARDS) in the absence of Lung infection (n = 16), severe pneumonia (PNEU; n = 88), ARDS and PNEU (n = 36), and cardiogenic Lung Edema (CLE; n = 13). The PNEU group was subdivided into groups with alveolar PNEU (n = 35), bronchial PNEU (n = 16), interstitial PNEU (n = 18) and nonclassified PNEU (n = 19). Comparison with healthy controls (n = 20) was undertaken. Total phospholipids (PL), proteins, PL classes (HPTLC) and surfactant apoproteins SP-A and SP-B (ELISA) were quantified in the original BALF. The 48,000 x g pellet from centrifugation of the BAL was used to assess the percentage of large surfactant aggregates (LSA) and the biophysical properties of the surfactant (pulsating bubble surfactometer). All groups with inflammatory Lung injury (PNEU and/or ARDS) showed some decrease in the lava...
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surfactant alterations in severe pneumonia acute respiratory distress syndrome and cardiogenic Lung Edema
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Andreas Gunther, Friedrich Grimminger, D Walmrath, C Siebert, S Ziegler, M Yabut, Bettina Temmesfeld, H Morr, Reinhold Schmidt, Werner SeegerAbstract:Bronchoalveolar lavage fluids (BALF) were analyzed for surfactant abnormalities in 153 patients with acute respiratory failure necessitating mechanical ventilation. Diagnoses were acute respiratory distress syndrome (ARDS) in the absence of Lung infection (n = 16), severe pneumonia (PNEU; n = 88), ARDS and PNEU (n = 36), and cardiogenic Lung Edema (CLE; n = 13). The PNEU group was subdivided into groups with alveolar PNEU (n = 35), bronchial PNEU (n = 16), interstitial PNEU (n = 18) and nonclassified PNEU (n = 19). Comparison with healthy controls (n = 20) was undertaken. Total phospholipids (PL), proteins, PL classes (HPTLC) and surfactant apoproteins SP-A and SP-B (ELISA) were quantified in the original BALF. The 48,000 x g pellet from centrifugation of the BAL was used to assess the percentage of large surfactant aggregates (LSA) and the biophysical properties of the surfactant (pulsating bubble surfactometer). All groups with inflammatory Lung injury (PNEU and/or ARDS) showed some decrease in the lavageable PL pool, a reduced LSA content in BALF, and a manifold increase in alveolar protein load. Marked changes in the PL profile were noted throughout the groups (a decrease in phosphatidylcholine (PC) and phosphatidylglycerol (PG) and an increase in phosphatidylinositol [PI] and sphingomyelin [SPH]). Concentrations of SP-A but not of SP-B in BALF were reduced. Minimum surface-tension values approached 0 mN/m in controls, and ranged from 10 to 25 mN/m in the absence of supernatant protein and from 20 to 35 mN/m in recombination with leaked protein in the groups with ARDS and/or PNEU. Abnormalities in alveolar PNEU surpassed those in bronchial PNEU, and interstitial PNEU presented a distinct pattern with extensive metabolic changes. All surfactant changes were absent in CLE except for a slight inhibition of surface activity by proteins. We conclude that pronounced surfactant abnormalities, comparable to those in ARDS in the absence of Lung infection, occur in different entities of severe PNEU, but not in CLE.
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staphylococcal alpha toxin induced ventilation perfusion mismatch in isolated blood free perfused rabbit Lungs
Journal of Applied Physiology, 1993Co-Authors: D Walmrath, Friedrich Grimminger, M Scharmann, R Konig, J Pilch, Werner SeegerAbstract:Gas exchange conditions in blood-free perfused isolated rabbit Lungs were assessed by the use of the multiple inert gas elimination technique. Under baseline conditions, unimodal narrow distribution of perfusion and ventilation to midrange-ventilation-perfusion (VA/Q) areas was noted. Intravascular challenge with staphylococcal alpha-toxin caused a rapid increase in pulmonary arterial pressure (to > 40 mmHg within approximately 15 min) and delayed-onset (> 10-15 min) Lung Edema formation, with unaltered ventilation pressures. The vasoconstrictor response was paralleled by a progressive, severe leftward shift of perfusion to areas with low-VA/Q ratios, accompanied by a minor fraction of shunt flow. At pulmonary arterial pressures > 40 mmHg, extreme VA/Q mismatch with near absence of perfusate flow to midrange-VA/Q areas was registered. Vasoconstrictor response and VA/Q mismatch, but not the progressive Edema formation, were virtually completely suppressed in Lungs pretreated with acetylsalicylic acid or the thromboxane receptor antagonist BM 13505. Moreover, "rescue" application of BM 13505 after onset of alpha-toxin-induced pressor response and gas exchange abnormalities completely reversed pressure elevation and loss of VA/Q matching. We conclude that the marked vasoconstrictor response to staphylococcal alpha-toxin is paralleled by severe VA/Q mismatch with predominant perfusion of low-VA/Q areas independent of Lung Edema formation. Pressor response and VA/Q mismatch, but not vascular leakage, are suppressed by thromboxane inhibition.
Wolfgang M Kuebler - One of the best experts on this subject based on the ideXlab platform.
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urgent reconsideration of Lung Edema as a preventable outcome in covid 19 inhibition of trpv4 represents a promising and feasible approach
American Journal of Physiology-lung Cellular and Molecular Physiology, 2020Co-Authors: Wolfgang M Kuebler, Sveneric Jordt, Wolfgang LiedtkeAbstract:Lethality of coronavirus disease (COVID-19) during the 2020 pandemic, currently still in the exponentially accelerating phase in most countries, is critically driven by disruption of the alveolo-capillary barrier of the Lung, leading to Lung Edema as a direct consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We argue for inhibition of the transient receptor potential vanilloid 4 (TRPV4) calcium-permeable ion channel as a strategy to address this issue, based on the rationale that TRPV4 inhibition is protective in various preclinical models of Lung Edema and that TRPV4 hyperactivation potently damages the alveolo-capillary barrier, with lethal outcome. We believe that TRPV4 inhibition has a powerful prospect at protecting this vital barrier in COVID-19 patients, even to rescue a damaged barrier. A clinical trial using a selective TRPV4 inhibitor demonstrated a benign safety profile in healthy volunteers and in patients suffering from cardiogenic Lung Edema. We argue for expeditious clinical testing of this inhibitor in COVID-19 patients with respiratory malfunction and at risk for Lung Edema. Perplexingly, among the currently pursued therapeutic strategies against COVID-19, none is designed to directly protect the alveolo-capillary barrier. Successful protection of the alveolo-capillary barrier will not only reduce COVID-19 lethality but will also preempt a distressing healthcare scenario with insufficient capacity to provide ventilator-assisted respiration.
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loss of cftr causes endothelial barrier failure in pneumonia via inhibition of wnk1 and trpv4 activation
European Respiratory Journal, 2017Co-Authors: Lasti Erfinanda, Wolfgang Liedtke, B Gutbier, Katrin Reppe, Jasmin Lienau, Andreas C Hocke, Martin Witzenrath, Wolfgang M KueblerAbstract:Rationale: Pneumonia is the most common cause of acute respiratory distress syndrome (ARDS). Cystic fibrosis transmembrane conductance regulator (CFTR) is downregulated in infectious and inflammatory conditions. Inhibition of CFTR was found increases Lung endothelial permeability in vitro. Objective: We hypothesized that loss of CFTR play role in endothelial barrier failure in pneumonia-induced ARDS, and aimed to elucidate the signaling mechanisms underlying this effect. Methods: CFTR expression was assessed from Streptococcus pneumoniae-infected human and C57/BL6J mice Lung tissue. In isolated rat Lungs, Edema formation, endothelial Cl− ([Cl−]i) and Ca2+ concentration ([Ca2+]i) was quantified by weight gain measurement and real time fluorescence imaging. Lung Edema was assessed from S. pneumoniae-infected TRPV4-deficient (trpv4−/-) mice and their wild type (C57/BL6J) controls. Results: CFTR expression decreased in infected human and murine Lung. In isolated rat Lungs, CFTR inhibition by CFTR-inh172 increased endothelial permeability, [Cl−]i and [Ca2+]i. Inhibition of the Cl− sensitive with no lysine kinase 1 (WNK1) by tyrphostin replicated the effect of CFTR inhibition, while temozolomide, a WNK1 activator, or HC-067047, a TRPV4 antagonist, blocked the CFTR-inh172 effect. In vivo, infected trpv4−/- developed less Lung Edema and protein leak than their controls. Conclusion:S. pneumoniae infection causes loss of CFTR which promotes endothelial barrier failure through inhibition of WNK1 and subsequent disinhibition of TRPV4, an endothelial Ca2+ channel negatively regulated by WNK1. Inhibition of TRPV4 may present a promising strategy to prevent or treat ARDS in pneumonia patients.
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negative feedback loop attenuates hydrostatic Lung Edema via a cgmp dependent regulation of transient receptor potential vanilloid 4
Circulation Research, 2008Co-Authors: Jun Yin, Liming Wang, Nils Neye, Wolfgang Liedtke, Julia Hoffmann, Stephanie M Kaestle, Joerg Baeurle, Hermann Kuppe, Axel R Pries, Wolfgang M KueblerAbstract:Although the formation of hydrostatic Lung Edema is generally attributed to imbalanced Starling forces, recent data show that Lung endothelial cells respond to increased vascular pressure and may thus regulate vascular permeability and Edema formation. In combining real-time optical imaging of the endothelial Ca(2+) concentration ([Ca(2+)](i)) and NO production with filtration coefficient (K(f)) measurements in the isolated perfused Lung, we identified a series of endothelial responses that constitute a negative-feedback loop to protect the microvascular barrier. Elevation of Lung microvascular pressure was shown to increase endothelial [Ca(2+)](i) via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca(2+)](i) transient increased K(f) via activation of myosin light-chain kinase and simultaneously stimulated NO synthesis. In TRPV4 deficient mice, pressure-induced increases in endothelial [Ca(2+)](i), NO synthesis, and Lung wet/dry weight ratio were largely blocked. Endothelial NO formation limited the permeability increase by a cGMP-dependent attenuation of the pressure-induced [Ca(2+)](i) response. Inactivation of TRPV4 channels by cGMP was confirmed by whole-cell patch-clamp of pulmonary microvascular endothelial cells and intravital imaging of endothelial [Ca(2+)](i). Hence, pressure-induced endothelial Ca(2+) influx via TRPV4 channels increases Lung vascular permeability yet concomitantly activates an NO-mediated negative-feedback loop that protects the vascular barrier by a cGMP-dependent attenuation of the endothelial [Ca(2+)](i) response. The identification of this novel regulatory pathway gives rise to new treatment strategies, as demonstrated in vivo in rats with acute myocardial infarction in which inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil reduced hydrostatic Lung Edema.
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nitric oxide dependent inhibition of alveolar fluid clearance in hydrostatic Lung Edema
American Journal of Physiology-lung Cellular and Molecular Physiology, 2007Co-Authors: Stephanie M Kaestle, Christian Reich, Ning Yin, Helmut Habazettl, Jorg Weimann, Wolfgang M KueblerAbstract:Formation of cardiogenic pulmonary Edema in acute left heart failure is traditionally attributed to increased fluid filtration from pulmonary capillaries and subsequent alveolar flooding. Here, we demonstrate that hydrostatic Edema formation at moderately elevated vascular pressures is predominantly caused by an inhibition of alveolar fluid reabsorption, which is mediated by endothelial-derived nitric oxide (NO). In isolated rat Lungs, we quantified fluid fluxes into and out of the alveolar space and endothelial NO production by a two-compartmental double-indicator dilution technique and in situ fluorescence imaging, respectively. Elevation of hydrostatic pressure induced Ca(2+)-dependent endothelial NO production and caused a net fluid shift into the alveolar space, which was predominantly attributable to impaired fluid reabsorption. Inhibition of NO production or soluble guanylate cyclase reconstituted alveolar fluid reabsorption, whereas fluid clearance was blocked by exogenous NO donors or cGMP analogs. In isolated mouse Lungs, hydrostatic Edema formation was attenuated by NO synthase inhibition. Similarly, Edema formation was decreased in isolated mouse Lungs of endothelial NO synthase-deficient mice. Chronic heart failure results in endothelial dysfunction and preservation of alveolar fluid reabsorption. These findings identify impaired alveolar fluid clearance as an important mechanism in the pathogenesis of hydrostatic Lung Edema. This effect is mediated by endothelial-derived NO acting as an intercompartmental signaling molecule at the alveolo-capillary barrier.
Michael A Matthay - One of the best experts on this subject based on the ideXlab platform.
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ligation of protease activated receptor 1 enhances alpha v beta6 integrin dependent tgf beta activation and promotes acute Lung injury
Journal of Clinical Investigation, 2006Co-Authors: R G Jenkins, Eric Camerer, Michael A Matthay, Chris J Scotton, G J Laurent, G E Davis, Rachel C Chambers, Dean SheppardAbstract:Activation of latent TGF-β by the αvβ6 integrin is a critical step in the development of acute Lung injury. However, the mechanism by which αvβ6-mediated TGF-β activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1 (PAR1), activate TGF-β in an αvβ6 integrin–specific manner. This effect is PAR1 specific and is mediated by RhoA and Rho kinase. Intratracheal instillation of the PAR1-specific peptide TFLLRN increases Lung Edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the αvβ6 integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-β activation; however, this is not observed in Itgb6–/– mice. Furthermore, Itgb6–/– mice are also protected from ventilator-induced Lung Edema. We also demonstrate that pulmonary Edema and TGF-β activity are similarly reduced in Par1–/– mice following bleomycin-induced Lung injury. These results suggest that PAR1-mediated enhancement of αvβ6-dependent TGF-β activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute Lung injury, and they identify PAR1 and the αvβ6 integrin as potential therapeutic targets in this condition.
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effect of pharmacological inhibition of chloride transport on Lung fluid balance in acute escherichia coli pneumonia in mice
Critical Care, 2005Co-Authors: Laurent Robriquet, Hans G Folkesson, James A Frank, Y Song, Michael A MatthayAbstract:Clearance of fluid from the alveolar spaces primary depends on the active sodium transport across distal Lung epithelium. Some experimental studies supported a potential role for the cystic fibrosis transmembrane conductance regulator (CFTR), especially in the cAMP-mediated upregulation of fluid clearance. Hypothetically, pharmacological inhibition of Cl-channels could worsen Lung Edema by decreasing the clearance of alveolar Edema. In this study, we tested the affect of chloride transport inhibition on Lung Edema formation in acute pneumonia.
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the alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome
Critical Care Medicine, 1999Co-Authors: Jerome Pugin, George Verghese, Marieclaude Widmer, Michael A MatthayAbstract:ObjectivesTo determine the concentrations of proinflammatory mediators, collagenases, and procollagen type III peptides in undiluted pulmonary Edema fluids and in plasma obtained in patients with early acute respiratory distress syndrome (ARDS) and in control patients with hydrostatic Lung Edema; an
D Walmrath - One of the best experts on this subject based on the ideXlab platform.
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subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Ralph T Schermuly, Axel Roehl, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christian Schudt, Herrmann Tenor, Friedrich Grimminger, Werner Seeger, D WalmrathAbstract:Aerosolized prostacyclin (PGI 2 ) has been suggested for selective pulmonary vasodilation, but its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition may offer a new strategy for amplification of the vasodilative response to nebulized PGI 2 . In perfused rabbit Lungs, continuous infusion of the thromboxane mimetic U46619 was used to establish stable pulmonary hypertension [increase in pulmonary arterial pressure (pPA) from ∼7 to ∼32 mm Hg], which is accompanied by progressive Edema formation and severe disturbances in gas exchange with a predominance of shunt flow (increase from 2 , dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibitor motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor tolafentrine on pulmonary hemodynamics were established (potency rank order: rolipram > tolafentrine ∼ motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI 2 was chosen to effect a moderate pPA decrease (∼4 mm Hg; rapidly returning to prenebulization values within 10–15 min) with only a slight reduction in shunt flow (∼49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmonary hemodynamics, caused prolongation of the post-PGI 2 decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI 2 to ∼9 to 10 mm Hg, prolonged the post-PGI 2 vasorelaxation to >60 min, reduced the extent of Lung Edema formation by 50%, and decreased the shunt flow to ∼19% (i.v. rolipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude that Lung PDE3/4 inhibition, achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplifies the pulmonary vasodilatory response to inhaled PGI 2 , concomitant with an improvement in ventilation-perfusion matching and a reduction in Lung Edema formation. The combination of nebulized PGI 2 and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension.
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surfactant alterations in severe pneumonia acute respiratory distress syndrome and cardiogenic Lung Edema
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Andreas Gunther, Friedrich Grimminger, D Walmrath, C Siebert, R E Schmidt, S Ziegler, M Yabut, Bettina Temmesfeld, H Morr, Werner SeegerAbstract:Bronchoalveolar lavage fluids (BALF) were analyzed for surfactant abnormalities in 153 patients with acute respiratory failure necessitating mechanical ventilation. Diagnoses were acute respiratory distress syndrome (ARDS) in the absence of Lung infection (n = 16), severe pneumonia (PNEU; n = 88), ARDS and PNEU (n = 36), and cardiogenic Lung Edema (CLE; n = 13). The PNEU group was subdivided into groups with alveolar PNEU (n = 35), bronchial PNEU (n = 16), interstitial PNEU (n = 18) and nonclassified PNEU (n = 19). Comparison with healthy controls (n = 20) was undertaken. Total phospholipids (PL), proteins, PL classes (HPTLC) and surfactant apoproteins SP-A and SP-B (ELISA) were quantified in the original BALF. The 48,000 x g pellet from centrifugation of the BAL was used to assess the percentage of large surfactant aggregates (LSA) and the biophysical properties of the surfactant (pulsating bubble surfactometer). All groups with inflammatory Lung injury (PNEU and/or ARDS) showed some decrease in the lava...
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surfactant alterations in severe pneumonia acute respiratory distress syndrome and cardiogenic Lung Edema
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Andreas Gunther, Friedrich Grimminger, D Walmrath, C Siebert, S Ziegler, M Yabut, Bettina Temmesfeld, H Morr, Reinhold Schmidt, Werner SeegerAbstract:Bronchoalveolar lavage fluids (BALF) were analyzed for surfactant abnormalities in 153 patients with acute respiratory failure necessitating mechanical ventilation. Diagnoses were acute respiratory distress syndrome (ARDS) in the absence of Lung infection (n = 16), severe pneumonia (PNEU; n = 88), ARDS and PNEU (n = 36), and cardiogenic Lung Edema (CLE; n = 13). The PNEU group was subdivided into groups with alveolar PNEU (n = 35), bronchial PNEU (n = 16), interstitial PNEU (n = 18) and nonclassified PNEU (n = 19). Comparison with healthy controls (n = 20) was undertaken. Total phospholipids (PL), proteins, PL classes (HPTLC) and surfactant apoproteins SP-A and SP-B (ELISA) were quantified in the original BALF. The 48,000 x g pellet from centrifugation of the BAL was used to assess the percentage of large surfactant aggregates (LSA) and the biophysical properties of the surfactant (pulsating bubble surfactometer). All groups with inflammatory Lung injury (PNEU and/or ARDS) showed some decrease in the lavageable PL pool, a reduced LSA content in BALF, and a manifold increase in alveolar protein load. Marked changes in the PL profile were noted throughout the groups (a decrease in phosphatidylcholine (PC) and phosphatidylglycerol (PG) and an increase in phosphatidylinositol [PI] and sphingomyelin [SPH]). Concentrations of SP-A but not of SP-B in BALF were reduced. Minimum surface-tension values approached 0 mN/m in controls, and ranged from 10 to 25 mN/m in the absence of supernatant protein and from 20 to 35 mN/m in recombination with leaked protein in the groups with ARDS and/or PNEU. Abnormalities in alveolar PNEU surpassed those in bronchial PNEU, and interstitial PNEU presented a distinct pattern with extensive metabolic changes. All surfactant changes were absent in CLE except for a slight inhibition of surface activity by proteins. We conclude that pronounced surfactant abnormalities, comparable to those in ARDS in the absence of Lung infection, occur in different entities of severe PNEU, but not in CLE.
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staphylococcal alpha toxin induced ventilation perfusion mismatch in isolated blood free perfused rabbit Lungs
Journal of Applied Physiology, 1993Co-Authors: D Walmrath, Friedrich Grimminger, M Scharmann, R Konig, J Pilch, Werner SeegerAbstract:Gas exchange conditions in blood-free perfused isolated rabbit Lungs were assessed by the use of the multiple inert gas elimination technique. Under baseline conditions, unimodal narrow distribution of perfusion and ventilation to midrange-ventilation-perfusion (VA/Q) areas was noted. Intravascular challenge with staphylococcal alpha-toxin caused a rapid increase in pulmonary arterial pressure (to > 40 mmHg within approximately 15 min) and delayed-onset (> 10-15 min) Lung Edema formation, with unaltered ventilation pressures. The vasoconstrictor response was paralleled by a progressive, severe leftward shift of perfusion to areas with low-VA/Q ratios, accompanied by a minor fraction of shunt flow. At pulmonary arterial pressures > 40 mmHg, extreme VA/Q mismatch with near absence of perfusate flow to midrange-VA/Q areas was registered. Vasoconstrictor response and VA/Q mismatch, but not the progressive Edema formation, were virtually completely suppressed in Lungs pretreated with acetylsalicylic acid or the thromboxane receptor antagonist BM 13505. Moreover, "rescue" application of BM 13505 after onset of alpha-toxin-induced pressor response and gas exchange abnormalities completely reversed pressure elevation and loss of VA/Q matching. We conclude that the marked vasoconstrictor response to staphylococcal alpha-toxin is paralleled by severe VA/Q mismatch with predominant perfusion of low-VA/Q areas independent of Lung Edema formation. Pressor response and VA/Q mismatch, but not vascular leakage, are suppressed by thromboxane inhibition.
Friedrich Grimminger - One of the best experts on this subject based on the ideXlab platform.
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subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Ralph T Schermuly, Axel Roehl, Norbert Weissmann, Hossein Ardeschir Ghofrani, Christian Schudt, Herrmann Tenor, Friedrich Grimminger, Werner Seeger, D WalmrathAbstract:Aerosolized prostacyclin (PGI 2 ) has been suggested for selective pulmonary vasodilation, but its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition may offer a new strategy for amplification of the vasodilative response to nebulized PGI 2 . In perfused rabbit Lungs, continuous infusion of the thromboxane mimetic U46619 was used to establish stable pulmonary hypertension [increase in pulmonary arterial pressure (pPA) from ∼7 to ∼32 mm Hg], which is accompanied by progressive Edema formation and severe disturbances in gas exchange with a predominance of shunt flow (increase from 2 , dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibitor motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor tolafentrine on pulmonary hemodynamics were established (potency rank order: rolipram > tolafentrine ∼ motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI 2 was chosen to effect a moderate pPA decrease (∼4 mm Hg; rapidly returning to prenebulization values within 10–15 min) with only a slight reduction in shunt flow (∼49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmonary hemodynamics, caused prolongation of the post-PGI 2 decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI 2 to ∼9 to 10 mm Hg, prolonged the post-PGI 2 vasorelaxation to >60 min, reduced the extent of Lung Edema formation by 50%, and decreased the shunt flow to ∼19% (i.v. rolipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude that Lung PDE3/4 inhibition, achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplifies the pulmonary vasodilatory response to inhaled PGI 2 , concomitant with an improvement in ventilation-perfusion matching and a reduction in Lung Edema formation. The combination of nebulized PGI 2 and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension.
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surfactant alterations in severe pneumonia acute respiratory distress syndrome and cardiogenic Lung Edema
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Andreas Gunther, Friedrich Grimminger, D Walmrath, C Siebert, R E Schmidt, S Ziegler, M Yabut, Bettina Temmesfeld, H Morr, Werner SeegerAbstract:Bronchoalveolar lavage fluids (BALF) were analyzed for surfactant abnormalities in 153 patients with acute respiratory failure necessitating mechanical ventilation. Diagnoses were acute respiratory distress syndrome (ARDS) in the absence of Lung infection (n = 16), severe pneumonia (PNEU; n = 88), ARDS and PNEU (n = 36), and cardiogenic Lung Edema (CLE; n = 13). The PNEU group was subdivided into groups with alveolar PNEU (n = 35), bronchial PNEU (n = 16), interstitial PNEU (n = 18) and nonclassified PNEU (n = 19). Comparison with healthy controls (n = 20) was undertaken. Total phospholipids (PL), proteins, PL classes (HPTLC) and surfactant apoproteins SP-A and SP-B (ELISA) were quantified in the original BALF. The 48,000 x g pellet from centrifugation of the BAL was used to assess the percentage of large surfactant aggregates (LSA) and the biophysical properties of the surfactant (pulsating bubble surfactometer). All groups with inflammatory Lung injury (PNEU and/or ARDS) showed some decrease in the lava...
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surfactant alterations in severe pneumonia acute respiratory distress syndrome and cardiogenic Lung Edema
American Journal of Respiratory and Critical Care Medicine, 1996Co-Authors: Andreas Gunther, Friedrich Grimminger, D Walmrath, C Siebert, S Ziegler, M Yabut, Bettina Temmesfeld, H Morr, Reinhold Schmidt, Werner SeegerAbstract:Bronchoalveolar lavage fluids (BALF) were analyzed for surfactant abnormalities in 153 patients with acute respiratory failure necessitating mechanical ventilation. Diagnoses were acute respiratory distress syndrome (ARDS) in the absence of Lung infection (n = 16), severe pneumonia (PNEU; n = 88), ARDS and PNEU (n = 36), and cardiogenic Lung Edema (CLE; n = 13). The PNEU group was subdivided into groups with alveolar PNEU (n = 35), bronchial PNEU (n = 16), interstitial PNEU (n = 18) and nonclassified PNEU (n = 19). Comparison with healthy controls (n = 20) was undertaken. Total phospholipids (PL), proteins, PL classes (HPTLC) and surfactant apoproteins SP-A and SP-B (ELISA) were quantified in the original BALF. The 48,000 x g pellet from centrifugation of the BAL was used to assess the percentage of large surfactant aggregates (LSA) and the biophysical properties of the surfactant (pulsating bubble surfactometer). All groups with inflammatory Lung injury (PNEU and/or ARDS) showed some decrease in the lavageable PL pool, a reduced LSA content in BALF, and a manifold increase in alveolar protein load. Marked changes in the PL profile were noted throughout the groups (a decrease in phosphatidylcholine (PC) and phosphatidylglycerol (PG) and an increase in phosphatidylinositol [PI] and sphingomyelin [SPH]). Concentrations of SP-A but not of SP-B in BALF were reduced. Minimum surface-tension values approached 0 mN/m in controls, and ranged from 10 to 25 mN/m in the absence of supernatant protein and from 20 to 35 mN/m in recombination with leaked protein in the groups with ARDS and/or PNEU. Abnormalities in alveolar PNEU surpassed those in bronchial PNEU, and interstitial PNEU presented a distinct pattern with extensive metabolic changes. All surfactant changes were absent in CLE except for a slight inhibition of surface activity by proteins. We conclude that pronounced surfactant abnormalities, comparable to those in ARDS in the absence of Lung infection, occur in different entities of severe PNEU, but not in CLE.
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staphylococcal alpha toxin induced ventilation perfusion mismatch in isolated blood free perfused rabbit Lungs
Journal of Applied Physiology, 1993Co-Authors: D Walmrath, Friedrich Grimminger, M Scharmann, R Konig, J Pilch, Werner SeegerAbstract:Gas exchange conditions in blood-free perfused isolated rabbit Lungs were assessed by the use of the multiple inert gas elimination technique. Under baseline conditions, unimodal narrow distribution of perfusion and ventilation to midrange-ventilation-perfusion (VA/Q) areas was noted. Intravascular challenge with staphylococcal alpha-toxin caused a rapid increase in pulmonary arterial pressure (to > 40 mmHg within approximately 15 min) and delayed-onset (> 10-15 min) Lung Edema formation, with unaltered ventilation pressures. The vasoconstrictor response was paralleled by a progressive, severe leftward shift of perfusion to areas with low-VA/Q ratios, accompanied by a minor fraction of shunt flow. At pulmonary arterial pressures > 40 mmHg, extreme VA/Q mismatch with near absence of perfusate flow to midrange-VA/Q areas was registered. Vasoconstrictor response and VA/Q mismatch, but not the progressive Edema formation, were virtually completely suppressed in Lungs pretreated with acetylsalicylic acid or the thromboxane receptor antagonist BM 13505. Moreover, "rescue" application of BM 13505 after onset of alpha-toxin-induced pressor response and gas exchange abnormalities completely reversed pressure elevation and loss of VA/Q matching. We conclude that the marked vasoconstrictor response to staphylococcal alpha-toxin is paralleled by severe VA/Q mismatch with predominant perfusion of low-VA/Q areas independent of Lung Edema formation. Pressor response and VA/Q mismatch, but not vascular leakage, are suppressed by thromboxane inhibition.
