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Biomedical subjects

Werner Seeger

Publications and source records attributed to Werner Seeger.

At least 91 records · Page 5Linked to original sources
PubMed2004

Surfactant abnormalities after single lung transplantation in dogs: impact of bronchoscopic surfactant administration.

OBJECTIVE: Disturbances of the alveolar surfactant system have been implicated in the pathogenesis of reperfusion injury. The aim of this study was to evaluate the influence of exogenous surfactant administration on surfactant properties in a model of single lung transplantation. METHODS: We performed heterologous, left lung transplantation (+4 degrees C ischemia; 24 hours, Euro-Collins solution) in 6 foxhounds (untreated) and in 6 animals that received calf lung surfactant extract (Alveofact) prior to explantation (only donor lung; 50 mg/kg body weight) and immediately after onset of reperfusion (both lungs, 200 mg/kg body weight). Separate but synchronized ventilation of each lung was performed, in a volume-controlled, pressure-limited mode, with animals in prone position. Bronchoalveolar lavage fluids were collected in pretransplantation lungs (control), after 24 hours of ischemia prior to transplantation (0 hours) and 6 and 12 hours after reperfusion in both the grafts and the recipient native lungs. RESULTS: Ischemic storage per se did not provoke any changes of the surfactant system; however, severe alterations occurred within 6 hours of reperfusion, resulting in a severe loss of surface activity, including a decrease in the percentage of the large surfactant aggregate fraction, reduction of the surfactant apoproteins SP-B and SP-C, the dipalmitoyl molecular species of phosphatidylcholine and phosphatidylglycerol within the large surfactant aggregate fraction. These abnormalities were restricted to the graft, with virtually normal surfactant function and composition being found in the recipient native lung. Surfactant administration fully normalized the biochemical and largely improved the biophysical surfactant properties, alongside maintenance of lung gas exchange properties. CONCLUSIONS: Severe surfactant abnormalities occur exclusively in the graft when performing separate, synchronized ventilation of each lung to attenuate ventilator-induced lung injury. Bronchoscopic surfactant administration provides protection against these abnormalities and may be a therapeutic strategy in lung transplantation.

Animals↗
PubMed2004

Bronchoscopic surfactant administration preserves gas exchange and pulmonary compliance after single lung transplantation in dogs.

BACKGROUND: Surfactant abnormalities have been implicated in reperfusion injury and respiratory failure in lung transplantation. METHODS: We investigated the efficacy of bronchoscopic administration of a bovine natural lung surfactant extract (Alveofact) to improve gas exchange and lung mechanics after heterologous left lung transplantation in foxhounds (+4 degrees C ischemia for 24 hours, conservation with Euro-Collins solution). Animals received either no surfactant therapy (untreated controls, n = 6) or 50 mg/kg body weight (prior to explantation, only graft) and 200 mg/kg body weight Alveofact (immediately after reperfusion, both lungs, n = 6). After lung transplantation, separate but synchronized ventilation of each lung was performed in a volume-controlled, pressure-limited mode for 12 hours, with the animals prone. Small catheters were inserted into the pulmonary veins of both the graft and the recipient's native lung for separate blood gas analysis. In the control group, marked protein leakage, influx of neutrophils into the alveolar space, and pulmonary edema formation (extravascular lung water; wet/dry ratio) were encountered in the transplanted lung but only to a very minor extent in the recipient's native lung. RESULTS: Lung compliance values and arterial oxygenation progressively deteriorated in the transplanted but not in the native lungs. Pulmonary hemodynamics did not change significantly. Surfactant administration did not significantly influence the development of reperfusion edema, protein leakage, and neutrophil influx into the grafts. However, surfactant restored the surface activity and the gas exchange (PaO2/FIO2 of 201.2 +/- 20.2 mm Hg vs 119.8 +/- 21.7 mm Hg in controls; P <.05) in the transplanted lungs, and compliance was markedly improved in the surfactant-treated animals (18.8 +/- 1.8 mL/mbar vs 11.5 +/- 1.6 mL/mbar in the controls; P <.05). CONCLUSION: Bronchoscopic surfactant administration does not prevent leukocyte influx or vascular leakage but does protect against respiratory failure and improves lung mechanics in single lung transplantation in dogs.

Animals↗
PubMed2004

Prostacyclin and its analogues in the treatment of pulmonary hypertension.

Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic and antiproliferative properties. All of these properties help to antagonize the pathological changes that take place in the small pulmonary arteries of patients with pulmonary hypertension. Indeed, several prostanoids have been shown to be efficacious to treat pulmonary hypertension, while the main mechanism underlying the beneficial effects remains unknown. There are indications of beneficial combination effects of prostaglandins and phosphodiesterase inhibitors and endothelin receptor antagonists. This speaks in favor of combination therapies for pulmonary hypertension in the future. The mode of application of prostanoids used in randomized controlled studies has been quite variable: continuous i.v. infusion of prostacyclin, continuous s.c. infusion of treprostinil, p.o. application of beraprost, and inhaled application of iloprost. In addition, the applied doses were quite different, ranging from 0.25 ng/kg/min for inhaled iloprost to 30-50 ng/kg/min for i.v. prostacyclin. While the principal pharmacological properties of all prostanoids are very similar due to a main action on IP receptors, there are considerable differences in pharmacokinetics and metabolism, with half-lives of 2 min for prostacyclin and about 34 min for treprostinil for i.v. infused drugs and half-lives of about 85 min for s.c. infused treprostinil. In addition, the adverse effects largely depend on the doses used and the mode of application, although there is great variability between subjects. It remains to be determined which patients will profit most from which substance (or combination) and mode of application.

Epoprostenol↗
PubMed2004

Inhibition of monocyte, lymphocyte, and neutrophil adhesion to endothelial cells by human milk oligosaccharides.

Excessive leukocyte infiltration causes severe tissue damage in a variety of inflammatory diseases. The initial step in leukocyte extravasation is mediated by selectins and oligosaccharides on their glycoconjugate ligands. Human milk is a rich source of lactose-derived oligosaccharides that are partly absorbed in the intestine and excreted with the urine. As these components contain binding determinants for the selectins we investigated whether human milk oligosaccharides are able to affect leukocyte rolling and adhesion to endothelial cells under dynamic conditions. Therefore, monocytes, lymphocytes, or neutrophils isolated from human peripheral blood were passed over TNF-alpha-activated HUVEC under shear stress. The influence of different oligosaccharide fractions was determined by video-microscopy and compared with the effects of various individual oligosaccharides. Within a physiological range (12.5 - 125 microg/ml) the acidic fraction significantly inhibited leukocyte rolling and adhesion (up to 24.0% and 52.8%, respectively) in a concentration-dependent manner. These effects were even more pronounced than those achieved by soluble sialyl-Lewis x, a physiological binding determinant for selectins. Several active components within the oligosaccharide fraction of human milk were identified, e.g. 3'-sialyl-lactose and 3'-sialyl-3-fucosyl-lactose. These results indicate that specific oligosaccharides in human milk may serve as anti-inflammatory components and might therefore contribute to the lower incidence of inflammatory diseases in human milk-fed infants.

Cell Adhesion↗
PubMed2004

Compartment- and cell-specific expression of coagulation and fibrinolysis factors in the murine lung undergoing inhalational versus intravenous endotoxin application.

Intraalveolar and intravascular fibrin formation are typical hallmarks of acute inflammatory lung diseases, and may foster subsequent fibroproliferative events. We investigated the regulation and cellular sources of key coagulation and fibrinolysis factors in lungs undergoing compartmentalized challenge with endotoxin (LPS). BALB/c mice received 15 ng LPS either by intravenous injection or by inhalation. Quantitative gene expression analysis (real-time RT-PCR) was performed for tissue factor (TF), TF pathway inhibitor (TFPI), tissue-type plasminogen activator (t-PA), urokinase-type-PA (u-PA), PA inhibitor-1 (PAI-1), and PAI-2 in peripheral white blood cells (PBC) as well as in alveolar macrophages (AM), type-II pneumocytes (ATII), endothelial cells (EC) and smooth muscle cells (SMC), all obtained by laser microdissection. Neither route of LPS administration caused substantial protein leakage or leukocyte recruitment into the alveolar space. Compartmentalized upregulation of procoagulant and downregulation of fibrinolytic activities was, however, observed in response to both modes of LPS challenge. Intraalveolar endotoxin, in particular, caused strong upregulation of TF ( approximately 20-fold increase in gene expression) and PAI-2 (225-fold increase) in microdissected AM, upregulation of PAI-1 in microdissected ATII (300-fold increase) and EC (180-fold increase), upregulation of t-PA in EC (40-fold), and downregulation of u-PA in vascular smooth muscle cells. TFPI was largely unchanged in all cell types, and PBC showed no major gene regulatory response to inhaled endotoxin. We conclude that the lung possesses a cell-specific alveolar coagulation and fibrinolysis system, being independent of the vascular coagulation cascade and responding readily with enhanced procoagulant and anti-fibrinolytic activities to LPS challenge.

Administration, Inhalation↗
PubMed2004

Reversal of nocturnal periodic breathing in primary pulmonary hypertension after lung transplantation.

Nocturnal periodic breathing (PB) closely resembling Cheyne-Stokes respiration in congestive heart failure has been reported to occur in end-stage primary pulmonary hypertension (PPH). We herein describe the clinical course of a 56-year-old female patient with PPH and severe hypoxemia, hypocapnia, and right ventricular compromise in whom sleep-disordered breathing (SDB) resolved after successful double-lung transplantation. This case illustrates the crucial roles of blood gas alterations and hemodynamic impairment in the emergence of PB in PPH, and is in favor of a genuine association between advanced right heart failure and the development of SDB.

Cheyne-Stokes Respiration↗
PubMed2003

RNA interference for HIF-1alpha inhibits its downstream signalling and affects cellular proliferation.

Transcription factor HIF-1 is a key determinant of oxygen-dependent gene regulation. Suppression of HIF-1alpha is important for exploring HIF-1-dependent processes and for interfering with hypoxia-induced pathophysiological events. This study applied RNA-interference targeting HIF-1alpha to the human lung A549 cell line. Transfection of HIF-1alpha-siRNA reduced HIF-1alpha synthesis as measured on mRNA and protein level by realtime RT-PCR, Western blot, and immuncytochemistry. A time kinetic for hypoxic stabilization of HIF-1alpha protein and its inhibition by HIF-1alpha-siRNA is included. Hypoxic induction of HIF-1-controlled target genes as heme oxygenase I (HO-1), phosphoglycerate kinase (PGK), and vascular endothelial growth factor (VEGF) was markedly attenuated by HIF-1alpha-siRNA treatment. Correspondingly, gene activation via hypoxia-responsive-element, as shown by reporter gene assay, was inhibited by HIF-1alpha-siRNA. Moreover, this approach was found to suppress the shift from from S-phase to G1-phase observed in A549 cells in response to hypoxia, supporting a role of HIF-1alpha in oxygen-dependent cell cycle regulation.

Cell Division↗
PubMed2003

Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.

Bleomycin is a well known fibrogenic agent, provoking an initial adult respiratory distress syndrome-like injury with subsequent strong fibroproliferative response. Severe abnormalities of the alveolar surfactant system, which may be linked to the appearance of alveolar fibrin deposition, have been implicated in the pathogenetic sequence of events. Using a model of standardized aerosol delivery of 1.8 U bleomycin/kg body weight in rabbits, we investigated the influence of repetitive nebulization of heparin or urokinase-type plasminogen activator (u-PA) on the development of lung fibrosis. In an "early" (Days 2-12 postbleomycin) or "late" (Days 14-24 post-bleomycin) treatment protocol, approximately 3,500 U heparin or approximately 6,500 U u-PA was delivered to the bronchoalveolar space. Within four weeks, the bleomycin challenge provoked severe pulmonary fibrosis with reduction of lung compliance, marked increase in soluble collagen (bronchoalveolar lavage fluid) and hydroxyproline content (lung tissue), a typical reticular fibrosis pattern on high-resolution computed tomography, and typical histologic findings. Therapeutic intervention resulted in a far-reaching normalization of compliance, suppression of soluble collagen and hydroxyproline accumulation, and virtual abrogation of the computed tomography scan and histologic features of lung fibrosis, with most prominent effects seen in the early heparin and late u-PA administration. No bleeding complications occurred. These findings strongly support the concept that alveolar fibrin generation is an important event in the development of postbleomycin lung fibrosis. "Compartmentalized" anticoagulation and/or fibrinolysis via inhalational deposition of interventional agents in the alveolar compartment may thus offer a new therapeutic strategy for prevention of fibrosis.

Administration, Inhalation↗
PubMed2003

Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans.

Potential impact of omega-3 fatty acids, as contained in fish oil, on immunological function has been suggested because observations of reduced inflammatory diseases in Greenland Inuit were published. A fish oil-based lipid emulsion has recently been approved for parenteral nutrition in many countries. We investigated the influence of a short infusion course of fish oil-based (omega-3) vs conventional (omega-6) lipid emulsion on monocyte function. In a randomized design, twelve healthy volunteers received omega-3 or omega-6 lipid infusion for 48 h, with cross-over repetition of the infusion course after 3 mo. Fatty acid profiles, monocyte cytokine release and adhesive monocyte-endothelium interaction were investigated. Resultant omega-6 lipid emulsion increased plasma-free fatty acids including arachidonic acid, whereas the omega-3/omega-6 fatty acid ratio in monocyte membranes remained largely unchanged. It also caused a tendency toward enhanced monocyte proinflammatory cytokine release and adhesive monocyte-endothelium interaction. In contrast, omega-3 lipid emulsion significantly increased the omega-3/omega-6 fatty acid ratio in the plasma-free fatty acid fraction and in monocyte membrane lipid pool, markedly suppressing monocyte generation of TNF-alpha, IL-1, IL-6, and IL-8 in response to endotoxin. In addition, it also significantly inhibited both monocyte-endothelium adhesion and transendothelial monocyte migration, although monocyte surface expression of relevant adhesive molecules (CD11b, CD18, CD49 days, CCR2) was unchanged. Although isocaloric, omega-3 and omega-6 lipid emulsions exert differential impact on immunological processes in humans. In addition to its nutritional value, fish oil-based omega-3 lipid emulsion significantly suppresses monocyte proinflammatory cytokine generation and features of monocyte recruitment.

Adult↗
PubMed2003

Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats.

Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.

Administration, Oral↗
PubMed2003

Omega-3 vs. omega-6 lipid emulsions exert differential influence on neutrophils in septic shock patients: impact on plasma fatty acids and lipid mediator generation.

OBJECTIVE: To compare the effects of a conventional omega-6 lipid infusion and a fish oil based (omega-3) lipid infusion for parenteral nutrition on neutrophil function, lipid mediators, and plasma free fatty acids. DESIGN AND SETTING: Open-label, randomized, pilot study in a university hospital medical intensive care unit and experimental laboratory. PATIENTS AND PARTICIPANTS: Ten patients with septic shock and eight healthy controls. INTERVENTIONS: Patients (five per group) requiring parenteral nutrition received intravenously either a omega-3 or a omega-6 lipid emulsion for a 10-day period. MEASUREMENTS AND RESULTS: At baseline levels of plasma free fatty acids were elevated several-fold, including high concentrations of the omega-6 lipid precursor arachidonic acid (AA). Neutrophils isolated from septic patients displayed markedly reduced responsiveness to ex vivo stimulation, including lipid mediator generation [leukotrienes (LT), PAF], respiratory burst, and phosphoinositide hydrolysis signaling. Under the omega-6 lipid infusion regimen abnormalities in plasma free fatty acids and impairment of neutrophil functions persisted or worsened. In contrast, a rapid switch in the plasma free fatty acid fraction to predominance of the omega-3 acids eicosapentaenoic acid and docosahexaenoic acid over AA occurred in response to omega-3 lipid infusion. LTB(5), in addition to LTB(4), appeared upon neutrophil stimulation originating from these patients, and neutrophil function was significantly improved in the omega-3 lipid group. CONCLUSIONS: omega-3 vs. omega-6 lipid emulsions differentially influence the plasma free fatty acid profile with impact on neutrophil functions. Lipid-based parenteral nutrition in septic patients may thus exert profound influence on sequelae and status of immunocompetence and inflammation.

Adult↗
PubMed2003

Circulating vascular progenitor cells do not contribute to compensatory lung growth.

The biological principles that underlie the induction and process of alveolization in the lung as well as the maintenance of the complex lung tissue structure are one of the major obstacles in pulmonary medicine today. Bone marrow-derived cells have been shown to participate in angiogenesis, vascular repair, and remodeling of various organs. We addressed this phenomenon in the lung vasculature of mice in a model of regenerative lung growth. C57BL/6 mice were transplanted with bone marrow from one of three different reporter gene-transgenic strains. flk-1+/lacZ mice, tie-2/lacZ transgenic mice (both exhibiting endothelial cell-specific reporter gene expression), and ubiquitously enhanced green fluorescent protein (eGFP)-expressing mice served as marrow donors. After hematopoietic recovery, compensatory lung growth was induced by unilateral pneumonectomy and led to complete restoration of initial lung volume and surface area. The lungs were consecutively investigated for bone marrow-derived vascular cells by lacZ staining and immunohistochemistry for phenotype identification of vascular cells. lacZ- or eGFP-expressing bone marrow-derived endothelial cells could not be found in microvascular regions of alveolar septa. Single eGFP-positive endothelial cells were detected in pulmonary arteries at very low frequencies, whereas no eGFP-positive vascular smooth muscle cells were observed. In conclusion, we demonstrate in a model of lung growth and alveolization in adult mice the absence of significant bone marrow-derived progenitor cell contribution to the concomitant vascular growth and remodeling processes.

Animals↗
PubMed2003

Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension.

OBJECTIVES: We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost. BACKGROUND: Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy. METHODS: Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged. RESULTS: Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Effects of mitochondrial inhibitors and uncouplers on hypoxic vasoconstriction in rabbit lungs.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange; however, the underlying mechanism has not yet been fully elucidated. Lung nitric oxide (NO) generation appears to be involved in this process. Recently, mitochondria have been proposed as oxygen sensors, with HPV signaling via a hypoxia-induced increase in the generation of reactive oxygen species derived from mitochondrial complex III and escaping through an anion channel into the cytoplasm. In addition, complex II has been suggested to be specifically involved in hypoxia-dependent generation of reactive oxygen species in the lung. We investigated the effects of several mitochondrial inhibitors and uncouplers on the strength of HPV, and asked for their capacity to mimic HPV during normoxia in isolated buffer-perfused rabbit lungs. Specificity of the agents for HPV was tested by comparison of their effects on non-hypoxia-induced vasoconstriction, elicited by the thromboxane mimetic U46619. Interference with NO metabolism was determined by performing parallel studies with blocked lung NO generation and by measurement of exhaled NO. Rotenone, 3-nitroproprionic acid, and myxothiazol dose-dependently inhibited HPV without being mimics of HPV during normoxia. The inhibitory effect of these agents was only partly specific for HPV by comparison with U46619-induced vasoconstriction. During pre-blocked lung NO synthesis, the selectivity for HPV inhibition was increased for rotenone, but largely lost for myxothiazol. 2-tenoyltrifluoroacetone resulted in an unspecific inhibition of HPV as compared with U46619-induced vasoconstriction. 1-methyl-4-phenylpyridinium iodide and 2-heptyl-4-hydroxyquinoline-N-oxide specifically suppressed HPV and increased normoxic vascular tone. Antimycin A suppressed HPV, an effect being specific in lungs with intact NO synthesis and only partly specific while blocking NO. However, this agent did not mimic HPV during normoxia, as may be expected for interference with the mitochondrial electron transport downstream in complex III. The uncouplers 2,4-dinitrophenol (DNP, 10-200 microM) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP, 1-3 microM) induced sustained vasoconstriction during normoxia, with enhancement of HPV by DNP at low and suppression of HPV for both agents at high concentrations. The anion channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid inhibited HPV and U46619-induced vasoconstriction with identical dose-response curves. These findings suggest that mitochondria are in some manner involved in the regulation of HPV in intact rabbit lungs. The hypothesis that enhanced superoxide leak at complex III of mitochondria represents the underlying mechanism of acute HPV is supported by the rotenone and 2-heptyl-4-hydroxyquinoline-N-oxide data, but partly contradicted by the findings with 1-methyl-4-phenylpyridinium iodide, antimycin A, DNP, and FCCP. Further studies are mandatory to clarify the link between mitochondrial respiratory chain and hypoxic pulmonary vasoconstriction.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2003

Impact of surface tension on the conversion rate of large to small surfactant aggregates.

The extracellular alveolar surfactant can be separated into the highly surface active large surfactant aggregates (LA) and the less active small surfactant aggregates (SA). Conversion of LA to SA is encountered upon cyclic surface area changes and demands the presence of enzymatic activity. In the present study we investigated the influence of surface tension on the conversion of LA to SA. Bronchoalveolar lavage fluid (BALF) obtained from healthy rabbits was cycled for various time periods in absence or presence of increasing amounts of serum proteins or oleic acid. LA were isolated, quantified and the minimum surface tension (gamma(min)) of uncycled or cycled LA was assessed in absence or presence of increasing amounts of serum proteins or oleic acid. In additional experiments, already cycled LA with a gamma(min) of approximately 20 mN/m were pooled, diluted to a similar PL concentration as original BALF and cycled a second time. Serum proteins and oleic acid dose-dependently: (i) increased the gamma(min) values of LA when added to the isolated LA; and (ii) decreased the LA to SA conversion when added to BALF. These events were directly correlated, suggesting inhibition of LA to SA conversion by increase in gamma(min) of the LA fraction. In line with this suggestion, already cycled LA displaying poor surface activity showed no further conversion in a second cycling maneuver, whereas LA being similarly prepared from uncycled BALF did. We conclude that LA to SA conversion is inversely correlated with the surface tension of the LA fraction. An increase in gamma(min) of the LA fraction during the cycling procedure blocks further LA to SA conversion and may thus represent a negative feedback mechanism.

Animals↗
PubMed2003

Subthreshold doses of nebulized prostacyclin and rolipram synergistaically protect against lung ischemia-reperfusion.

BACKGROUND: Pulmonary edema caused by increased microvascular permeability is an important feature of lung ischemia-reperfusion (I/R) injury. METHODS: We investigated the impact of co-aerosolized prostaglandin (PG)I(2) and the 3',5-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor rolipram on microvascular leakage following I/R injury. Buffer-perfused rabbit lungs were exposed to 270 minutes of warm ischemia while anoxic ventilation and a positive intravascular pressure were maintained. RESULTS: On reperfusion, a massive increase of the capillary filtration coefficient and severe edema formation were noted, whereas microvascular pressures displayed only minor changes. Short-time aerosolization of subthreshold doses of either rolipram (33 microg) or PGI(2) (2.6 microg) at the beginning of ischemia did not attenuate the leakage response, whereas the co-aerosolization of both agents largely blocked any permeability increase and edema formation, independent of hemodynamic effects. The same was true when the co-aerosolization was undertaken before onset of ischemia. Similarly, the intravascular administration of rolipram and PGI(2) showed a synergistic reduction of I/R-induced vascular leak but demanded 10-fold higher doses. Intravascular release of cAMP was markedly enhanced on combined PGI(2)-rolipram administration but depended on the mode of delivery of these agents. CONCLUSIONS: Low doses of aerosolized prostacyclin and rolipram synergistically protect against severe lung I/R injury and can be used independently of lung perfusion. This strategy may be suitable for an improvement of organ preservation in lung transplantation including early management of non-heart-beating donors.

Animals↗
PubMed2003

Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis.

Coordinated neutrophil and monocyte recruitment is a characteristic feature of acute lung inflammatory responses. We investigated the role of monocyte chemotactic protein-1 (CCL2, JE) and the chemokine receptor CCR2 in regulating alveolar leukocyte traffic. Groups of wild-type (WT) mice, CCR2-deficient mice, lethally irradiated CCR2-deficient and WT mice that were reciprocally bone marrow transplanted (chimeric CCR2 deficient and WT, respectively), chimeric CCR2-deficient mice with an enriched CCR2(+) alveolar macrophage population, and CCR2-deficient mice transfused with CCR2(+) mononuclear cells were treated with intratracheal CCL2 and/or Escherichia coli endotoxin. Our data show that alveolar monocyte recruitment is strictly dependent on CCR2. LPS-induced neutrophil migration to the lungs is CCR2 independent. However, when CCR2-bearing blood monocytes are present, alveolar neutrophil accumulation is accelerated and drastically amplified. We suggest that this hitherto unrecognized cooperativity between monocytes and neutrophils contributes to the strong, coordinated leukocyte efflux in lung inflammation.

Adoptive Transfer↗