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Biomedical subjects

D Walmrath

Publications and source records attributed to D Walmrath.

At least 37 records · Page 2Linked to original sources
PubMed2000

Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome.

Changes in the alveolar hemostatic balance in severe pneumonia were compared with those in the acute respiratory distress syndrome (ARDS). Analysis was performed in bronchoalveolar lavage fluids (BALF) of patients with ARDS triggered by nonpulmonary underlying events in the absence of lung infection (ARDS; n = 25), pneumonia demanding mechanical ventilation (PNEU-vent; n = 114), spontaneously breathing patients with pneumonia (PNEU-spon; n = 40), and ARDS in combination with lung infection (ARDS+PNEU; n = 43); comparison with healthy control subjects (n = 35) was performed. In all groups of patients, BALF total procoagulant activity was increased by nearly two orders of magnitude, being largely attributable to the tissue factor pathway of coagulation. Concomitantly, markedly reduced overall fibrinolytic capacity (fibrin plate assay) was noted in the lavage fluids of all patients. BALF levels of urokinase-type plasminogen activator were significantly reduced throughout, whereas the lavage concentrations of tissue-type plasminogen activator did not differ from those in control subjects. In addition, markedly enhanced levels of plasminogen activator- inhibitor I and alpha(2)-antiplasmin were noted in ARDS, ARDS+PNEU, and PNEU-vent, but not in PNEU-spon. In all groups of patients, the changes in the lavage enzymatic activities were paralleled by manifold increased BALF concentrations of fibrinopeptide A and D-dimer, reflecting in vivo coagulation processes. Within the overall number of patients with pneumonia, changes in the alveolar hemostatic balance were more prominent in alveolar and interstitial pneumonia than in bronchopneumonia. Acute inflammatory lung injury, whether triggered by nonpulmonary systemic events or primary lung infection, is thus consistently characterized by both enhanced procoagulant and depressed fibrinolytic activities in the alveolar lining layer, with the appearance of fibrin formation in this compartment. Profile and extent of changes in severe pneumonia demanding respirator therapy are virtually identical to those in ARDS, whereas somewhat less prominent alterations of the alveolar hemostatic balance are noted in spontaneously breathing patients with pneumonia.

Adolescent↗
PubMed2000

Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange.

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 approximately 7 to approximately 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 to approximately 58%, as assessed by the multiple inert gas elimination technique). In the absence of PGI(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 approximately motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI(2) was chosen to effect a moderate pPA decrease (approximately 4 mm Hg; rapidly returning to prenebulization values within 10-15 min) with only a slight reduction in shunt flow (approximately 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 approximately 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 approximately 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.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease.

Bronchoalveolar lavage fluids (BALF) from patients with hypersensitivity pneumonitis (HP; n = 35), idiopathic pulmonary fibrosis (IPF, n = 41) and sarcoidosis (SARC, n = 48) were investigated for alterations in the alveolar hemostatic balance. Healthy individuals (n = 21) served as Controls. Procoagulant activity (PCA), tissue factor (TF) activity and F VII activity were assessed by means of specific recalcification assays. The overall fibrinolytic activity (FA) was measured using the (125)I-labeled fibrin plate assay. Fibrinopeptide A (FP-A), D-Dimer, plasminogen activators (PA) of the urokinase (u-PA) or tissue type (t-PA), PA-inhibitor I (PAI-1) and alpha2-antiplasmin (alpha2-AP) were determined by ELISA technique. As compared to Controls, all groups with interstitial lung disease (ILD) displayed an increase in BALF PCA by approximately one order of magnitude, and this was ascribed to enhanced TF activity by >98%. Accordingly, F VII-activity was increased in all ILD groups, and elevated FP-A levels were noted. There was no significant difference in procoagulant activities between the different ILD entities, but the increase in TF was significantly correlated with deterioration of lung compliance. Overall fibrinolytic activity did not significantly differ between ILD entities and Controls, although some reduction in IPF subjects was observed. Nevertheless, changes in the profile of the different pro- and antifibrinolytic compounds were noted. U-PA, but not t-PA levels were significantly reduced in all ILD groups. alpha2-AP was markedly elevated throughout, whereas PAI-1 levels were lowered. As a balance of

Adolescent↗
PubMed1999

Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis.

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I(2) caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mm Hg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn. s. cm(-)(5) (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn. s. cm(-)(5). In contrast, both intravenous PGI(2) and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI(2) infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI(2) analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI(2) or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Administration, Inhalation↗
PubMed1999

Prostacyclin enhances stretch-induced surfactant secretion in alveolar epithelial type II cells.

Inhalative vasodilator therapy, employing gaseous nitric oxide (NO) or aerosolized prostaglandin PGI(2), is of interest for regional pulmonary vasodilation in ARDS and pulmonary hypertension. We investigated the impact of the NO donor spermine NONOate as well as PGI(2) and its stable chemical analog iloprost on cultured rat alveolar epithelial type II cell (ATII) surfactant secretion. The NO donor provoked a significant increase in the ATII cGMP content, further enhanced by type V phosphodiesterase (PDE) inhibition, but affected neither baseline nor mechanical stretch-induced surfactant secretion. The prostanoids caused a marked increase in the epithelial cAMP content, further amplified by coadministration of type III/IV PDE inhibitors. Baseline surfactant secretion was not altered by this approach, but mechanical stretch-induced liberation of surfactant was significantly increased, most prominently in the ATII with the highest cAMP levels due to the presence of both iloprost and PDE III/IV inhibitors. In contrast, epithelial phosphoinositide metabolism, well responsive to purinergic stimulation as positive control, was unchanged in prostanoid-exposed cells. We conclude that the PGI(2)-cAMP axis, but not the NO-cGMP axis, forwards a markedly enhanced secretory response to the physiological stimulus of cell surface stretching, which may be relevant for therapeutic use of these agents.

Analysis of Variance↗
PubMed1999

Ventilation-perfusion mismatch after lung ischemia-reperfusion. Protective effect of nitric oxide.

Lung ischemia-reperfusion provokes pulmonary hypertension and increased microvascular permeability with subsequent edema formation and hypoxemia. We exposed buffer-perfused rabbit lungs to 120 and 180 min of warm ischemia. After reperfusion, gas exchange disturbances were analyzed by the multiple inert gas elimination technique (MIGET). Additionally, ischemic lungs were treated with different doses of inhaled nitric oxide (NO) throughout reperfusion. Reperfusion provoked a transient pulmonary artery pressure elevation, followed by progressive pulmonary edema formation. After 120 min of ischemia, severe ventilation-perfusion (V A/Q) mismatch developed within 15 min of reperfusion, with the appearance of low V A/Q areas and marked broadening of both perfusion and ventilation distribution in the midrange V A/Q regions. In parallel, shunt flow increased from less than 2% to approximately 17%. Inhalation of NO suppressed the pressor response, edema formation, as well as V A/Q mismatch and shunt flow. Concentrations of 10 and 50 ppm NO were equipotent, surpassing the efficacy of 1 or 250 ppm NO. Inhalation of NO, however, did not protect from the overwhelming gas exchange and fluid balance disturbances provoked by 180 min ischemia. In conclusion, severe abnormalities in gas exchange occurred rapidly upon reperfusion of ischemic lungs. Prophylactic NO inhalation may be considered for maintenance of gas exchange in settings of ischemia-reperfusion including lung transplantation.

Administration, Inhalation↗
PubMed1999

Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.

Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Recovery from circulatory shock in severe primary pulmonary hypertension (PPH) with aerosolization of iloprost.

OBJECTIVE: The treatment of decompensated right ventricular failure with vasodilators is difficult due to reduced systemic pressure and/or ventilation/perfusion (V/Q) mismatch with hypoxemia. In a recent study we demonstrated that inhaled vasodilatory prostanoids may offer a new strategy to achieve pulmonary selective vasodilatation and improvement of right ventricular function. We applied this new approach to a patient with circulatory shock due to primary pulmonary hypertension (PPH), complicated by a pulmonary infiltrate, who did not tolerate intravenous prostacyclin. DESIGN: Case report. SETTING: Intensive Care Unit (ICU), Medizinische Klinik Giessen, Germany. PATIENT: A 45-year-old woman with PPH presenting with decompensated right heart failure (ascites, pleural effusion), circulatory shock and commencing renal and hepatic failure, despite maximum therapy including the use of catecholamines. INTERVENTION: Intermittent inhalation of aerosolized iloprost, the stable analogue of prostacyclin, and comparison to inhaled nitric oxide (NO). Subsequent long-term therapy with aerosolized iloprost, 150 microg/day. MEASUREMENTS AND RESULTS: In response to inhaled iloprost, pulmonary arterial pressure (PAP) decreased from 65 to 61 mmHg, cardiac index (CI) increased from 1.25 to 1.85 l/min per m2, and pulmonary vascular resistance (PVR) decreased from 2416 to 1549 dyn/s per cm5 while inhaled NO decreased the PVR from 2280 to 1920 dyn/s per cm5 without a decrease in PAP. Both of these interventions increased the arterial pO2 but did not change the systemic arterial pressure. In contrast, intravenous prostacyclin was not tolerated, due to systemic side effects. During repeated inhalations with iloprost, the baseline hemodynamics and gas exchange improved dramatically and renal and liver functions normalized. During 1 year of continued therapy, the clinical status improved very much, concomitant with improved hemodynamics, and the patient has been taken off the transplantation list. CONCLUSIONS: Inhalation of aerosolized iloprost may offer a new life-saving strategy in near desperate cases of pulmonary hypertension in which intravenous prostacyclin cannot be applied due to severe side effects.

Administration, Inhalation↗
PubMed1998

Cyclooxygenase isoenzyme localization and mRNA expression in rat lungs.

Prostanoid generation may proceed via both isoforms of cyclooxygenase, Cox-1 and Cox-2. Cox-1 is thought to be ubiquitously expressed, whereas Cox-2 is mostly assumed to be dynamically regulated, responding to inflammatory stimuli. The cellular localization of Cox-1 and Cox-2 in the lung, an organ with high cyclooxygenase activity, is not known. In normal rat lungs the expression and localization of Cox-1 and Cox-2 were examined with immunogold-silver staining and the RT-PCR technique. Quantitative image analysis of the staining intensity was performed by measuring mean gray values of digitized epipolarization images. Expression of both Cox-1 and Cox-2 was readily detectable in rat lungs. Cox-1 immunoreactivity localized predominantly to bronchial epithelial cells, smooth muscle cells of large hilum veins, and (with lower expression) to alveolar macrophages and pulmonary artery endothelial cells. The most intense Cox-2 staining was noted in macrophage- and mast cell-like cells, detected in close vicinity to the bronchial epithelium and in the connective tissue surrounding the vessels. In addition, strong Cox-2 expression was found in smooth muscle cells of partially muscular vessels and large veins of the hilum. Bronchial epithelial cells displayed Cox-2 immunoreactivity with limited intensity. Alveolar macrophages and alveolar septal cells were only occasionally stained with anti-Cox-2 antibodies. Both Cox-1 and Cox-2 are constitutively expressed in several cell types of normal rat lung, but display clearly different patterns of cellular localization. Cox-2 may not be related only to lung inflammation, but is suggested to be implicated in regulatory processes under physiological conditions as well.

Animals↗
PubMed1997

Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs.

In prior studies of perfused lungs, endotoxin priming markedly enhanced thromboxane (Tx) generation and Tx-mediated vasoconstriction in response to secondarily applied bacterial exotoxins. The present study addressed this aspect in more detail by employing precursor and intermediates of prostanoid synthesis and performing functional testing of vasoreactivity and measurement of product formation. Rabbit lungs were buffer perfused in the absence or presence of 10 ng/ml endotoxin. Repetitive intravascular bolus applications of free arachidonic acid provoked constant pulmonary arterial pressor responses and constant release reactions of TxA2 and prostaglandin (PG) I2 in nonprimed lungs. Within 60-90 min of endotoxin recirculation, which provoked progressive liberation of tumor necrosis factor-alpha but did not effect any hemodynamic changes by itself, both pressor responses and prostanoid release markedly increased, and both events were fully blocked by cyclooxygenase (Cyclo) inhibition with acetylsalicylic acid (ASA). The unstable intermediate PGG2 provoked moderate pressor responses, again enhanced by preceding endotoxin priming and fully suppressed by ASA. Vasoconstriction also occurred in response to the direct Cyclo product PGH2, again amplified after endotoxin pretreatment, together with markedly enhanced liberation of TxA2 and PGI2. In the presence of ASA, the priming-related increase in pressor responses and the prostanoid formation were blocked, but baseline vasoconstrictor responses corresponding to those in nonprimed lungs were maintained. Pressor responses to the stable Tx analog U-46619 were not significantly increased by endotoxin pretreatment, but some generation of TxA2 and PGI2 was also noted under these conditions. We conclude that endotoxin priming exerts profound effects on the lung vascular prostanoid metabolism, increasing the readiness to react with Tx-mediated vasoconstrictor responses to various stimuli, suggesting that enhanced Cyclo activity is an important underlying event.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Impact of arachidonic versus eicosapentaenoic acid on exotonin-induced lung vascular leakage: relation to 4-series versus 5-series leukotriene generation.

Escherichia coli hemolysin (HlyA) is a proteinaceous pore-forming exotoxin that is implicated as a significant pathogenicity factor in extraintestinal E. coli infections including sepsis. In perfused rabbit lungs, subcytolytic concentrations of the toxin evoke thromboxane-mediated vasoconstriction and prostanoid-independent protracted vascular permeability increase (11). In the present study, the influence of submicromolar concentrations of free arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the HlyA-induced leakage response was investigated. HlyA at concentration from 0.02 to 0.06 hemolytic units/ml provoked a dose-dependent, severalfold increase in the capillary filtration coefficient (Kfc), accompanied by the release of leukotriene(LT)B4, LTC4, and LTE4 into the recirculating buffer fluid. Simultaneous application of 100 nmol/L AA markedly augmented the HlyA-elicited leakage response, concomitant with an amplification of LTB4 release and a change in the kinetics of cysteinyl-LT generation. In contrast, 50 to 200 nmol/L EPA suppressed in a dose-dependent manner the HlyA-induced increase in Kfc values. This was accompanied by a blockage of 4-series LT generation and a dose-dependent appearance of LTB5, LTC5, and LTE5. In addition, EPA fully antagonized the AA-induced amplification of the HlyA-provoked Kfc increase, again accompanied by a shift from 4-series to 5-series LT generation. We conclude that the vascular leakage provoked by HlyA in rabbit lungs is differentially influenced by free AA versus free EPA, related to the generation of 4- versus 5-series leukotrienes. The composition of lipid emulsions used for parenteral nutrition may thus influence inflammatory capillary leakage.

Animals↗
PubMed1997

Ultrasonic nebulization for efficient delivery of surfactant in a model of acute lung injury. Impact on gas exchange.

We investigated the effect of ultrasonic nebulization versus instillation of exogenous surfactant on gas exchange abnormalities provoked by detergent inhalation in perfused rabbit lungs. Ventilation-perfusion (VA/Q) distribution was assessed by the multiple inert gas elimination technique. For nebulization of natural bovine surfactant (Alveofact), an ultrasonic device was placed in line with the inspiratory gas flow tubing, manufacturing particles with a mass median aerodynamic diameter of approximately 4.5 microM and high aerosol concentration. In vitro studies demonstrated biochemical and biophysical integrity of postnebulization surfactant. Lung aerosol deposition was monitored by a laser-photometric technique. In lungs with sham inhalation of saline, tracheal instillation of surfactant (approximately 11 mg/kg body weight, infused over 50 min) provoked substantial VA/Q mismatch and limited shunt flow, whereas lung surfactant deposition by ultrasonic nebulization (approximately 7 to 9 mg/kg body weight; nebulization time, 50 min) did not interfere with physiologic gas exchange. Tween 20 inhalation provoked severe VA/Q mismatch with predominant shunt-flow (approximately 21%). This was not reversed by "rescue" application of instilled surfactant, but largely reversed by nebulized surfactant (shunt reduced to 5.5%; p < 0.01). Analysis of postaerosol lavage fluid demonstrated partial reconstitution of surface activity by nebulized surfactant. We conclude that ultrasonic nebulization may be employed for efficient delivery of functionally intact natural surfactant to the distal bronchoalveolar space. This approach effects rapid improvement of gas exchange in a model of acute homogeneous lung injury.

Aerosols↗
PubMed1997

Synergism between endotoxin priming and exotoxin challenge in provoking severe vascular leakage in rabbit lungs.

Lipopolysaccharides (LPS) of gram-negative bacteria prime rabbit lungs for enhanced thromboxane-mediated vasoconstriction upon subsequent challenge with the exotoxin Escherichia coli hemolysin (HlyA) (Walmrath et al. J. Exp. Med. 1994;180:1437-1443). We investigated the impact of endotoxin priming and subsequent HlyA challenge on lung vascular permeability while maintaining constancy of capillary pressure. Rabbit lungs were perfused in a pressure-controlled mode in the presence of the thromboxane receptor antagonist BM 13.505, with continuous monitoring of flow. Perfusion for 180 min with 10 ng/ml LPS did not provoke vasoconstriction or alteration of capillary filtration coefficient (Kfc) values. HlyA (0.021 hemolytic units/ml) induced thromboxane release and a transient decrease in perfusion flow in the absence of significant changes in Kfc. Similar results were obtained when LPS and HlyA were coapplied simultaneously. However, when the HlyA challenge was undertaken after 180 min of LPS priming, a manifold increase in Kfc values was noted, with concomitant severe lung edema formation, although capillary pressure remained unchanged. Thus, endotoxin primes the lung vasculature to respond with a severe increase in vascular permeability to a subsequent low-dose application of HlyA. Such synergism between endotoxin priming and exotoxin challenge in provoking lung vascular leakage may contribute to the pathogenesis of respiratory failure in sepsis and severe lung infection.

Animals↗
PubMed1997

Synthesis of 4- and 5-series leukotrienes in the lung microvasculature challenged with Escherichia coli hemolysin: critical dependence on exogenous free fatty acid supply.

Escherichia coli hemolysin (HlyA) has been identified as a potent inductor of phosphoinositide hydrolysis and related metabolic responses in neutrophils (Grimminger and colleagues, 1991, J. Clin. Invest. 88:1531-1539). In isolated perfused rabbit lungs, which harbor a large number of entrapped microvascular leukocytes, we investigated the effect of a low dose of HlyA on lipoxygenase product formation in the presence of exogenous free arachidonic acid (AA), eicosapentaenoic acid (EPA), or both precursor fatty acids. Leukotrienes (LT) and hydroxyeicosatetra(penta)enoic acids (HET[P]E) in the recirculating perfusate were quantified using high-performance liquid chromatography techniques. In the absence of exogenous precursor fatty acid supply, 0.02 hemolytic units/ml HlyA elicited only minor amounts of LTs and 5-HETE. AA, 10 microM, provoked the generation of limited quantities of LTB4, LTE4, and 5-HETE. Combined application of HlyA and AA caused a manifold amplification of 4-series LT and 5-HETE generation, with predominance of cysteinyl-LTs. EPA, 10 microM, elicited the synthesis of 5-series LTs accompanied by marked quantities of 5-HEPE. Dual stimulation with HlyA and EPA provoked exclusive generation of excessive quantities of all 5-series 5-lipoxygenase products. When HlyA was administered in the presence of both AA (10 microM) and EPA (10 microM), the n-3 fatty acid clearly turned out to be the preferred substrate, with ratios of the various 5-series to 4-series products ranging between 1.8 and 14.5. Moreover, the absolute quantities of AA-derived metabolites and the total sum of all 5-lipoxygenase products was markedly reduced under these conditions. We conclude that the HlyA-evoked 5-lipoxygenase product formation in the pulmonary vasculature of the rabbit is critically dependent on the presence of free precursor fatty acids. The profile of LTs suggests neutrophil (PMN)-related transcellular eicosanoid synthesis as a major underlying metabolic pathway. EPA represents the preferred substrate as compared with AA, resulting in a marked suppression of AA metabolite formation. Therapeutic attempts to provide n-3 fatty acids via the intravenous route may have a major impact on lipid mediator profiles in PMN-related inflammatory events.

Animals↗
PubMed1997

Effects of inhaled versus intravenous vasodilators in experimental pulmonary hypertension.

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation and improves gas exchange in acute lung failure. In experimental pulmonary hypertension, we compared the influence of the aerosolized vasodilatory prostaglandins (PG) PGI2 and PGE1 on vascular tone and gas exchange to that of infused prostanoids (PGI2, PGE1) and inhaled NO. An increase of pulmonary artery pressure (Ppa) from 8 to approximately 34 mmHg was provoked by continuous infusion of U-46619 (thromboxane A2 (TxA2) analogue) in blood-free perfused rabbit lungs. This was accompanied by formation of moderate lung oedema and severe ventilation-perfusion (V'/Q') mismatch, with predominance of shunt flow (>50%, assessed by the multiple inert gas elimination technique). When standardized to reduce the Pps by approximately 10 mmHg, inhaled NO (200 ppm), aerosolized PGI2 (4 ng x kg(-1) x min(-1)) and nebulized PGE1 (8 ng x kg(-1) x min(-1)) all reduced both pre- and postcapillary vascular resistance, but did not affect formation of lung oedema. All inhalative agents improved the V'/Q' mismatch and reduced shunt flow, the rank order of this capacity being NO > PGI2 > PGE1. In contrast, lowering of Ppa by intravascular administration of PGI2 and PGE1 did not improve gas exchange. "Supratherapeutic" doses of inhaled vasodilators in control lungs (400 ppm NO, 30 ng x kg(-1) x min(-1) of PGI2 or PGE1) did not provoke vascular leakage or affect the physiological V'/Q' matching. We conclude that aerosolization of prostaglandins I2 and E1 is as effective as inhalation of nitric oxide in relieving pulmonary hypertension. When administered via this route instead of being infused intravascularly, the prostanoids are capable of improving ventilation-perfusion matching, suggesting selective vasodilation in well-ventilated lung areas.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.

Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, but demands continuous supply of the gaseous agent. We investigated the suitability of aerosolization of NO-donor drugs for achieving sustained reduction of pulmonary vascular tone. In buffer-perfused rabbit lungs, stable pulmonary hypertension was achieved by continuous infusion of the thromboxane-analogue U46619. The NO-donor drugs molsidomine, 3-morpholinosydnone-imine (SIN-1), sodium nitroprusside (SNP) and glyceryl-trinitrate reduced the pulmonary hypertension in a dose-dependent fashion, whether admixed to the perfusate or inhaled as alveolar-accessible aerosol particles (aerosolization time 3-6 min), with an efficiency ranking of SNP > SIN-1 >> molsidomine and glyceryl-trinitrate. Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation. Appearance of sydnonimines in the perfusate after aerosolization and reduction of SIN-1 efficacy when nebulized in nonrecirculatingly perfused lungs demonstrated substantial entry of this prodrug into the vascular space after alveolar deposition. In contrast, undiminished vasodilatory efficacy of aerosolized SNP under conditions of non-recirculating perfusion suggested predominant efficacy via local NO release for this agent. We conclude that short aerosolization maneuvers of NO-donor drugs are suitable to achieve dose-dependent, extensive and sustained vasodilation in the pulmonary circulation, thus offering a new therapeutic approach in pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗