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Biomedical subjects

D Walmrath

Publications and source records attributed to D Walmrath.

At least 55 records · Page 3Linked to original sources
PubMed1996

Aerosolized prostacyclin and iloprost in severe pulmonary hypertension.

OBJECTIVE: To compare the effects of aerosolization of prostacyclin and its stable analog iloprost with those of nasal oxygen, inhaled nitric oxide, and intravenous prostacyclin on hemodynamics and gas exchange in patients with severe pulmonary hypertension. DESIGN: Open uncontrolled trial. SETTING: Justus-Liebig-University, Giessen Germany. PATIENTS: 4 patients with primary pulmonary hypertension and 2 patients with severe pulmonary hypertension associated with calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (the CREST syndrome). All were classified as New York Heart Association class III or class IV. INTERVENTION: Short-term applications of O2, inhaled nitric oxide, intravenous prostacyclin, aerosolized prostacyclin, and aerosolized iloprost during repeated catheter investigation of the right side of the heart within a 1-month period. One patient had long-term therapy with inhaled iloprost. RESULTS: Aerosolized prostacyclin decreased pulmonary artery pressure in 6 patients from (mean +/- SE) 62.3 +/- 4.1 mm Hg to 50.8 +/- 5.5 mm Hg and reduced pulmonary vascular resistance from 1721 +/- 253 dyne/s cm-5 to 1019 +/- 203 dyne/s cm-5, and it increased cardiac output from 2.75 +/- 0.21 L/min to 4.11 +/- 0.54 L/min, mixed venous oxygen saturation from 51.1% +/- 3/4% to 66.3% +/- 4.1% and arterial oxygen saturation from 90.6% +/- 2.7% to 93.8% +/- 23% (P<0.05 for all changes). Mean systemic arterial pressure was only slightly affected. The responses lasted for 10 to 30 minutes after inhalation was terminated. Aerosolized iloprost had an identical efficacy profile but was associated with a longer duration of the pulmonary vasodilatory effect (60 min to 120 min). In comparison, intravenous prostacyclin reduced pulmonary vascular resistance with corresponding efficacy but produced a more pronounced decline in systemic artery pressure and no clinically significant decrease in pulmonary artery pressure. Nitric oxide and O2 were less potent pulmonary vasodilators in these patients. In one patient, 1 year of therapy with aerosolized iloprost (100 microgram/d in six aerosol doses) resulted in sustained efficacy of the inhaled vasodilator regimen and clinical improvement. CONCLUSION: Aerosolization of prostacyclin or its stable analog iloprost causes selective pulmonary vasodilatation, increases cardiac output, and improves venous and arterial oxygenation in patients with severe pulmonary hypertension. Thus, it may offer a new strategy for treatment of this disease.

Adult↗
PubMed1996

Compartmentalized lung cytokine release in response to intravascular and alveolar endotoxin challenge.

Lung cytokine generation has been implicated in pulmonary injury and systemic inflammatory responses. In bufferperfused rabbit lungs, intravascular endotoxin (10 ng/ml perfusate; total amount 7 micrograms) provoked the liberation of 212,100 +/- 119,700 pg tumor necrosis factor-alpha (TNF-alpha) into the vascular space within 3 h. This was augmented to 3,564,400 +/- 1,285,900 pg in the presence of 1% serum. Bronchoalveolar lavages demonstrated the absence of buffer-admixed endotoxin and transition of only minor fractions of the vascular TNF-alpha load into the alveolar space. Aerosolization of 22 micrograms endotoxin liberated 824,400 +/- 48,750 pg TNF-alpha into the alveolar compartment, which was even increased to 16,980,000 +/- 6,066,350 pg on co-nebulization of serum. No endotoxin and only minor amounts of the alveolar TNF-alpha burden spilled over into the vascular compartment. Vascular pressures and lung vascular permeability did not change. We conclude that both intravascular and alveolar endotoxin challenge provokes excessive lung TNF-alpha generation, amplified manyfold in the presence of small serum quantities. For both routes of application, however, the cytokine responses were found to be largely compartmentalized under the given conditions of integer lung barrier properties.

Aerosols↗
PubMed1996

Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema.

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.

Acute Disease↗
PubMed1996

Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome.

Inhalation of NO and aerosolization of PGI2 have been suggested to achieve selective pulmonary vasodilation and improvement of arterial oxygenation in patients with ARDS. We directly compared these two modes of transbronchial vasodilator therapy in 16 ARDS patients mechanically ventilated (mean lung injury score [1] 2.75 +/- 0.05). Patients were randomized to receive either first NO and then PGI2, or vice versa. Each drug was individually titrated to find the maximum improvement of arterial oxygenation. Gas exchange variables, including data from the multiple inert gas elimination technique (MIGET), and hemodynamics under application of NO/PGI2 were compared with pre- and post-challenge values. NO (17.8 +/- 2.7 ppm) increased Pa O2/FI O2 from 115 +/- 12 to 144 +/- 15 mm Hg (p<0.01) and reduced the shunt-flow from 33.1 +/- 3.6 to 26.6 +/- 4.5% (p<0.05). Aerosolized PGI2 (7.5 +/- 2.5 ng/kg min) augmented Pa O2/FI O2 from 114 +/- 12 to 135 +/- 12 mm Hg (p<0.01), and decreased shunt from 33.5 +/- 3.8 to 26.0 +/- 3.9% (p<0.05). In 10 patients, both NO and PGI2 caused an increase in Pa O2/FI O2 by at least 10 mm Hg. Two further patients displayed an improvement of arterial oxygenation in response to either NO or PGI2. NO decreased mean pulmonary artery pressure from 34.8 +/- 2.2 to 33.0 +/- 1.8 mm Hg, and PGI2 from 35.0 +/- 2.2 to 31.9 +/- 1.7 mm Hg (p<0.05). We conclude that individually titrated doses of inhaled NO and aerosolized PGI2 effect selective pulmonary vasodilation and redistribute blood-flow from shunt-areas to well-ventilated regions with nearly identical efficacy profiles.

Administration, Inhalation↗
PubMed1996

Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis.

The present study was performed on 10 patients with severe adult respiratory distress syndrome (ARDS), all suffering from sepsis (mean lung injury score [LIS] (1): 3.25 +/- 0.1; duration of mechanical ventilation upon study entry: 3.1 +/- 0.6 d). Ex vivo analysis of the alveolar surfactant system, obtained by bronchoalveolar lavage (BAL), showed severe impairment of surfactant function. Three hundred milligrams of natural surfactant/kg body weight (Alveofact) was delivered bronchoscopically in separate doses to each segment of both lungs. This caused an immediate increase in PaO2/FlO2 from 85 +/- 7 mm Hg to 200 +/- 20 mm Hg (p < 0.001), mainly due to a decrease in shunt flow (42 +/- 4 to 20 +/- 2% [p < 0.001]). Reanalysis of the alveolar surfactant showed that its function was significantly improved. In five patients the increase in arterial oxygenation was partially lost within the next few hours, and a second dose of 200 mg/kg surfactant was applied 18 to 24 h later, again increasing PaO2/FlO2 values. Eight patients survived the subsequent 14-d observation period with progressive improvement of gas exchange, and five patients were definitely weaned from the respirator. All fatalities were due to non-respiratory causes. We conclude that the bronchoscopic application of a high dose of surfactant aimed at overcoming inhibitory factors in the alveolar space of these patients, may offer a feasible and safe approach to improving gas exchange in severe ARDS.

Adolescent↗
PubMed1996

Synergism of alveolar endotoxin "priming" and intravascular exotoxin challenge in lung injury.

Both endotoxin (lipopolysaccharides of gram-negative bacteria; LPS) and bacterial exotoxins may induce pulmonary microcirculatory disturbances when infused into the lung vasculature, and synergism between these types of microbial challenge has recently been noted. We now asked whether a bronchoalveolar LPS load in perfused rabbit lungs alters the responsiveness to a subsequent intravascular challenge with Escherichia coli hemolysin (ECH). In control lungs (sham aerosolization) and lungs undergoing LPS nebulization (alveolar deposition of approximately 22 micrograms), normal pulmonary artery pressure (PAP), lung weight, and ventilation/perfusion (V/Q) matching were observed. Intravascular ECH (0.013 hemolytic units/ml buffer fluid) increased PAP by approximately 10 mm Hg and lung weight by approximately 4 g within 10 min, paralleled by V/Q mismatch and a shunt flow of approximately 15%. In lungs "primed" for 3 h by a preceding bronchoalveolar LPS deposition, the same ECH dose provoked a dramatic increase in PAP to 40 to 50 mm Hg, a weight gain of approximately 10 g, and shunt flow of 60%. Both vasoconstrictor response and V/Q mismatch were completely suppressed by preadministration and "rescue" application of the thromboxane receptor antagonist BM13.505. We conclude that a bronchoalveolar endotoxin load, though effecting no changes in pulmonary function by itself and showing no spillover into the vascular compartment, primes the lungs for a manifold increased vascular response to a subsequently infused exotoxin. Enhanced thromboxane-mediated vasoconstriction, largely redistributing perfusate flow from normally ventilated to shunt areas, is suggested as the predominant underlying event.

Administration, Inhalation↗
PubMed1995

Hydrogen peroxide-induced increase in lung endothelial and epithelial permeability--effect of adenylate cyclase stimulation and phosphodiesterase inhibition.

Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in inflammatory lung injury. We investigated the influence of pharmacological agents that increase intracellular c-AMP levels on endothelial and epithelial leakage in response to intravascular H2O2 challenge in buffer-perfused rabbit lungs. Endothelial permeability was assessed by determination of the capillary filtration coefficient (Kfc) and lung weight gain. Measurement of the clearance rate of inhaled aerosolized technetium-99m-labeled diethylenetriamine pentaacetic acid ([99mTc]DTPA) from the lungs into the perfusion fluid was used as an index of alveolar epithelial permeability. Experiments were performed in the presence of acetylsalicylic acid to suppress H2O2-induced lung prostanoid generation and concomitant vasoconstriction. Under these conditions, H2O2 admixture to the perfusate (250 microM) caused a greater than eight-fold increase in Kfc values, resulting in > 30 g lung weight gain within 30 min in the absence of any significant vasopressor response. Pretreatment with the adenylate cyclase activators prostaglandin E1 (0.1 microM) and forskolin (0.1 microM), the dual phosphodiesterase type III/IV inhibitor zardaverine (10 microM) as well as combinations of these drugs all caused a nearly complete suppression of this early Kfc increase; and severe edema formation (> 30 g) was retarded to approximately 50-55 min. In addition to the microvascular leakage response, H2O2 caused a four- to five-fold increase in the [99mTc]DTPA clearance rate, starting within 15 min and culminating after approximately 35 min. Adenylate cyclase activation reduced this epithelial leakage response by approximately 30%, whereas zardaverine exerted no significant effect. We conclude that both microvascular endothelial and alveolar epithelial barrier function are severely compromised by intravascular H2O2 challenge in intact lungs. Pharmacological approaches to increase c-AMP levels, including both adenylate cyclase activation and phosphodiesterase inhibition, partially block the endothelial response and, to a lesser extent, the epithelial response.

Adenylyl Cyclases↗
PubMed1995

Prevention and therapy of the adult respiratory distress syndrome.

The complex pathophysiology of adult respiratory distress syndrome (ARDS) makes preventive and therapeutic concepts difficult. Ample experimental evidence indicates that ARDS can be prevented by blocking systemic inflammatory agents. Clinically, only heparin, for inhibition of coagulation phenomena, is presently used among this array of approaches. Corticosteroids have not proven to be beneficial in ARDS. Alternative antiinflammatory agents are being proposed and are under current clinical investigation (e.g. indomethacin, acetylcysteine, alpha 1-proteinase inhibitor, antitumor necrosis factor, interleukin 1 receptor antagonist, platelet-activating factor antagonists). Symptomatic therapeutic strategies in early ARDS include selective pulmonary vasodilation (preferably by inhaled vasorelaxant agents) and optimal fluid balance. Transbronchial surfactant application, presently tested in pilot studies, may be available for ARDS patients in the near future and may have acute beneficial effects on gas exchange, pulmonary mechanics, and lung hemodynamics; its impact on survival cannot be predicted at the present time. Strong efforts should be taken to reduce secondary nosocomial pneumonia in ARDS patients and thus avoid the vicious circle of pneumonia, sepsis from lung infection, and perpetuation of multiple organ dysfunction syndrome. Optimal respirator therapy should be directed to ameliorate gas-exchange conditions acutely but at the same time should aim at minimizing potentially aggravating side effects of artificial ventilation (barotrauma, O2 toxicity). Several new techniques of mechanical ventilation and the concept of permissive hypercapnia address these aspects. Approaches with extracorporeal CO2 removal and oxygenation are being used in specialized centers.

Humans↗
PubMed1995

Hypoxic vasoconstriction in buffer-perfused rabbit lungs.

Isolated rabbit lungs were buffer-perfused under constant flow-conditions with separate control of alveolar (PAO2) and mixed venous (PvO2) O2 tension. Alveolar hypoxia caused an increase in pulmonary artery pressure (PAP) with sigmoidal dose-dependency. Erythrocytes increased the strength of the hypoxic pulmonary vasoconstriction (HPV). The contractile and vasorelaxant responses to the onset and release of alveolar hypoxia, respectively, occurred within seconds. Kinetics of the PAP increase, but not the magnitude of response, were related to the velocity of PAO2 decline. In contrast, changes in PvO2, both in the absence and presence of erythrocytes, did neither provoke any pressor response nor amplify the response to concomitant alveolar hypoxia. Repeatedly performed HPV manoeuvres revealed excellent reproducibility, and long-term alveolar hypoxia (90 min) provoked a biphasic pressor response. We conclude that the isolated rabbit lung is a feasible model for the characterization of hypoxic vasoconstriction, with specific features hitherto not described for perfused lungs of other species.

Animals↗
PubMed1995

Differential influence of arachidonic vs. eicosapentaenoic acid on experimental pulmonary hypertension.

The impact of the 2- and 3-series prostanoid precursors arachidonic acid (AA) and eicosapentaenoic acid (EPA) on experimental pulmonary hypertension was investigated. The model of buffer-perfused rabbit lungs was stimulated by infusion of Escherichia coli hemolysin (HlyA), which is known to provoke sustained thromboxane (Tx)-mediated pulmonary hypertension. Release of di- and trienoic Tx into the recirculating perfusate was quantified by a post-high-performance liquid chromatography enzyme-linked immunosorbent assay technique. HlyA at 0.08 hemolytic unit/ml caused a sustained rise in pulmonary arterial pressure (PAP; maximum increase 14 +/- 2 mmHg) accompanied by progressive TxB2 liberation (maximum perfusate concn 33 +/- 4 pg/ml, baseline < 2 pg/ml). Between 5 and 30 nM, AA provoked a transient monophasic rise in PAP (maximum pressor response 1.5-15 mmHg) and concomitant TxB2 release (peak concn 2-30 pg/ml). Simultaneous administration of HlyA and AA exhibited additive effects with regard to mediator release and pressor responses. EPA at 200-2,000 nM caused a transient rise in PAP similar to that provoked by 5-30 nM AA (maximum pressor response 3-18 mmHg). This was accompanied by liberation of TxB2 (peak concn 16 +/- 5 and 28 +/- 4 pg/ml after 1,000 and 2,000 nM EPA) and TxB3 (peak concn 9 +/- 4 and 30 +/- 3 pg/ml). Combined application of HlyA and EPA resulted in approximate addition of the TxB2 release reaction to each single compound, and TxB3 liberation more than doubled (maximum concn 59 +/- 12 pg/ml). The pressor responses to HlyA-EPA (200-2,000 nM) did not, however, surpass those to HlyA-AA (5-30 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Role of endothelial cytoskeleton in high-permeability edema due to botulinum C2 toxin in perfused rabbit lungs.

The cytoskeleton of the endothelial cell has been suggested to regulate endothelial barrier function. We investigated the role of actin in the maintenance of pulmonary capillary integrity in perfused rabbit lungs. As a tool for selective perturbation of actin, we employed Clostridium botulinum C2 toxin, which is composed of a membrane translocation component (C2II) and a component (C2I) effecting ADP-ribosylation of nonmuscle G-actin. ADP-ribosylated actin no longer capable of polymerization but acts as a barbed end-capping protein, thereby effecting selective loss of the nonmuscle F-actin content. In buffer-perfused rabbit lungs, combined application of both toxin components (range 50 pg/ml-5 ng/ml C2I) resulted in a time- and dose-dependent increase in the capillary filtration coefficient (Kfc) with concomitant edema formation. Only 300:600 pg/ml C2I:II sufficed to induce a > 10-fold rise of Kfc values within 110 min. This severe lung permeability increase occurred in the absence of vasomotor responses and potassium release or lactate dehydrogenase release. Application of each single toxin component displayed markedly reduced efficacy. Similar to the C2 toxin effect, severe permeability increase without concomitant hemodynamic changes was evoked by cytochalasin D, known to possess F-actin-disrupting properties. Preloading of lung cells with phallacidin, which in opposition to C2 toxin decreases F-actin depolymerization, significantly reduced the C2 toxin-induced increase in vascular permeability. Electron microscopic examination of C2 toxin-poisoned lungs showed early, extensive endothelial cell attenuations, followed by disruptions of the endothelial layer and marked interstitial edema formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

On-line measurement of nitric oxide generation in buffer-perfused rabbit lungs.

In buffer-perfused rabbit lungs, the mixed expired gas was continuously analyzed for nitric oxide (NO) by chemiluminescence detection, and recovery data in dependency of the alveolar O2 tension were established. A small aliquot of the lung effluent was continuously forwarded to a reaction vessel in which the NO decomposition products nitrite, peroxynitrite, and nitrate [summarized as NOx; acidic vanadium (III) chloride reagent] or nitrite (acidic sodium iodide reagent) were quantitatively reduced back to NO, which was then transferred to a second chemiluminescence detector. Under baseline conditions, the perfused lungs continuously released 2.2 +/- 0.21 nmol/min of NO (n = 10) into the gas space. NO was permanently liberated into the intravascular compartment at 7.0 +/- 0.3 nmol/min (n = 4). According to a very low buffer-gas partition coefficient of NO (estimated to be 0.0292 +/- 0.005 in separate equilibration experiments), NO aerated into the prelung perfusate largely escaped into the alveolar space within one lung passage, whereas only low percentages of inhaled NO were detected as NOx in the buffer medium. Immediate increase of lung NO generation in response to A-23187 challenge and inhibition by NG-monomethyl-L-arginine were demonstrated. In conclusion, in buffer-perfused lungs, total NO generation may be monitored by continuous analysis of NO exhalation and perfusate NOx accumulation.

Animals↗
PubMed1995

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs.

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J. Appl. Physiol. 78(4): 1509-1515, 1995.--We investigated the role of nitric oxide (NO) generation in hypoxic pulmonary vasoconstriction in buffer-perfused rabbit lungs. Exhaled NO was detected by chemiluminescence, and intravascular NO release was quantified as perfusate accumulation of nitrite, peroxynitrite, and nitrate (NOx). Under baseline conditions, exhaled NO was 45.3 +/- 4.1 parts per billion (1.8 +/- 0.2 nmol/min), and lung NOx release into the perfusate was 4.1 +/- 0.4 nmol/min. Alveolar hypoxia (alveolar PO2 of approximately 23 Torr) induced readily reproducible pressor responses preceded by a sharp drop in exhaled NO concentration. In contrast, perfusate NOx accumulation was not affected. Vasoconstrictor responses to U-46619 and angiotensin II were not accompanied by a decrease in NO exhalation. NG-monomethyl-L-arginine dose-dependently suppressed NO exhalation and amplified pressor responses to hypoxia > U-46619 and angiotensin II. In conclusion, portions of baseline NO generation originating from sites with ready access to the gaseous space sharply decrease in response to alveolar hypoxia, whereas the intravascular release of NO is unchanged. Such differential regulation of lung NO synthesis in response to hypoxia may suggest a complex role in the regulation or modulation of hypoxic pulmonary vasoconstriction.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Effects of aerosolized prostacyclin in severe pneumonia. Impact of fibrosis.

The effects of aerosolized prostaglandin (PG) I2 on gas exchange and hemodynamics were investigated in patients ventilated mechanically because of severe community-acquired pneumonia. Group A were patients without preexisting lung disease (n = 6), and Group B were those with underlying chronic fibrotic interstitial lung disease (n = 6). Ventilation-perfusion distribution was assessed by the multiple inert gas elimination technique. In Group A, low doses of aerosolized PGI2 (mean, 6.6 +/- 3.0 ng/kg/min) sufficed to decrease the mean pulmonary artery pressure (Ppa) from 35.0 +/- 1.5 to 31.0 +/- 1.6 mm Hg (p < 0.05), to improve the ratio of arterial oxygen to the fraction of inspired oxygen (PaO2/FIO2 increase from 100 +/- 18 to 134 +/- 18; p < 0.05), and to decrease intrapulmonary shunt (36.9 +/- 4.7 to 27.5 +/- 4.5%; p < 0.05). Systemic arterial pressure (Psa) and cardiac output remained unchanged. In Group B, aerosolized PGI2 was ineffective in doses less than 10 ng/kg/min. A dosage of 33.6 +/- 12 ng/kg/min reduced Ppa (38.0 +/- 2.4 to 30.8 +/- 2.1 mm Hg; p < 0.05), but it also decreased Psa (80.3 +/- 3.6 to 71.3 +/- 4.7 mm Hg; NS) and PaO2/FIO2 (73.8 +/- 6.6 to 65.5 +/- 6.8 mm Hg; p < 0.05) values and increased intrapulmonary shunt (44.7 +/- 3.0 to 49.4 +/- 5.0%, NS). After withdrawal of the PGI2 aerosol, all gas exchange and hemodynamic changes returned to preaerosol baseline values within 60 min in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Endotoxin "priming" potentiates lung vascular abnormalities in response to Escherichia coli hemolysin: an example of synergism between endo- and exotoxin.

The pore-forming hemolysin of Escherichia coli (HlyA), an important virulence factor in extraintestinal E. coli infections, causes thromboxane generation and related vasoconstriction in perfused rabbit lungs (Seeger, W., H. Walter, N. Suttorp, M. Muhly, and S. Bhakdi. 1989. J. Clin. Invest. 84:220). We investigated the influence of pulmonary vascular "priming" with endotoxin on the responsiveness of the lung to a low-dose HlyA challenge. Rabbit lungs were perfused with Krebs Henseleit buffer containing 0.1-100 ng/ml Salmonella abortus equii lipopolysaccharide (LPS) for 60-180 min. This treatment caused protracted release of tumor necrosis factor into the recirculating medium, but did not induce significant alterations of pulmonary hemodynamics and fluid balance. At a dose of 1 ng/ml, HlyA elicited only moderate thromboxane release (< 200 pg/ml) and pulmonary artery pressure increase (< or = 6 mmHg) in control lungs. Acceleration and potentiation of both the metabolic and vasoconstrictor response occurred in lungs primed with LPS. This priming effect displayed dose (threshold integral of 0.1-1 ng/ml LPS) and time dependencies (threshold integral of 60-90 min LPS incubation). Maximum thromboxane release and pulmonary artery pressure increase surpassed the responses to HlyA in nonprimed lungs by more than 15-fold. Cyclooxygenase inhibition and thromboxane-receptor antagonism blocked these effects. These data demonstrate that LPS priming synergizes with HlyA challenge to provoke vascular abnormalities that are possibly relevant to the pathogenesis of organ failure in severe local and systemic infections.

Animals↗