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F Grimminger

Publications and source records attributed to F Grimminger.

At least 163 records · Page 9Linked to original sources
PubMed1995

[Immunosuppressive effect of parenteral fat emulsions in defined immunostimulation].

BACKGROUND: In the heterotopic rat heart allotransplant model we have previously shown that intravenous fat emulsions are to a various extent immunosuppressive or immunoneutral, dependent on their n-3/n-6 fatty acid ratio. Safflower oil (n-3: n-6 = 1:370), fish oil (7.6:1) and soybean oil (1:6.5) prolonged the transplant survival time to 13.3, 12.3 and 10.4 days compared to 6.7 days (oil control group; 1.2.1) and 7.8 days (saline control group) (p < 0.01), respectively. This study presents a correlation of graft survival to immunohistological, cell biological and biochemical parameters. MATERIALS AND METHODS: 20% emulsions of safflower oil, fish oil, soybean oil and a 1:1 mixture of safflower and fish oil (oil control group) were continuously infused (9 g fat/kg body weight/day; n = 10 each group) after transplantation. Subpopulations of infiltrating and circulating immunocompetent cells and leukotriene B4 and B5 release of circulating mononuclear cells were analyzed (on the 4th postoperative day). RESULTS: In the 2 groups with the highest prolongation of graft survival the number of infiltrating cells was reduced by up to 40% and the peripheral blood mononuclear cell interleukin-6 release by up to 45%. Beyond that, circulating T cells were reduced in the fish oil group. Leukotriene B4 was released in all groups to the same extent, leukotriene B5 exclusively in the fish oil group. CONCLUSIONS: Intravenous fat emulsions show a varying immunomodulatory effect in dependence of the n-3/n-6 fatty acid ratio. Both n-6 and n-3 fatty acids, if applied as main fatty acid source, exert immunosuppressive effects by a diminished infiltration and mobilisation of immunocompetent cells. Soybean oil with a more balanced n-3/n-6 fatty acid ratio than safflower oil is significantly less immunosuppressive than safflower oil, and fat emulsions with a n-3/n-6 fatty acid ratio of 1:2 are immunologically neutral.

Animals↗
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↗
PubMed1994

Severe VA/Q mismatch in perfused lungs evoked by sequential challenge with endotoxin and E. coli hemolysin.

Escherichia coli hemolysin (ECH), an important pathogenicity factor in extraintestinal E. coli infections, provokes pulmonary hypertension and microvascular leakage in buffer-perfused rabbit lungs. We investigated gas exchange abnormalities in response to low doses of ECH, lipopolysaccharides (LPS), and sequential and combined application of these bacterial agents by using the multiple inert gas elimination technique. In control lungs and after admixture of 100 ng/ml of LPS, unimodal narrow distribution of perfusion and ventilation to midrange ventilation-perfusion (VA/Q) areas was noted. ECH [0.08 hemolytic units (HU)/ml] caused a moderate increase in pulmonary arterial pressure (< 10 mmHg), progressive lung edema formation (approximately 10 g within 20 min), and a broadening of perfusate and gas flow dispersion. Application of 0.08 HU/ml of ECH in lungs "primed" with 100 ng/ml of LPS in a preceding 125-min perfusion period provoked a large increase in pulmonary arterial pressure (> 50 mmHg within 5 min), rapid edema formation (approximately 10 g within 10 min), and severe VA/Q mismatch with predominance of shunt flow. Vasoconstrictor response and VA/Q mismatch, but not edema formation, were largely inhibited by pretreatment of lungs with acetylsalicylic acid or the thromboxane receptor antagonist BM-13.505. In addition, "rescue" application of BM-13.505 rapidly reversed pressure rise and shunt flow due to sequential LPS and/or ECH stimulation, whereas edema formation was not affected. We conclude that the marked pulmonary hypertension in response to low doses of ECH in LPS-primed lungs is paralleled by severe gas exchange abnormalities with predominance of shunt flow. Both the vasoconstrictor response and the development of shunt are closely related to toxin-induced thromboxane generation.

Animals↗
PubMed1993

Aerosolised prostacyclin in adult respiratory distress syndrome.

We studied the effects of aerosolised prostacyclin (PGI2) in three patients with acute severe adult respiratory distress syndrome. 17-50 ng/kg per min, nebulised into the afferent limb of the ventilator circuit, decreased mean pulmonary artery pressure (SEM) from 40.3 (13.5) to 32.0 (3.8) mm Hg (pulmonary vascular resistance fell by 30%); systemic arterial pressure decreased slightly from 76.8 (2.2) to 74.5 (6.1) mm Hg. Concomitantly, the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen increased from 120 (19) to 173 (18), mainly due to redistribution of blood flow from shunt areas to regions of normal ventilation-perfusion. All effects were reversed on drug withdrawal.

Adult↗
PubMed1993

Pore-forming bacterial toxins potently induce release of nitric oxide in porcine endothelial cells.

Nitric oxide (NO) is believed to play an important role in sepsis-related hypotension. We examined the effects of two pore-forming bacterial exotoxins, Escherichia coli hemolysin and Staphylococcus aureus alpha-toxin, on NO formation in cultured porcine pulmonary artery endothelial cells. NO was quantified using a difference-spectrophotometric method based on the rapid and stoichiometric reaction of NO with oxyhemoglobin. Endothelial cyclic guanosine monophosphate levels were also monitored. Both exotoxins increased NO synthesis in endothelial cells in a time- and dose-dependent manner to an extent exceeding that observed with the ionophore A23187 or thrombin. The capacity of exotoxins to induce NO formation may be relevant in patients with severe local or systemic bacterial infections.

Animals↗
PubMed1993

Alveolar surfactant and adult respiratory distress syndrome. Pathogenetic role and therapeutic prospects.

The adult respiratory distress syndrome (ARDS) is characterized by extended inflammatory processes in the lung microvascular, interstitial, and alveolar compartments, resulting in vasomotor disturbances, plasma leakage, cell injury, and complex gas exchange disturbances. Abnormalities in the alveolar surfactant system have long been implicated in the pathogenetic sequelae of this life-threatening syndrome. This hypothesis is supported by similarities in pulmonary failure between patients with ARDS and preterm babies with infant respiratory distress syndrome, known to be triggered primarily by lack of surfactant material. Mechanisms of surfactant alterations in ARDS include: (a) lack of surface-active compounds (phospholipids, apoproteins) due to reduced generation/release by diseased pneumocytes or to increased loss of material (this feature includes changes in the relative composition of the surfactant phospholipid and/or apoprotein profiles); (b) inhibition of surfactant function by plasma protein leakage (inhibitory potencies of different plasma proteins have been defined); (c) "incorporation" of surfactant phospholipids and apoproteins into polymerizing fibrin upon hyaline membrane formation; and (d) damage/inhibition of surfactant compounds by inflammatory mediators (proteases, oxidants, nonsurfactant lipids). Alterations in alveolar surfactant function may well contribute to a variety of pathophysiological key events encountered in ARDS. These include decrease in compliance, ventilation-perfusion mismatch including shunt flow due to altered gas flow distribution (atelectasis, partial alveolar collapse, small airway collapse), and lung edema formation. Moreover, more speculative at the present time, surfactant abnormalities may add to a reduction in alveolar host defense competence and an upregulation of inflammatory events under conditions of ARDS. Persistent atelectasis of surfactant-deficient and in particular fibrin-loaded alveoli may represent a key event to trigger fibroblast proliferation and fibrosis in late ARDS ("collapse induration"). Overall, the presently available data on surfactant abnormalities in ARDS lend credit to therapeutic trials with transbronchial surfactant administration. In addition to the classical goals of replacement therapy defined for preterm infants (rapid improvement in lung compliance and gas exchange), this approach will have to consider its impact on host defense competence and inflammatory and proliferative processes when applied in adults with respiratory failure.

Apoproteins↗
PubMed1993

A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis. Rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile.

Twenty patients hospitalized for acute psoriasis guttata with a minimum 10% of body surface area involvement (range 10-90%) completed a 10-day trial in which they were randomly allocated to receive daily infusions with either an n-3 fatty acid based lipid emulsion [100 ml/day with 2.1 g eicosapentaenoic (EPA) and 21 g docosahexaenoic acid (DHA)] or a conventional n-6 lipid emulsion (EPA + DHA < 0.1 g/100 ml). The severity of disease was evaluated by scoring daily erythema, infiltration, and desquamation and by a subjective scoring of clinical manifestations offered by the patients. Leukotriene (LT) and platelet-activating factor (PAF) generation were investigated in ionophore-stimulated neutrophils obtained on days 0, 1, 3, 5, 10, and 40. Moderate improvement in clinical manifestations was noted in the n-6 group (changes in score systems between 16-25% from baseline within 10 days). In contrast, the severity of disease markedly decreased in all patients of the n-3 group, with improvements in all score systems ranging between 45% and 76% within 10 days (P < 0.05 for each variable). The difference in response to the two regimens was evident within 4-7 days after onset of lipid infusion. A more than ten fold increase in neutrophil EPA-derived 5-lipoxygenase product formation (LTB5, its omega-oxidation products, non-enzymatic degradation products of LTA5 and 5-hydroxyeicosapentaenoic acid) was noted in the n-3 group but not in the n-6 group. Neutrophil PAF generation increased in the n-6 group but decreased in the n-3 group. In conclusion, modulation of eicosanoid metabolism by intravenous n-3 fatty acid supplementation appears to exert a rapid beneficial effect on inflammatory skin lesions in acute guttate psoriasis.

Acute Disease↗
PubMed1993

Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis.

N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d-1 fish oil-derived lipid emulsion (eicosapentaenoic acid [EPA], 4.2 g; docosahexaenoic acid [DHA], 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Staphylococcal alpha-toxin induced ventilation-perfusion mismatch in isolated blood-free perfused rabbit lungs.

Gas exchange conditions in blood-free perfused isolated rabbit lungs were assessed by the use of the multiple inert gas elimination technique. Under baseline conditions, unimodal narrow distribution of perfusion and ventilation to midrange-ventilation-perfusion (VA/Q) areas was noted. Intravascular challenge with staphylococcal alpha-toxin caused a rapid increase in pulmonary arterial pressure (to > 40 mmHg within approximately 15 min) and delayed-onset (> 10-15 min) lung edema formation, with unaltered ventilation pressures. The vasoconstrictor response was paralleled by a progressive, severe leftward shift of perfusion to areas with low-VA/Q ratios, accompanied by a minor fraction of shunt flow. At pulmonary arterial pressures > 40 mmHg, extreme VA/Q mismatch with near absence of perfusate flow to midrange-VA/Q areas was registered. Vasoconstrictor response and VA/Q mismatch, but not the progressive edema formation, were virtually completely suppressed in lungs pretreated with acetylsalicylic acid or the thromboxane receptor antagonist BM 13505. Moreover, "rescue" application of BM 13505 after onset of alpha-toxin-induced pressor response and gas exchange abnormalities completely reversed pressure elevation and loss of VA/Q matching. We conclude that the marked vasoconstrictor response to staphylococcal alpha-toxin is paralleled by severe VA/Q mismatch with predominant perfusion of low-VA/Q areas independent of lung edema formation. Pressor response and VA/Q mismatch, but not vascular leakage, are suppressed by thromboxane inhibition.

Animals↗
PubMed1993

Endotoxin primes perfused rabbit lungs for enhanced vasoconstrictor response to staphylococcal alpha-toxin.

The major pore-forming exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, causes thromboxane-mediated pulmonary hypertension and prostanoid-independent protracted vascular leakage in perfused rabbit lungs. We asked whether lung responsiveness to the staphylococcal agent would be altered by a preceding period of endotoxin priming. Isolated rabbit lungs were perfused with Krebs-Henseleit buffer in the presence or absence of 100 ng/ml Salmonella abortus equii endotoxin for up to 5 h. The lipopolysaccharide exposure evoked the release of large quantities of tumor necrosis factor into the vascular and alveolar spaces but did not significantly alter pulmonary artery pressure, organ weight, or the repeatedly assessed capillary filtration coefficient (Kfc). Two and 4 h after endotoxin administration, alpha-toxin (10 to 30 ng/ml) was bolus-injected into the pulmonary artery. Toxin-evoked prostanoid generation (TxB2, 6-keto-PGF1 alpha) and pressor responses were markedly accelerated and enhanced in endotoxin-primed lungs, both for the 2 h and the 4 h priming period. No significant influence of endotoxin was noted when applied simultaneously with alpha-toxin. Cyclooxygenase inhibition suppressed the alpha-toxin-evoked pressure rise in both endotoxin-primed and nonprimed lungs. Endotoxin priming did not influence the alpha-toxin-induced protracted increase in Kfc values, assessed in the presence of cyclooxygenase inhibition. We conclude that endotoxin primes rabbit lungs for enhanced prostanoid generation and pulmonary hypertension in response to S. aureus alpha-toxin. Such cooperativity of endotoxin priming and exotoxin triggering may be relevant in critically ill patients suffering from both endotoxemia and gram-positive sepsis.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Differential vasoconstrictor potencies of free fatty acids in the lung vasculature: 2-versus 3-series prostanoid generation.

Pulmonary vasoconstrictor potencies of the 2- and 3-series prostanoid precursors arachidonic acid (AA) and eicosapentaenoic acid (EPA) were compared with each other and three reference fatty acids [palmitic acid (PAL), oleic acid (OA) and eicosatrienoic acid (ETA)]. Dose-effect curves were established from transient pulmonary artery pressor responses (approximately 5-50 mm Hg) evoked by intravascular application of nonesterified fatty acids in buffer-perfused rabbit lungs. Release of di- and trienoic prostanoids into the recirculating perfusate was quantified by a post high-performance liquid chromatography enzyme-linked immunosorbent assay technique. EPA and the three reference fatty acids were used in concentrations up to 10 microM; the rank order of vasoconstrictor potencies was ETA < PAL < OA < EPA. In contrast, AA evoked even larger pressor responses at concentrations two orders of magnitude lower (up to 80 nM). All fatty acids induced both thromboxane A2 and prostaglandin I2 release, ranking with ETA approximately PAL approximately OA < EPA as established for 10 microM concentrations; the dienoic prostanoid release in response to 80 nM AA approximated that elicited by 10 microM EPA. The n-3 fatty acid, however, provoked the liberation of excessive quantities of thromboxane A3 and prostaglandin I3, which surpassed the respective 2-series prostanoids 15- to 20-fold; no 3-series cyclooxygenase products were detected in response to AA, ETA, PAL or OA stimulation. Cyclooxygenase (acetylsalicylic acid) and thromboxane synthetase (OKY 046, Ozagrel, (E)-p-(imidazol-1-ylmethyl)cinnamic acid, C13H12N2O2, MW 228.2) inhibition largely suppressed the EPA-evoked pressor responses.(ABSTRACT TRUNCATED AT 250 WORDS)

8,11,14-Eicosatrienoic Acid↗
PubMed1993

Increased LTB4 metabolites and PGD2 in BAL fluid after methacholine challenge in asthmatic subjects.

The bronchoconstrictor potency of inhaled methacholine is widely used to assess airway responsiveness. However, evidence has accumulated that methacholine inhalation challenge may lead to an inflammatory response in the lower respiratory tract. We therefore compared cellular, leukotriene and prostanoid profiles in bronchoalveolar lavages (BAL) obtained five hours after methacholine challenge to control lavages without prior challenge. Eight subjects with asymptomatic to mild bronchial asthma and nine nonatopic healthy controls were enrolled in the study. Without prior challenge, the percentage of BAL eosinophils was higher in the asthmatic subjects ((mean +/- SD), 1.1 +/- 0.9%) than in the control subjects (0.1 +/- 0.1%. Leukotriene B4 (LTB4), and its omega-oxidation products (20-OH-LTB4 and 20-COOH-LTB4) were the only leukotrienes detectable in the baseline BAL fluids in five of the eight asthmatic patients. After methacholine challenge, no change in BAL cell profile occurred, but in the asthmatic patients, the total amounts of LTB4 and its omega-oxidation products rose from 0.52 +/- 0.50 ng.ml-1 (pre-challenge) to 1.55 +/- 1.32 ng.ml-1 (post-challenge), and prostaglandin D2 (PGD2) rose from 49.1 +/- 15.7 (pre-challenge) to 94.4 +/- 25.4 pg.ml-1 (post-challenge), with no change in 6-keto-PGF1 alpha, thromboxane B2 (TXB2), and prostaglandins F2 alpha and E2 (PGF2 alpha and PGE2). In the healthy controls, no consistent change in BAL cell profile and mediators occurred after methacholine provocation. We conclude that inhaled methacholine stimulates LTB4 and PGD2 release in asthmatics, but not in healthy controls, without affecting the number of inflammatory cells in BAL fluid.

Adult↗
PubMed1992

Ventilation-perfusion relationships in isolated blood-free perfused rabbit lungs.

The multiple inert gas elimination technique (MIGET) was applied to blood-free perfused isolated rabbit lungs. Commonly accepted criteria for reliability of the method were found to be fulfilled in this model. Ventilation-perfusion (VA/Q) distributions in isolated control lungs corresponded to those repeatedly detected under physiological conditions. In particular, a narrow unimodal dispersion of perfusate flow was observed: perfusion of low-VA/Q areas ranged below 1% and shunt flow approximately 2-3%; perfusion of high-VA/Q regions was not detected. Gas flow was characterized by narrow dispersion in the midrange-VA/Q areas. Application of a low level of PEEP (1 cmH2O) reduced shunt flow to less than 1%, and low-VA/Q areas were no longer noted. By using this PEEP-level, stable gas exchange conditions were maintained for greater than 5 h of extracorporeal perfusion. Graded embolization with small air bubbles caused a typical rightward shift (to higher VA/Q ratios) of mean ventilation, associated with the appearance of high-VA/Q regions and an increase in dead space ventilation. Mean perfusion was shifted leftward, and shunt flow was approximately doubled. Whole lung lavage with saline for washout of surfactant evoked a progressive manifold increase in shunt flow, accompanied by a moderate rise of perfusate flow to low-VA/Q areas. We conclude that the MIGET can be applied to isolated blood-free perfused rabbit lungs for assessment of gas exchange and that typical patterns of VA/Q mismatch are reproduced in this model.

Animals↗
PubMed1992

Type II alveolar epithelial eicosanoid metabolism: predominance of cyclooxygenase pathways and transcellular lipoxygenase metabolism in co-culture with neutrophils.

Arachidonic acid (AA) metabolism was studied in freshly isolated type II alveolar epithelial cells of rabbits. Substantial basal secretion of prostanoids with predominance of prostaglandin (PG) I2 was noted. Challenge with the calcium ionophore A23187 resulted in a time- and dose-dependent increase in the generation of all AA cyclooxygenase products to severalfold values following the rank order of 12-heptadecatrienoic acid (12-HHT) greater than PGI2 greater than PGE2 greater than or equal to thromboxane A2 greater than PGF2 alpha approximately PGD2. Even larger augmentation of prostanoid generation was evoked by challenge with free exogenous AA. Generation of the different AA cyclooxygenase products was inhibited by acetylsalicylic acid with IC50 in the range between 250 and 500 microM. In addition to the prostanoid release, ionophore-challenged type II pneumocytes liberated substantial amounts of AA lipoxygenase products with leukotriene (LT) B4 greater than 15-hydroxyeicosatetraenoic acid (HETE) greater than 12-HETE greater than 5-HETE. Generation of LTs and HETEs was markedly increased upon simultaneous disposal of free exogenous AA. No omega-oxidation of LTB4 was noted, and no evidence for secretion of intact LTA4 was obtained. The epithelial cells displayed avid uptake of exogenously offered LTA4 with subsequent enzymatic conversion to LTB4. Co-stimulation of pneumocytes with neutrophils (PMN) resulted in an amplification of LTB4 generation, paralleled by a decrease in nonenzymatic decay products of PMN-derived LTA4; both phenomena were dose dependent on the pneumocyte-PMN ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗