[Intensive care management of acute diseases of the aorta]. / Intensivmedizinisches Management akuter Aortenerkrankungen.

Acute aortic diseases represent a group of complex severe and often fatal medical conditions. Although they are significantly rarer than cardiac or thromboembolic events, they are an important differential diagnosis to be ruled out, e.g., in the clinical work-up of acute chest pain.Treatment, especially surgical interventions, depends on the progression, extent and size of the pathology and whenever possible should be performed in specialized centers with the appropriate experience.Intensive care monitoring is advisable as a range of peracute complications can occur even in initially stable patients. Depending on the clinical presentation and affected structures, a number of severe complications need to be anticipated by critical care physicians. Additionally, a notable symptom is severe and refractory hypertension, especially in the acute phase. This article provides a summary of the most frequent clinical pictures and corresponding treatment options. Furthermore, the principles of initial patient stabilization and treatment as well as the perioperative management of complex surgical procedures on the aorta are discussed.

Infectivity of deceased COVID-19 patients.

The duration of infectivity of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in living patients has been demarcated. In contrast, a possible SARS-CoV-2 infectivity of corpses and subsequently its duration under post mortem circumstances remain to be elucidated. The aim of this study was to investigate the infectivity and its duration of deceased COVID-19 (coronavirus disease) patients. Four SARS-CoV-2 infected deceased patients were subjected to medicolegal autopsy. Post mortem intervals (PMI) of 1, 4, 9 and 17 days, respectively, were documented. During autopsy, swabs and organ samples were taken and examined by RT-qPCR (real-time reverse transcription-polymerase chain reaction) for the detection of SARS-CoV-2 ribonucleic acid (RNA). Determination of infectivity was performed by means of virus isolation in cell culture. In two cases, virus isolation was successful for swabs and tissue samples of the respiratory tract (PMI 4 and 17 days). The two infectious cases showed a shorter duration of COVID-19 until death than the two non-infectious cases (2 and 11 days, respectively, compared to > 19 days), which correlates with studies of living patients, in which infectivity could be narrowed to about 6 days before to 12 days after symptom onset. Most notably, infectivity was still present in one of the COVID-19 corpses after a post-mortem interval of 17 days and despite already visible signs of decomposition. To prevent SARS-CoV-2 infections in all professional groups involved in the handling and examination of COVID-19 corpses, adequate personal safety standards (reducing or avoiding aerosol formation and wearing FFP3 [filtering face piece class 3] masks) have to be enforced for routine procedures.

Socio-ecological vulnerability to tipping points: A review of empirical approaches and their use for marine management.

Sustainability in the provision of ecosystem services requires understanding of the vulnerability of social-ecological systems (SES) to tipping points (TPs). Assessing SES vulnerability to abrupt ecosystem state changes remains challenging, however, because frameworks do not operationally link ecological, socio-economic and cultural elements of the SES. We conducted a targeted literature review on empirical assessments of SES and TPs in the marine realm and their use in ecosystem-based management. Our results revealed a plurality of terminologies, definitions and concepts that hampers practical operationalisation of these concepts. Furthermore, we found a striking lack of socio-cultural aspects in SES vulnerability assessments, possibly because of a lack of involvement of stakeholders and interest groups. We propose guiding principles for assessing vulnerability to TPs that build on participative approaches and prioritise the connectivity between SES components by accounting for component linkages, cascading effects and feedback processes.

Trisomy 21 in forensic autopsies: Review of a 20-year period.

BACKGROUND: Trisomy 21 is the most common human chromosomal abnormality. Its manifestation includes intellectual impairment and more or less typical anatomical malformations and functional deficiencies that can cause sudden or unexpected deaths. Typical medicolegal questions at autopsy are related to medical malpractice, improper care, neglect, or abuse, and, depending on the cause of death, whether the death might have been avoidable. The aim of this study was to examine whether the causes of death in individuals with trisomy 21 were linked to the known health risks for this condition and to consider how these deaths might have been prevented. MATERIAL AND METHODS: A retrospective study was performed at the Institutes for Legal Medicine in Giessen and Frankfurt am Main, Hesse, Germany. All records for forensic autopsy cases within a 20-year period from 1998 to 2017 were reviewed for the diagnosis trisomy 21", respectively, "Down's syndrome". RESULTS: Twenty-three cases complied with the inclusion criteria trisomy 21 and autopsy. The age of the deceased ranged from 23 days to 61 years. Infectious diseases, mainly respiratory, were the leading cause of death, followed by accidental deaths. CONCLUSION: The medicolegal relevance of the known health risks in Down's syndrome could be illustrated by the autopsy findings and the results of the additional examinations. The known high susceptibility to infections, with an increased risk of a rapid course and lethal outcome, in individuals with Down's syndrome could be confirmed in our study. A sound knowledge of the risks and abnormalities associated with trisomy 21 are helpful in medicolegal assessments, particularly, in relation to medical malpractice charges.

High doses of pseudoephedrine hydrochloride accelerate onset of CNS oxygen toxicity seizures in unanesthetized rats.

Pseudoephedrine (PSE) salts (hydrochloride and sulfate) are commonly used as nasal and paranasal decongestants by scuba divers. Anecdotal reports from the Divers Alert Network suggest that taking PSE prior to diving while breathing pure O2 increases the risk for CNS oxygen toxicity (CNS-OT), which manifests as seizures. We hypothesized that high doses of PSE reduce the latency time to seizure (LS) in unanesthetized rats breathing 5 atmospheres absolute (ATA) of hyperbaric oxygen. Sixty-three male rats were implanted with radio-transmitters that recorded electroencephalogram activity and body temperature. After ≥7-day recovery, and 2 h before "diving", each rat was administered either saline solution (control) or PSE hydrochloride intragastrically at the following doses (mg PSE/kg): 0, 40, 80, 100, 120, 160, and 320. Rats breathed pure O2 and were dived to 5ATA until the onset of behavioral seizures coincident with neurological seizures. LS was the time elapsed between reaching 5ATA and exhibiting seizures. We observed a significant dose-dependent decrease in the LS at doses of 100-320 mg/kg, whereas no significant differences in LS from control value were observed at doses ≤80 mg/kg. Our findings showed that high doses of PSE accelerate the onset of CNS-OT seizures in unanesthetized rats breathing 5ATA of poikilocapnic hyperoxia. Extrapolating our findings to humans, we conclude that the recommended daily dose of PSE should not be abused prior to diving with oxygen-enriched gas mixes or pure O2.

[Delirium in the intensive care unit : Overview for nurses and physicians]. / Das Delir auf Intensivstationen : Ein Überblick für Pflegekräfte und Ärzte.

Delirium is a severe but frequent organ dysfunction in intensive care units (ICU) affecting nearly 80% of mechanically ventilated patients and up to 50% of non-ventilated patients. Although guidelines for diagnosis and treatment of delirium exist it often remains underdiagnosed due to the lack of implementation of these guidelines. Therefore, the chance of a positive outcome for patients can be significantly reduced. Delirium results in longer mechanical ventilation, extended hospital stay, more nosocomial infections and an increased mortality. Measures which improve the frequency of diagnosis and increase the quality of treatment will only be successful if physicians, nursing staff and other medical staff on ICUs realize strategies together and raise their awareness on delirium.

Alphabeta T cell receptor-positive cells and interferon-gamma, but not inducible nitric oxide synthase, are critical for granuloma necrosis in a mouse model of mycobacteria-induced pulmonary immunopathology.

The immunological basis of tuberculin-induced necrosis, known for more than a century as "Koch's phenomenon," remains poorly understood. Aerosol infection in mice with the highly virulent Mycobacterium avium strain TMC724 causes progressive pulmonary pathology strongly resembling caseating necrosis in human patients with tuberculosis. To identify the cellular and molecular mediators causing this pathology, we infected C57BL/6 mice and mice selectively deficient in recombinase activating gene (RAG)-1, alphabeta T cell receptor (TCR), gammadelta TCR, CD4, CD8, beta2-microglobulin, interferon (IFN)-gamma, interleukin (IL)-10, IL-12p35, IL-12p35/p40, or iNOS with M. avium by aerosol and compared bacterial multiplication, histopathology, and respiratory physiology in these mice. The bacterial load in the lung was similarly high in all mouse groups. Pulmonary compliance, as a surrogate marker for granulomatous infiltrations in the lung, deteriorated to a similar extent in all groups of mice, except in alphabeta TCR-knockout (KO) and IL-12-KO mice in which compliance was higher, and in IFN-gamma and inducible nitric oxide synthase-KO mice in which compliance was reduced faster. Progressive caseation of pulmonary granulomas never occurred in alphabeta TCR-KO, IL-12-KO, and IFN-gamma-KO mice and was reduced in CD4-KO mice. In summary, alphabeta TCR(+) cells and IFN-gamma are essential for the development of mycobacteria-induced pulmonary caseous necrosis. In contrast, high mycobacterial load and extensive granulomatous infiltration per se are not sufficient to cause caseation, nor is granuloma necrosis linked to the induction of nitric oxide.

Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids.

Recent clinical trials have shown that the survival of patients with acute respiratory distress syndrome (ARDS) is improved by ventilation with reduced volumes. These studies suggested that overinflation of the lungs causes overactivation of the immune system. The present study investigated the hypothesis that ventilation with increased tidal volumes results in early responses similar to those caused by stimulation with one of the major risk factors for ARDS: bacterial lipopolysaccharide (LPS). We therefore compared the effects of ventilation (-10 cm H2O or -25 cm H2O end-inspiratory pressure) and LPS (50 microg/ml) on nuclear factor (NF)-kappaB activation, chemokine release, and cytokine release in isolated perfused lungs obtained from BALB/C mice. We found that both LPS and ventilation with -25 cm H2O (overventilation; OV) caused translocation of NF-kappaB, which was abolished by pretreatment with the steroid dexamethasone. Furthermore, both treatments resulted in similar increases in perfusate levels of alpha-chemokines (macrophage inflammatory protein; [MIP]-2; KC), beta-chemokines (macrophage chemotactic protein-1; MIP-1alpha), and cytokines (tumor necrosis factor-alpha, interleukin-6), which were largely prevented by dexamethasone pretreatment. In LPS-resistant C3H/HeJ mice, only OV, and not LPS, caused translocation of NF-kappaB and release of MIP-2. We conclude that OV evokes early inflammatory responses similar to those evoked by LPS (i.e., NF-kappaB translocation and release of proinflammatory mediators). The NF-kappaB translocation elicited by OV appears to be independent of Toll-like receptor 4 and not due to LPS contamination introduced by the ventilator. Our data further suggest that steroids might be considered as a subsidiary treatment during artificial mechanical ventilation.

Beyond nearest-neighbor spacing distributions: A new indicator for core-induced chaos

We present a method for the statistical analysis of quantum spectra which goes beyond the standard nearest-neighbor spacing distribution. The method exploits a peculiar correlation of oscillator strength and level spacing distributions. For diamagnetic Rydberg spectra we demonstrate that core-induced chaos and generic chaos can be distinguished in an experimentally accessible regime far below the semiclassical limit and with already a few hundred lines per spectrum. We present two hypotheses for a generalization of our findings.

Mechanisms of endotoxin-induced airway and pulmonary vascular hyperreactivity in mice.

Endotoxin is thought to contribute to pulmonary hyperresponsiveness in byssinosis, asthma, and the acute respiratory distress syndrome (ARDS). The aim of this study was to elucidate the mechanism of this phenomenon in the isolated, blood-free perfused mouse lung. Perfusion with lipopolysaccharide (LPS) had no effect on pulmonary resistance or pulmonary artery pressure, but induced airway hyperreactivity (AHR) to methacholine (MCh) and pulmonary vascular hyperreactivity (VHR) to platelet-activating factor (PAF). Blockade of the thromboxane/endoperoxide (TP) receptor with SQ29.548 completely protected against LPS-induced AHR and VHR. Blockade of cyclooxygenase-2 (COX-2) abolished LPS-induced VHR but suppressed LPS-induced AHR only marginally. COX-2 messenger RNA was upregulated in LPS-treated lungs, and inhibition of transcription with actinomycin D or of protein biosynthesis with cycloheximide protected against LPS-induced VHR but not AHR. Pretreatment with the radical scavenger N-acetylcysteine partly protected against LPS-induced AHR. In addition, perfusion of mouse lungs with the isoprostane 8-epiprostaglandin F(2alpha) (8-epi-PGF(2alpha)), which may be formed as a consequence of oxidative stress in the lung, elicited AHR, which was completely blocked by SQ29.548. Enzyme immunoassay did not detect either 8-epi-PGF(2alpha )or thromboxane B(2) in perfusate samples. Our findings show that LPS induces AHR and VHR in mouse lungs via activation of the TP receptor. Although induction of VHR depends on COX-2 activity, AHR is largely mediated by a non-COX-derived TP agonist, which might be a product of radical-induced lipid peroxidation.

Ether lipids in the cell membrane of Mycoplasma fermentans.

Two new ether lipids, 1-O-alkyl/alkenyl-2-O-acyl-glycero-3-phosphocholine and its lyso form, 1-O-alkyl/alkenyl-glycero-3-phosphocholine, were identified in the cell membrane of Mycoplasma fermentans using chemical analyses, GLC-MS, MALDI-TOF MS, and 1D and 2D NMR spectroscopy. The lipids are heterogeneous with respect to both acyl and alkyl/alkenyl residues. The acyl residues at position 2 of glycerol are hexadecanoyl and octadecanoyl in a molar ratio of 3.6 : 1 with a trace amount of octadecenoyl. The alkyl/alkenyl residues at position 1 of glycerol are hexadecyl (78%), octadecyl (7%), octadecenyl (14%), and hexadecenyl (traces). In the octadecenyl residue, the double bond has a cis configuration and is located at either position 1' (plasmalogen-type lipid) or 9' in a ratio approximately 1 : 1. This is the first report of the presence of alkyl and vinyl (alk-1'-enyl) ether lipids in the cell membrane of aerobically grown mycoplasmas. Lipids of this type have been found in some Gram-positive bacteria, thus supporting the hypothesized close taxonomical relationship of these bacteria to mycoplasmas. The ether lipids of M. fermentans are structurally similar to platelet activating factor; it was demonstrated that the 2-O-acetylated lyso form lipid can mimic platelet-activating factor activity in isolated perfused and ventilated rat lungs.

Differential effects of the mixed ET(A)/ET(B)-receptor antagonist bosentan on endothelin-induced bronchoconstriction, vasoconstriction and prostacyclin release.

Endothelins are a family of potent endogenous mediators that have been implicated in a number of airway and other diseases. Recently, the non-peptide mixed ET(A)/ET(B) endothelin receptor antagonist bosentan has been successfully tested in the treatment of cardiovascular diseases. It was the aim of the present study to characterize the effects of bosentan on the pulmonary actions of endothelin- (ET-1), endothelin-3 (ET-3) and the ET(B)-receptor agonist IRL1620 in the isolated perfused and ventilated rat lung (IPL) and in precision-cut lung slices (PCLS). In the IPL, bosentan completely prevented the IRL1620-induced vasoconstriction (IC50 3 microM). The inhibition by bosentan of ET-1-elicited vasoconstriction showed a biphasic course, reflecting the inhibition of ET(A)-and ET(B)-mediated vasoconstriction (IC50 0.2 microM and 19 microM, respectively). In addition, bosentan prevented the ET-1- (IC50 6 microM) and IRL1620-induced (IC50 3 microM) prostacyclin release. Bosentan also completely prevented the bronchoconstriction induced by IRL1620 in the IPL (IC50 20 microM) and in PCLS (IC50 13 microM). In PCLS, the pD2-values were ET-1 7.20+/-0.23, ET-3 7.51+/-0.27 and IRL1620 7.33+/-0.29. Bosentan at 100 microM caused a rightward shift of the concentration-response curve of ET-1, ET-3 and IRL1620 by a factor of 5, 46 and 64, respectively. In all cases the slope of the Schild regression was lower than unity, disregarding a simple interaction of bosentan with one receptor. With respect to ET-1-induced bronchoconstriction, in the IPL bosentan in concentrations of up to 10 microM aggravated ET-1-induced bronchoconstriction probably due to the blockade of bronchodilatory ET(A)-receptors (IC50 0.3 microM) and even at 100 microM showed only very little protection from ET- -induced bronchoconstriction in the IPL and in the PCLS. The similar IC50-values for ET-1-induced vasoconstriction and bronchodilation suggest that only one type of ET(A)-receptor is involved. The differing IC50-values between IRL1620-induced bronchoconstriction and prostacyclin release, the slope of the Schild regression and the failure of bosentan to prevent the ET-1-induced bronchoconstriction suggest a complex interaction between the known ET-receptors or the existence of unknown ET(B)-receptor subtypes.

Basal lung mechanics and airway and pulmonary vascular responsiveness in different inbred mouse strains.

Little is known about interstrain variations in baseline lung functions or smooth muscle contractility in murine lungs. We therefore examined basal lung mechanics and airway, as well as vascular reactivity to methacholine, thromboxane (using U-46619), and endothelin-1 (ET-1), A/J, AKR, BALB/c, C3H/HeN, C57BL/6, and SCID mice. All experiments were performed with isolated perfused mouse lungs. Except AKR mice (which were excluded from further analysis), all other strains showed stable pulmonary compliance, pulmonary resistance, and pulmonary arterial pressure within a control period of 45 min. Among these strains, C3H/HeN mice exhibited higher dynamic pulmonary compliance and lower pulmonary resistance, whereas SCID mice had higher baseline pulmonary resistance than the other strains. Concentration-response experiments with methacholine showed a lower airway reactivity for C57BL/6 mice compared with the other strains. Perfusion with 1 microM U-46619 or 100 nM ET-1 revealed a similar pattern: the agonist-inducible broncho- and vasoconstriction was lower in C57BL/6 mice than in all other strains, whereas it tended to be higher in SCID mice. The present study demonstrates a correlation between airway and vascular responsiveness in all tested strains. SCID mice are hyperreactive, whereas C57BL/6 mice are hyporeactive, to smooth muscle constrictors. Lung mechanics, as well as airway and vascular responsiveness, appear to be genetically controlled.

Different ventilation strategies affect lung function but do not increase tumor necrosis factor-alpha and prostacyclin production in lavaged rat lungs in vivo.

BACKGROUND: Using an in vivo animal model of surfactant deficiency, the authors compared the effect of different ventilation strategies on oxygenation and inflammatory mediator release from the lung parenchyma. METHODS: In adult rats that were mechanically ventilated with 100% oxygen, acute lung injury was induced by repeated lung lavage to obtain an arterial oxygen partial pressure < 85 mmHg (peak pressure/positive end-expiratory pressure [PEEP] = 26/6 cm H2O). Animals were then randomly assigned to receive either exogenous surfactant therapy, partial liquid ventilation, ventilation with high PEEP (16 cm H2O), ventilation with low PEEP (8 cm H2O), or ventilation with an increase in peak inspiratory pressure (to 32 cm H2O; PEEP = 6 cm H2O). Two groups of healthy nonlavaged rats were ventilated at a peak pressure/PEEP of 32/6 and 32/0 cm H2O, respectively. Blood gases were measured. Prostacyclin (PGI2) and tumor necrosis factor-alpha (TNF-alpha) concentrations in serum and bronchoalveolar lavage fluid (BALF) as well as protein concentration in BALF were determined after 90 and 240 min and compared with mechanically ventilated and spontaneously breathing controls. RESULTS: Surfactant, partial liquid ventilation, and high PEEP improved oxygenation and reduced BALF protein levels. Ventilation with high PEEP at high mean airway pressure levels increased BALF PGI2 levels, whereas there was no difference in BALF TNF-alpha levels between groups. Serum PGI2 and TNF-alpha levels did not increase as a result of mechanical ventilation when compared with those of spontaneously breathing controls. CONCLUSIONS: Although alveolar protein concentration and oxygenation markedly differed with different ventilation strategies in this model of acute lung injury, there were no indications of ventilation-induced systemic PGI2 and TNF-alpha release, nor of pulmonary TNF-alpha release. Mechanical ventilation at high mean airway pressure levels increased PGI2 levels in the bronchoalveolar lavage-accessible space.

Characterization of airway and vascular responses in murine lungs.

UNLABELLED: 1. We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. 2. Airways: The EC50 (microM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml(-1), respectively. Adenosine (< or =1 mM), bombesin (< or =100 microM), histamine (< or =10 mM), LTC4 (< or =1 microM), PAF (0.25 microM) and substance P (< or =100 microM) had only weak effects (<5% of Mch) on RL. 3. Vessels: The EC50 (microM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05

Redesigning nucleic acids.

A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.

Rat big endothelin-1-induced bronchoconstriction and vasoconstriction in the isolated perfused rat lung: role of endothelin converting enzyme and neutral endopeptidase 24.11.

Treatment of animals with big endothelin-1 (bET) causes pulmonary hypertension and bronchoconstriction, both in vivo and in perfused lungs. The biological activity of bET requires proteolytic cleavage to ET-1 by endothelin converting enzymes (ECE) and possibly other proteases such as neutral endopeptidase 24.11 (NEP 24.11). Since the role of NEP 24.11 in the physiological activation of bET is unclear, we investigated the effects of the selective NEP 24.11 inhibitor thiorphan on bET-induced vaso- and bronchoconstriction in the isolated perfused rat lung. We also studied the effects of phosphoramidon and (S)-2-biphenyl-4-yl-1-(1H-tetraol-5-yl)-ehtylaminomethylphosphonic acid (CGS-26303), i.e. agents which block not only NEP 24.11 but also ECE. The bET-induced vasoconstriction was much less prominent than the bronchoconstriction, i.e. after exposure for 110 min vascular and airway conductance were decreased by 33% and 80% respectively. The small bET-induced vasoconstriction was attenuated to a similar degree by pretreatment with any of the three protease inhibitors. However, thiorphan up to a concentration of 10 microM had only little effect on the bET-induced bronchoconstriction, while 10 microM phosphoramidon or CGS-26303 provided half-maximal and 100 microM phosphoramidon complete protection in this model. This profile of inhibitor action suggests that in rat lung ECE is the major enzyme responsible for activation of bET.

Phosphodiesterase inhibitors prevent endothelin-1-induced vasoconstriction, bronchoconstriction, and thromboxane release in perfused rat lung.

Endothelin-1 (ET-1) causes broncho- and vasoconstriction in the rat isolated perfused lung and induces the release of thromboxane and prostacyclin. Pharmacological inhibition of phosphodiesterases (PDE) is known to relax airway and vascular smooth muscle and it attenuates the release of pro-inflammatory mediators. Therefore, we examined whether and how rolipram (specific for PDE IV) and motapizone (specific for PDE III) affect ET-1-elicited changes in lung function. 5 microM motapizone attenuated broncho- and vasoconstriction to a greater extent than 5 microM rolipram. Simultaneous pretreatment with both PDE inhibitors protected completely. Thromboxane release was suppressed by rolipram, but not by motapizone. Prostacyclin release was neither influenced by single, nor by combined pretreatment with either compound. We conclude that combined inhibition of PDE III and IV counteracts ET-1-elicited pressor- and inflammatory actions in the lung.

[Carving expands the skiing field]. / Carving erweitert das Skifahren.

Carving is only the logical consequence of the past developments in alpine skiing. The modern ski-theories as well as the professional racing aim for a perfect control over the ski to master the variable conditions. New is not the technic but the equipment. Driving on the edge covers everything from drifting up to carving. Carving is a big chance for the alpine skiing to break up old standards and experience a new quality in skiing.

Attenuation by phosphodiesterase inhibitors of lipopolysaccharide-induced thromboxane release and bronchoconstriction in rat lungs.

Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes induction of cyclooxygenase-2 followed by thromboxane (TX)-mediated bronchoconstriction (BC). Recently, phosphodiesterase (PDE) inhibitors have received much interest because they not only are bronchodilators but also can suppress release of proinflammatory mediators. In the present study, we investigated the effect of three different PDE inhibitors on TX release and BC in LPS-exposed perfused rat lungs. The PDE inhibitors used were motapizone (PDE III specific), rolipram (PDE IV specific), and zardaverine (mixed PDE III and IV specific). At 5 microM, a concentration at which all three compounds selectively block their respective PDE isoenzyme, rolipram (IC50 = 0.04 microM) and zardaverine (IC50 = 1.8 microM) largely attenuated the LPS-induced BC, whereas motapizone was almost ineffective (IC50 = 40 microM). In contrast to LPS, BC induced by the TX-mimetic U46619 was prevented with comparable strength by motapizone and rolipram. In LPS-treated lungs, the TX release was reduced to 50% of controls by rolipram and zardaverine but was unaltered in the presence of 5 microM motapizone. Increasing intracellular cAMP through perfusion of db-cAMP or forskolin (activates adenylate cyclase) also reduced TX release and BC. We conclude that PDE inhibitors act via elevation of intracellular cAMP. Although both PDE III and PDE IV inhibitors can relax airway smooth muscle, in the model of LPS-induced BC, PDE IV inhibitors are more effective because (in contrast to PDE III inhibitors) they also attenuate TX release.