Search PubMed⌕ Search

Biomedical subjects

W Seeger

Publications and source records attributed to W Seeger.

At least 145 records · Page 8Linked to original sources
PubMed1998

Effects of arachidonic acid metabolism on hypoxic vasoconstriction in rabbit lungs.

Hypoxic pulmonary vasoconstriction is an essential mechanism that matches lung perfusion to ventilation, thus optimising pulmonary gas exchange. Despite its pathophysiological relevance, the mechanism of hypoxic pulmonary vasoconstriction still remains enigmatic. We investigated whether arachidonic acid metabolism is involved in the regulation of hypoxic pulmonary vasoconstriction in isolated, buffer-perfused rabbit lungs. Seven inhibitors were employed to determine the contribution of different vasoactive lipoxy- and cyclooxygenase mediators as well as cytochrome P450 products on the magnitude of hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction was not affected by (i) the cyclooxygenase inhibitor acetylsalicylic acid, (ii) the thromboxane A2 receptor antagonist BM13.505, (iii) the 5'-lipoxygenase inhibitor MK886, and (iv) the lipoxygenase and cyclooxygenase inhibitor BW755c. The hypoxia-elicited pressor response was prominently inhibited by (i) nordihydroguaiaretic acid (50-150 microM), an inhibitor of lipoxygenase and cyclooxygenase and (ii) methoxsalen (100 microM) and 1-aminobenzotriazole (1-10 mM), two inhibitors of cytochrome P450-derived metabolites. However, no specificity for the regulation of hypoxic pulmonary vasoconstriction was found, as corresponding inhibitory potency of these agents was noted when vasoconstriction was achieved by the stable thromboxane analogue U46619 under conditions of normoxia. We conclude that there is no evidence for a specific involvement of different pathways of arachidonic acid metabolism in the mechanism of hypoxic pulmonary vasoconstriction in rabbits.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1998

Simultaneous analysis of 4- and 5-series lipoxygenase and cytochrome P450 products from different biological sources by reversed-phase high-performance liquid chromatographic technique.

Quantification of lipoxygenase and cytochrome P450 products of both arachidonic acid (AA) and eicosapentaenoic acid (EPA) is of broad interest due to the multiple biological activities of these compounds. We developed a method combining (i) solid-phase extraction, (ii) isocratic reversed-phase high-performance liquid chromatographic separation, and (iii) online photodiode array detection with spectrum analysis for identification and measurement of all main 4- and 5-series eicosanoids (leukotrienes, hydroxyeicosatetraenoic acids/hydroxyeicosapentaenoic acids, epoxyeicosatrienoic acids) within one run. With these procedures, standard mixtures of AA- and EPA-derived lipid mediators were recovered from different biological liquids, like lung perfusate, human bronchoalveolar lavage fluid, and cell supernatant with linear characteristics for each compound. Recoveries of the different lipid mediators exceeded 80% showing excellent reproducibility. Application of the method to isolated, perfused, and ventilated human lungs challenged with the calcium ionophore A23187 and to human neutrophils stimulated in the presence of arachidonic acid and eicosapentaenoic acid with N-formyl-methionyl-leucyl-phenylalanine demonstrated the generation of a large array of lipoxygenase and cytochrome P450 products. Thus, convenient quantification of 4- and 5-series eicosanoids in fluids of biological interest is achieved by a technique comprising solid-phase extraction, isocratic reversed-phase high-performance liquid chromatography, and photodiode array-based online spectrum analysis of eluting compounds.

Arachidonate 5-Lipoxygenase↗
PubMed1998

Wegener's granulomatosis: anti-proteinase 3 antibodies are potent inductors of human endothelial cell signaling and leakage response.

Anti-neutrophil cytoplasmic antibodies (ANCAs) targeting proteinase 3 (PR3) have a high specifity for Wegener's granulomatosis (WG), and their role in activating leukocytes is well appreciated. In this study, we investigated the influence of PR3-ANCA and murine monoclonal antibodies on human umbilical vascular endothelial cells (HUVECs). Priming of HUVECs with tumor necrosis factor alpha induced endothelial upregulation of PR3 message and surface expression of this antigen, as measured by Cyto-ELISA, with a maximum occurrence after 2 h. Primed cells responded to low concentrations of both antibodies (25 ng-2.5 microg/ml), but not to control immunoglobulins, with pronounced, dose-dependent phosphoinositide hydrolysis, as assessed by accumulation of inositol phosphates. The signaling response peaked after 20 min, in parallel with the appearance of marked prostacyclin and platelet-activating factor synthesis. The F(ab)2 fragment of ANCA was equally potent as ANCA itself. Disrupture of the endothelial F-actin content by botulinum C2 toxin to avoid antigen-antibody internalization did not affect the response. In addition to the metabolic events, anti-PR3 challenge, in the absence of plasma components, provoked delayed, dose-dependent increase in transendothelial protein leakage. We conclude that anti-PR3 antibodies are potent inductors of the preformed phosphoinositide hydrolysis-related signal tranduction pathway in human endothelial cells. Associated metabolic events and the loss of endothelial barrier properties suggest that anti-PR3-induced activation of endothelial cells may contribute to the pathogenetic sequelae of autoimmune vasculitis characterizing WG.

Antibodies, Antineutrophil Cytoplasmic↗
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

Omega-3 fatty acid-based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial.

BACKGROUND: Profound changes in the metabolism of eicosanoids with increased concentrations of free arachidonic acid (AA) and its proinflammatory metabolites have been observed in psoriatic lesions. Free eicosapentaenoic acid (EPA) may compete with liberated AA and result in an antiinflammatory effect. OBJECTIVE: Our purpose was to assess the efficacy and safety of intravenously administered fish-oil-derived lipid emulsion on chronic plaque-type psoriasis. METHODS: A double-blind, randomized, parallel group study was performed in eight European centers. Eighty-three patients hospitalized for chronic plaque-type psoriasis with a severity score of at least 15 according to the Psoriasis Area and Severity Index (PASI) participated in a 14-day trial. They were randomly allocated to receive daily infusions with either a omega-3 fatty acid-based lipid emulsion (Omegavenous; 200 ml/day with 4.2 gm of both EPA and docosahexaenoic acid (DHA); 43 patients) or a conventional omega-6-lipid emulsion (Lipovenous; EPA+DHA < 0.1 gm/100 ml; 40 patients). The groups were well matched with respect to demographic data and psoriasis-specific medical history. Efficacy of therapy was evaluated by changes in PASI, in an overall assessment of psoriasis by the investigator, and a self-assessment by the patient. In one center neutrophil 4- versus 5-series leukotriene (LT) generation and platelet 2- versus 3- thromboxane generation were investigated and plasma-free fatty acids were determined. RESULTS: The total PASI score decreased by 11.2 +/- 9.8 in the omega-3 group and by 7.5 +/- 8.8 in the omega-6 group (p = 0.048). In addition, the omega-3 group was superior to the omega-6 group with respect to change in severity of psoriasis per body area, change in overall erythema, overall scaling and overall infiltration, as well as change in overall assessment by the investigator and self-assessment by the patient. Response (defined as decrease in total PASI of at least 50% between admission and last value) was seen in 16 of 43 patients (37%) receiving the omega-3 emulsion and 9 of 40 patients (23%) receiving omega-6 fatty acid-based lipid emulsion. No serious side effects were observed. Within the first few days of omega-3 lipid administration, but not in the omega-6 supplemented patients, a manifold increase in plasma-free EPA concentration, neutrophil leukotriene B5 and platelet thromboxane B3 generation occurred. CONCLUSION: Intravenous omega-3-fatty acid administration is effective in the treatment of chronic plaque-type psoriasis. This effect may be related to changes in inflammatory eicosanoid generation.

Adult↗
PubMed1998

Hemifacial spasm due to posterior fossa tumors: the impact of tumor location on electrophysiological findings.

Ephaptic transmission is one of the electrophysiological hallmarks of hemifacial spasm. It is generally accepted that in the majority of patients with idiopathic hemifacial spasm, microvascular compression of the facial nerve at the site where the nerve exits the brain stem is the underlying cause. Whether the actual site of the ephapse is at the site of the lesion or at a nuclear level due to hyperexcitability of the facial motor nucleus is still controversial. Rarely, hemifacial spasm may be due to space occupying lesions in the cerebellopontine angle or in the brain stem. We report the electrophysiological findings of four patients with hemifacial spasm due to extra-axial tumors in different locations of the posterior fossa. The location of the tumor was intrameatal in one patient, in the cerebellopontine angle in two patients and in the brain stem in another patient. Facial nerve motor neurographies including transcranial magnetic stimulation revealed abnormal findings in two patients. Selective stimulation of facial nerve branches demonstrated delayed (ephaptic) responses in all but one patient whose hemifacial spasm had disappeared after treatment with carbamazepine. The latencies of the delayed responses did not correlate with the tumor location. In sum, the site of ephaptic transmission cannot be reliably determined by latency measurements of the delayed response because of its variability which is probably caused by the different size and diameter of the axons participating in ephaptic transmission as well as by the extent of focal demyelination at the site of the lesion. A neuroradiological work up including MR imaging should be mandatory in all patients with hemifacial spasm because electrophysiological studies fail to differentiate between idiopathic and symptomatic hemifacial spasm.

Adult↗
PubMed1998

Real-time quantitative RT-PCR after laser-assisted cell picking.

The present study describes a technique for quantitation of mRNA in a few isotypic cells obtained from an intact organ structure by combining laser-assisted cell picking and real-time PCR. The microscopically controlled lasering of selected cells in stained tissue sections was applied to lung alveolar macrophages, which are unique in that they can alternatively be gathered as a pure cell population from intact lungs by bronchoalveolar lavage as a reference technique. TNF-alpha was chosen as the transcriptionally inducible target gene to be quantified in alveolar macrophages of control rat lung, as well as low- and high-challenge lungs stimulated by endotoxin and IFN-gamma nebulization. Online fluorescence detection for quantitation of the number of amplified copies was based on 5' nuclease activity of Taq polymerase cleaving a sequence-specific dual-labeled fluorogenic hybridization probe. A pseudogene-free sequence of PBGD served as an internal calibrator for comparative quantitation of target. A quick procedure and minimized loss of template were achieved by avoiding RNA extraction, DNase digestion and nested-PCR. Using this approach, we demonstrated dose-dependent manifold upregulation of the ratio of TNF-alpha mRNA copies per one copy of PBGD mRNA in alveolar macrophages of the challenged lungs. The quantitative data obtained from laser-picked alveolar macrophages were well matched with those of lavaged alveolar macrophages carried out in parallel. We suggest that this new combination of laser-assisted cell picking and real-time PCR has great promise for quantifying mRNA expression in a few single cells or oligocellular clusters in intact organs, allowing assessment of transcriptional regulation in defined cell populations.

Animals↗
PubMed1998

Clinical use of lipids to control inflammatory disease.

Selective dietary supplementation with lipids has long been used to influence the course of chronic inflammatory diseases. This review describes new aspects of the molecular mechanism of lipids to modulate leukocyte activity and highlights some recent clinical studies on therapeutic lipid administration. New promising advances in parenteral application of lipids as well as the impact on acute inflammatory disorders are discussed.

Animals↗
PubMed1998

Nitro blue tetrazolium inhibits but does not mimic hypoxic vasoconstriction in isolated rabbit lungs.

It has been suggested that hypoxic pulmonary vasoconstriction (HPV) may mainly proceed via loss of normoxic vasodilation, forwarded by tonic O2-dependent formation of nitric oxide and superoxide (23). Both agents may stimulate guanylate cyclase, the latter via conversion to hydrogen peroxide and formation of compound I with catalase. We probed this hypothesis in perfused rabbit lungs, employing the superoxide scavengers superoxide dismutase (SOD), 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), and nitro blue tetrazolium (NBT) and the catalase inhibitor aminotriazole (AT). NBT turned out to be a potent dose-dependent inhibitor of HPV in a concentration range of 200 nM to 1 microM, and superimposable dose-inhibition curves were obtained when lung synthesis of nitric oxide and vasodilatory prostanoids was preblocked by NG-monomethyl-L-arginine (L-NMMA) and acetylsalicylic acid (ASA). The NBT effect was specific because no inhibition in the vasoconstrictor responses to the stable thromboxane analog U-46619 and angiotensin II was observed. In contrast, SOD and Tiron were ineffective. AT exerted nonspecific inhibition of the hypoxia- and chemical vasoconstrictor-induced pressor responses. When applied under normoxic conditions, however, NBT alone or coapplied with L-NMMA or ASA, both for blockage of parallel vasodilatory pathways, did not mimic the hypoxia-induced vasoconstrictor response. In conclusion, the present study supports an important role for superoxide in the basic mechanism of HPV, but it questions the concept that loss of tonic vasorelaxation via this pathway is the underlying event in rabbit lungs. The mechanisms relating O2 tension-dependent superoxide and hydrogen peroxide generation to the vasoconstrictor event occurring in HPV remain to be further elucidated.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1998

Vascular distension and continued ventilation are protective in lung ischemia/reperfusion.

Biophysical factors have been implicated in the development of pulmonary ischemia-reperfusion injury. In isolated rabbit lungs, the impact of vascular and alveolar distension, with and without alveolar oxygen supply, was investigated. With interruption of both perfusion (zero intravascular pressure) and ventilation, reperfusion after 120 min of warm ischemia resulted in transient pulmonary hypertension, with largely unchanged microvascular pressures, followed by a dramatic leakage response with approximately 10-fold increased capillary filtration coefficients (Kfc) and severe edema. Maintenance of vascular distension during ischemia (intravascular pressure of approximately 2 to 3 mm Hg) reduced the hypertension and fully suppressed the leakage. Employing ischemic periods of 180 and 240 min, ventilation of the lungs with 21 or 100% oxygen > ventilation with nitrogen during perfusion stop, but not static anoxic inflation, further enhanced the protective effect of vascular distension. At optimal biophysical support (vascular distension and ongoing normoxic ventilation), even 240 min of warm ischemia was tolerated with only moderate Kfc increase. We conclude that biophysical factors exert marked influence on pulmonary ischemia-reperfusion injury. Maintenance of vascular distension possesses strong protective potency, further enhanced by continued ventilation and alveolar oxygen supply during ischemia. These results may have important implications for organ preservation in lung transplantation.

Animals↗
PubMed1998

Nitric oxide biosynthesis in an exotoxin-induced septic lung model: role of cNOS and impact on pulmonary hemodynamics.

Nitric oxide (NO) is an important vasodilator that is produced by constitutive (cNOS) as well as inducible (iNOS) isoforms of nitric oxide synthase. The pore-forming hemolysin of Escherichia coli (HlyA), an important virulence factor in extraintestinal E. coli infections, was found to be a potent stimulator of NO liberation in isolated endothelial cells, and that it also causes thromboxane generation and related vasoconstriction in rabbit lungs. We investigated the effect of different concentrations of HlyA on pulmonary NO synthesis in buffer-perfused rabbit lungs. NO release into the alveolar as well as the intravascular compartment was monitored on-line by chemiluminescence detection of expired NO and by measurement of (peroxy-)nitrite/nitrate release into the perfusate. HlyA induced a pressor response and an immediate dose-dependent increase of exhalative and intravascular NO liberation, further enhanced by the addition of the NOS substrate L-arginine. The nonspecific NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), but not the iNOS selective inhibitors aminoguanidine and 2-(2-aminoethyl)-2-thiopseudourea-dihydrobromide, blocked the HlyA-evoked NO liberation into both the alveolar and the intravascular compartments. Enhancement of NO formation (L-arginine) slightly reduced, and inhibition of NO synthesis (L-NMMA) amplified greatly, the HlyA-elicited vasoconstrictor response. Inhibition of the pressor response by a thromboxane receptor antagonist did not interfere with the exotoxin-elicited NO formation. We conclude (1) that marked NO biosynthesis occurs in this model of the septic lung, (2) that the signal transduction in response to HlyA proceeds via activation of cNOS directly related to exotoxin activity and not to secondary changes in shear stress, and (3) that this vasodilator release mitigates the HlyA-induced pulmonary vasoconstriction. These findings may have important implications for therapeutic approaches using NOS inhibitors in sepsis.

Animals↗
PubMed1998

Abnormalities of gastric mucosal oxygenation in septic shock: partial responsiveness to dopexamine.

Splanchnic mucosal perfusion abnormalities have been implicated in the development of sepsis and multiorgan failure. We employed reflectance spectrophotometry for direct assessment of the microvascular hemoglobin oxygen saturation (HbiO2) and hemoglobin concentration (rel Hb(conc)) in the mucosa of the upper gastrointestinal tract. Owing to the high recording frequency together with a small catchment volume, assessment of spatial heterogeneity is enabled. Results were as follows: In healthy controls (n = 7), mean HbiO2 was 70.3 +/- 2.1%, with narrow dispersion and near-Gaussian distribution of the histogram. In patients presenting with hyperdynamic septic shock (n = 15) mean HbiO2 was reduced to 51.0 +/- 1.6% in spite of high normal whole-body oxygen delivery, with tailing of the histogram to severely hypoxic values (18.4 % of data < 40%). In parallel, markedly reduced rel Hb(conc) values were recorded and the standardized intramucosal pH (pHi) was lowered to 7.25 +/- 0.01. Short-term infusion of dopexamine (2 microg/kg/min) caused a significant rise in HbiO2 and rel Hb(conc), whereas whole-body oxygen uptake and standardized pHi values were not altered. In conclusion, decreased oxygenation and tissue hemoglobin concentration, with the appearance of severely hypoxic microdomains, were noted in patients with hyperdynamic sepsis, strongly suggesting pronounced microcirculatory disturbances in this compartment. The partial responsiveness of these abnormalities to dopexamine warrants further elucidation.

Adult↗
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↗
PubMed1998

[[Assessment of quality of life of patients with brain tumors].

In the treatment of patients with brain tumours, quality of life, as subjectively assessed according to the needs, stresses and circumstances of the patient and the subjectively experienced effects of the brain tumour, has recently been considered. While much has been written relating to the difficulty in defining and measuring the construct "quality of life" in the fields of clinical oncology and geriatrics, possible alterations in the quality of life following brain tumour have been largely ignored. The present article describes the targets of research on quality of life in brain tumour patients and difficulties in defining this construct. Furthermore, it discusses the limitations of the assessment of quality of life, in particular with regard to available tests and the reliability of brain damaged patients' self-assessment. In addition, a short overview is given concerning research on quality of life in meningioma patients.

Brain Neoplasms↗
PubMed1998

Expression of pro-inflammatory cytokines by flow-sorted alveolar macrophages in severe pneumonia.

The aim of the present study was to further characterize the role of alveolar macrophages (AM) in acute human lung inflammation by evaluating their capacity to produce pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8. Patients with severe community-acquired pneumonia (CAP; n=12) and healthy volunteers (n=10) underwent bronchoalveolar lavage (BAL). AM were separated to high purity (>96%) using fluorescence-activated cell sorting. We determined the TNF-alpha, IL-6 and IL-8 cytokine gene expression in AM ex vivo using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Moreover, we measured in vitro unstimulated, lipopolysaccharide (LPS)- and LPS/interferon-gamma inducible TNF-alpha, IL-6 and IL-8 cytokine release and evaluated samples of BAL fluids for the same pro-inflammatory cytokines using an enzyme-linked immunosorbent assay (ELISA). We found increased TNF-alpha, IL-6 and IL-8 messenger ribonucleic acid (mRNA) levels in AM from CAP patients that were significantly elevated only for IL-8. When challenged with endotoxin in vitro, AM obtained from CAP patients showed a strongly reduced potential to release TNF-alpha and IL-6 compared to healthy controls, whereas IL-8 secretion did not differ significantly between groups. Moreover, stimulation of AM from CAP patients with LPS plus IFN-gamma augmented TNF-alpha and IL-6 cytokine release to near normal levels. Interestingly, no TNF-alpha protein was measured in BAL samples from CAP patients, whereas IL-6 and IL-8 protein levels were found to be significantly increased. Together, highly purified alveolar macrophages from community-acquired pneumonia patients show relatively low ex vivo tumour necrosis factor-alpha and interleukin-6 but not interleukin-8 messenger ribonucleic acid levels that are associated with a decreased pro-inflammatory cytokine release in vitro which, however, can be restored by concurrent interferon-gamma stimulation.

Adult↗
PubMed1998

Vasoregulatory prostanoid generation proceeds via cyclooxygenase-2 in noninflamed rat lungs.

Prostanoids have been implicated in the regulation of lung vascular tone both under physiological and inflammatory conditions. The conversion of arachidonic acid (AA) to prostaglandin H2 is catalyzed at least by two isoforms of cyclooxygenase, named Cox-1 and Cox-2. Cox-1 is thought to be ubiquitously expressed, enrolled in physiological processes, whereas Cox-2 is mostly assumed to be dynamically regulated, responding to inflammatory conditions. We have recently shown by immunohistochemistry that Cox-2 is constitutively expressed in control rat lungs, with a predominant localization in smooth muscle cells of partially muscular vessels. We now asked whether Cox-2 is basically involved in the physiological regulation of pulmonary vascular tone. Isolated perfused rat lungs were challenged with intravascular bolus application of free AA to elicit thromboxane-related vasoconstrictor responses and to investigate the effects of three different selective Cox-2 inhibitors (NS-398, DUP697, SC-236). AA induced the liberation of prostaglandin I2 and thromboxane A2 into the intravascular space, and it provoked marked pulmonary artery pressure responses and concomitant lung edema formation. All events were dose-dependently inhibited by 1 to 50 micromol/liter NS-398, whereas control vasoconstrictor responses to angiotensin II and the stable thromboxane analogue U46619 were not affected by this agent. Similarly, marked inhibition of the AA elicited pressor response was achieved by 25 micromol/l DUP697 and by 10 micromol/l SC-236. These data suggest a physiological role of Cox-2 rather than Cox-1 in the regulation of vascular tone in rat lungs.

Animals↗