Intermittent Hypoxia Contributes to the Lung Damage by Increased Oxidative Stress, Inflammation, and Disbalance in Protease/Antiprotease System.

INTRODUCTION: Intermittent hypoxia as a surrogate of obstructive sleep apnea is associated with different cardiovascular complications. However, the effects of intermittent hypoxia on the lung tissue are less known. Therefore, the aim of our present study was to investigate if intermittent hypoxia may influence oxidative stress, inflammation, and protease/antiprotease system in the lung. Additionally, potential protective properties of anti-inflammatory and anti-oxidative drugs have been evaluated. METHODS: 32 mice were divided into four groups: (1) intermittent hypoxia, (2) intermittent hypoxia with infliximab, (3) intermittent hypoxia with L-glutathione, and (4) normoxia. After 4 weeks, lungs and blood were collected. Levels of reactive oxygen species in the lung were calculated by L-O12-enhanced chemiluminescence. CD68-positive lung macrophages were detected by immunofluorescence. Concentrations of elastase and desmosine in lung and of alpha-1-antitrypsin in blood were calculated by means of enzyme-linked immunosorbent assay. RESULTS: Compared to a control, intermittent hypoxia augmented the release of free oxygen radicals, expression of CD68+ macrophages, and concentration of elastase in the lung tissue. Despite increased blood levels of protective alpha-1-antitrypsin, concentrations of desmosine-degradation product of elastin were higher versus control. The application of anti-inflammatory infliximab und anti-oxidative L-glutathione prevented at least partly the above-observed hypoxia-associated changes. CONCLUSIONS: Intermittent hypoxia contributes to the lung damage by increased oxidative stress, inflammation, and disbalance in protease/antiprotease system. Infliximab and L-glutathione may prevent adverse hypoxia-induced lung alternations.

Anti-inflammatory properties of the monoterpene 1.8-cineole: current evidence for co-medication in inflammatory airway diseases.

1,8-cineole is a natural monoterpene, also known as eucalyptol. It is a major compound of many plant essential oils, mainly extracted from Eucalyptus globulus oil. As an isolated compound, 1,8-cineole is known for its mucolytic and spasmolytic action on the respiratory tract, with proven clinical efficacy. 1,8-cineole has also shown therapeutic benefits in inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). This clinical evidence refers to its anti-inflammatory and anti-oxidant mode of action, which has been proven in numerous pre-clinical studies. In vitro studies found strong evidence that 1,8-cineole controls inflammatory processes and mediator production of infection- or inflammation-induced mucus hypersecretion by its action as anti-inflammatory modifier rather than a simple mucolytic agent. The aim of this review is to present these preclinical studies performed with the pure monoterpene, and to summarize the current knowledge on the mode of action of 1,8-cineole. The actual understanding of the pure 1,8-cineole compared to mixtures of natural volatile oils containing 1,8-cineole as a major compound and to mixtures of natural terpenes, known as essential oils, will be discussed. Based on the anti-oxidative and anti-inflammatory properties, recent clinical trials with 1,8-cineole have shown first evidence for the beneficial use of 1,8-cineole as long-term therapy in the prevention of COPD-exacerbations and to improve asthma control.

Pro-fibrotic processes in human lung fibroblasts are driven by an autocrine/paracrine endothelinergic system.

BACKGROUND AND PURPOSE: Since endothelin (ET) may act as pro-fibrotic mediator, expression and release of ET isoforms, their receptors and potential pro-fibrotic ET effects were studied in human lung fibroblasts. EXPERIMENTAL APPROACH: MRC-5 and primary human lung fibroblasts (phLFb) were cultured. Expression of prepro-ET isoforms was determined by qPCR and release of ET-1 by elisa. ET receptor function was analysed by real-time measurement of dynamic mass redistribution (DMR). Incorporation of [(3) H]-thymidine was determined as measure of proliferation and that of [(3) H]-proline for collagen synthesis. Phospho-p42/44 MAP kinase was determined by Western blot. KEY RESULTS: ET-1 is the predominant ET in human lung fibroblasts (hLF), and TGF-ß caused a further, selective and sustained up-regulation of ET-1 resulting in increased extracellular ET-1 accumulation. hLFb express mRNA encoding ET-A and ET-B receptors. Expression of both receptors was confirmed at protein level. ET-1 induced marked DMR signals, an effect that involved ET-A and ET-B receptors. Stimulatory effects of ET-1 on hLFb proliferation and collagen synthesis were mediated exclusively via ET-A receptors. ET-1, again via ET-A receptors, induced rapid activation of ERK MAPK, shown to be a crucial cellular signal in ET-1-induced collagen synthesis. ET-1-induced activation of ERK and collagen synthesis was, in contrast to corresponding effect of a muscarinic agonist, largely insensitive to pertussis toxin. CONCLUSIONS AND IMPLICATIONS: hLFb are endowed with all elements necessary to build a functional autocrine/paracrine endothelinergic system, which appears to drive pro-fibrotic airway and lung remodelling processes, effects for which only ET-A, but not ET-B receptors appear to be of significance.

Characterization of proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) in human lung fibroblasts.

Insulin has been approved for inhaled application, but safety concerns remain, because of un-physiologically high insulin concentrations in the lung. Since insulin may act as growth factor, possible proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) on human lung fibroblasts were studied. As measure of proliferation [(3)H]-thymidine incorporation was studied in HEL-299, MRC-5, IMR-90 and primary human lung fibroblasts. In all cells, mRNA encoding IGF-1 receptors and two variants of insulin receptors was detected. Insulin and IGF-1 stimulated [(3)H]-thymidine incorporation in all cells. Comparison of the concentration-dependent effects in HEL-299 cells showed that IGF-1 and insulin glargine were more potent (EC(50), 3 and 6 nM) and more effective (maximum increase, by 135-150%) than insulin and insulin detemir (EC(50), 22 and 110 nM; maximum increase: by 80%). Proliferative effects of IGF-1 and insulin were inhibited to the same extent by an antibody (1H7) directed against the IGF-1 receptor α-subunit. Insulin-induced stimulation of [(3)H]-thymidine incorporation was reduced by 83% after siRNA-mediated down-regulation of IGF-1 receptor by about 75%, but not affected by a similar down-regulation of the insulin receptor. Insulin and IGF-1 caused rapid up-regulation of the early genes FOS, EGR-1 and EGR-2 as well as of the gene coding for IGF-1. In conclusion, in human lung fibroblasts insulin exerts marked proliferative effects and the pharmacological profile of this response as well as specific receptor knock-down experiments suggest mediation via IGF-1 receptors. The risk of unwanted structural lung alterations by long-term inhalative application of insulin should be considered.

[Uniliteral wheezes as the first clinical sign of a bronchial carcinoid]. / Einseitiges Giemen als klinische Erstmanifestation eines Bronchuskarzinoids.

HISTORY AND CLINICAL FINDINGS: A 58-years-old non-smoking woman presented at our Thoracic Centre with increasing exertional dyspnea and on examination was found to have wheezing and decreased breath sounds over the left lung. INVESTIGATIONS: Chest X-ray revealed an atelectasis of the left anterobasal lung segment. Computed tomography revealed a 3.5 cm mass at the left inferior lobe. Bronchioscopy showed a total occlusion of the segmental bronchus because of an endobronchial tumor. Histology of a biopsy showed the tumor to be a carcinoid. Staging by whole-body ocreotide scintigraphy showed no evidence of metastases. TREATMENT AND COURSE: The patient recovered quickly from resection of the left inferior lobe and radical lymphadenectomy. Two years later, she has remained free of symptoms and without evidence of recurrence. CONCLUSIONS: Although rare (ca. 1.0 % of all primary lung tumors), the differential diagnosis of dyspnea and uniliteral wheezing should include a bronchial carcinoid. It is a potentially curable tumor, if detected and treated early. An interdisciplinary approach is pivotal to its perioperative management.

Species differences in expression pattern of arginase isoenzymes and differential effects of arginase inhibition on collagen synthesis in human and rat pulmonary fibroblasts.

Arginase was shown to be up-regulated in different animal models of inflammatory and fibrotic airway diseases. Since arginase provides L-ornithine, one precursor for L-proline, an essential substrate for collagen synthesis, it has been suggested that arginase might be a key enzyme in airway remodelling. The present study aimed to characterize expression of arginase isoenzymes in rat and human pulmonary fibroblasts, and to test whether arginase inhibition affects collagen synthesis. In primary rat tracheal and lung fibroblasts, mRNA for arginase I and II could be detected, with arginase I as predominant isoenzyme. In contrast, in human lung fibroblasts (primary cells and different cells lines) mRNA levels for arginase I were at or below detection limit whereas arginase II mRNA was markedly higher than in rat pulmonary fibroblasts. Arginase activity in rat tracheal and lung fibroblasts was between 20 and 30 mU/mg protein, but was below detection limit (2.5 mU/mg) in human lung fibroblasts. In rat tracheal and lung fibroblasts cultured in proline-free medium, arginase inhibition by N(omega)-hydroxy-nor-L-arginine caused a reduction by about one-third of basal collagen I accumulation (determined by western blot analysis) and largely attenuated transforming growth factor beta 1 (TGF-beta(1))-induced increase in collagen accumulation, whereas basal and TGF-beta(1)-induced collagen accumulation by human lung fibroblasts was not affected by arginase inhibition. In conclusion, arginase isoenzymes reveal a species specific expression pattern. Arginase contributes significantly to L-proline supply for collagen synthesis in rat fibroblasts, in which arginase I is the predominant isoenzyme, but not in human fibroblasts, in which arginase II is the only isoenzyme expressed.

Role of Epac1 in mediating anti-proliferative effects of prostanoid EP(2) receptors and cAMP in human lung fibroblasts.

In lung fibroblasts, proliferation is inhibited by activation of EP(2) prostanoid receptors which are known to couple to adenylyl cyclase. Beside the classic target of cAMP, protein kinase A (PKA), alternative cAMP effectors have been identified, among them Epac (exchange protein activated by cAMP). The present study aimed to illuminate transduction pathways mediating the anti-proliferative effects of EP(2) receptors in lung fibroblasts. Proliferative activity of human lung fibroblasts was determined by measuring [(3)H]-thymidine incorporation. The selective EP(2) receptor agonist butaprost inhibited [(3)H]-thymidine incorporation by 75%, an effect mimicked by forskolin, the phosphodiesterase inhibitor IBMX, the stable cAMP analogues dibutyryl-cAMP and bromo-cAMP, as well as by the Epac selective cAMP analogues 8-pCPT-2'-O-Me-cAMP and Sp-8-pCPT-2'-O-Me-cAMPS, whereas the PKA selective agonist 6-Bnz-cAMP was inactive. The PKA inhibitor Rp-8-Br-cAMPS inhibited butaprost-induced phosphorylation of CREB (cAMP response element-binding protein), but did not affect butaprost-induced inhibition of [(3)H]-thymidine incorporation. Partial knockdown of Epac1 by specific siRNA transfection resulted in a marked attenuation of the inhibitory potency of butaprost, whereas transfection of Epac2 siRNA or non-silencing siRNA did not affect the effectiveness of butaprost to inhibit [(3)H]-thymidine incorporation. In conclusion, Epac1 rather than the classic cAMP effector PKA is a crucial element in the signal transduction pathway mediating anti-proliferative effects of EP(2) receptor activation.

[Methods to improve patient's adherence: is there hope?]. / Therapieadhärenz bei Asthma bronchiale: Methoden zur Verbesserung.

An estimated 50% of all asthma patients do not take the medication as prescribed, i.e. are non-compliant. Numerous interventions have been done to improve patients' compliance have been evaluated in clinical studies, ranging from simple adjustments in the medication regimen to complex multidisciplinary interventions that address health system barriers and communication between patients and health care professionals. Beliefs or disbeliefs of health care professionals affect patients' compliance. Efforts to improve the adherence of physicians to asthma guidelines have been tested in numerous studies. Although several types of interventions are effective in improving compliance to medication for asthma, only a few indicated whether this success would actually result in clinical improvement. This review surveys the different options for enhancing compliance rates in patients with asthma.

Muscarinic receptors mediate stimulation of collagen synthesis in human lung fibroblasts.

Clinical observations indicate that in chronic obstructive pulmonary disease patients, the long-acting muscarinic antagonist tiotropium delays decline in airway function, suggesting that cholinergic mechanisms contribute to long-term structural changes. Human lung fibroblasts express muscarinic receptors and the present study aimed to explore their role in controlling collagen synthesis. MRC-5, HEL-299 and primary human lung fibroblasts (phLFb) were cultured. Incorporation of [(3)H]-proline into cellular proteins was determined as measure of collagen synthesis. In MRC-5 cells, the muscarinic agonist carbachol enhanced [(3)H]-proline incorporation in a concentration-dependent manner (effective concentration of 50%: 220 nM, increase at 10 microM by 40-55%, in a different series of experiments). Likewise, 10 microM oxotremorine caused an increase of approximately 65%. For comparison, transforming growth factor-beta1 (5 ng x mL(-1)) caused an increase of approximately 80%. Effects of carbachol on total [(3)H]-proline incorporation and collagenase-sensitive [(3)H]-proline fraction were similar. The effect of 10 microM carbachol was inhibited by tiotropium (inhibitory concentration of 50%: 110 pM), prevented by pertussis toxin and the mitogen-activated protein kinase inhibitor, PD 98059. Muscarinic agonists also enhanced [(3)H]-proline incorporation in a tiotropium-sensitive manner in HEL-299 cells and phLFb. In human lung fibroblasts, muscarinic receptors exert stimulatory effects on collagen synthesis. Prolonged blockade of muscarinic-induced collagen synthesis may contribute to reported beneficial long-term effects of anticholinergics in chronic obstructive pulmonary disease.

[Friend or foe: combination therapy with inhaled corticosteroids and long-acting beta2-agonists in chronic obstructive pulmonary disease (COPD)]. / Indikationen und Limitationen einer fixen Kombinationstherapie mit inhalativen Kortikosteroiden und langwirksamen beta2-Mimetika bei der chronisch-obstruktiven Lungenerkrankung (COPD).

Inhaled corticosteroids (ICS) used in COPD (chronic obstructive pulmonary disease) are recommended only in combination with a long-acting beta2-agonist (LABA) in stage 3 and higher in COPD treatment guidelines. In comparison to placebo and the single components, a superior control by means of the ICS/LABA fixed combination therapy has been demonstrated for clinical improvement in the following parameters: reduction of exacerbation rate and hospitalisations, reduction of dyspnoea and improvement of forced expiratory volume in one second (FEV1). In contrast to data from database studies, the large prospective TORCH (Towards a Revolution in COPD Health) trial found in the ICS/LABA group a beneficial effect on the reduction of mortality only as a trend in the ICS/LABA group, which did not reach statistical significance. In long-term trials, ICS treated patients experienced up to 10% oral and/or pharyngeal candidiasis. ICS was associated with an excess risk of pneumonia, which doubles the pneumonia incidence in patients not receiving ICS. The probability of having pneumonia reported as an adverse event was 18-19 % in the ICS groups and resulted in a 1.7-2.2 elevated pneumonia risk. Because ICS therapy is recommended only in conjunction with a bronchodilator, fixed ICS/LABA combinations are a logical consequence for COPD long-term therapy.

[Adherence to therapy in bronchial asthma]. / Therapieadhärenz bei Asthma bronchiale.

Asthma is a chronic disease requiring regular use of controller medication (e.g. inhaled corticosteroids at step 2 of treatment guidelines) to improve symptoms and prevent exacerbations. However, inadequate patient adherence/compliance to prescribed treatment regimens is a major cause of poor clinical outcome. Adherence rates in these patients are generally about 50%. Typically, adherence with reliever medication is better than with controller medications. Poor compliance most often results in infrequent and lower than prescribed taking of medication. While older age or female gender are fixed factors, some modifiable characteristics which can achieve better adherence include formal education, higher socioeconomic status, belief that asthma is a serious illness, fewer concerns about the side effects of their medication, shortened and simple treatment regimens (including the prescription of inhaled fixed-combination devices), patient-oriented devices for inhalation therapy, and good patient-physician relationship. There is no gold standard for quantifying patient adherence. In general, direct measures of assessing patient behavior, such as direct observation or electronic inhaler monitoring, give a more accurate, valid indication than indirect methods such as patient diaries, self-reporting, weighting of inhaler devices or doctors' judgment. An understanding of the barriers that impede guideline adherence, described in this article, is necessary before programs are designed to initiate changes in the practices of the treating doctor.

[Talc pleurodesis in malignant pleural effusions]. / Effektivität und zugrunde liegende Mechanismen der Talkumpleurodese bei malignem Pleuraerguss.

Pleural effusions associated with malignancy--either malignant or paramalignant diseases--were found in ca. 20% of these patients. Large pleural effusions cause mainly dyspnoea but also cough and chest pain. The presence and degree of dyspnoea depend on the size of the effusion and the patient's underlying pulmonary function. In acute cases and large effusions immediate chest drainage is indicated in symptomatic patients, followed by the treatment of the underlying disease, e. g. chemotherapy. The most effective therapy for controlling reiterated malignant pleural effusions is the thoracoscopic talc poudrage (2.5-10 g) which has been shown to have a success rate of > 90%. Talc induces a broad inflammatory reaction involving mesothelial cells of the pleura, coagulation parameters, fibroblast proliferation eventually leading to symphysis of the pleura. This procedure is reserved for patients who are in good general conditions, who are expected to have a reasonably long survival, and who failed chemical pleurodesis. A good predictor for longer survival time is a Karnofsky Performance Scale > or = 40 indicating a survival time > 30 days, which therefore should be considered prior to the procedure. The adult respiratory distress syndrome (ARDS) is the most important complication initially observed in the US in up to 9% of all cases. ARDS incidence was strongly related to high number (50%) of small talc particles < 15 microm. In summary, talc poudrage or slurry (talc particle size > 10 microm) in malignant pleura effusions is a safe and effective method to induce pleura symphysis. Complaints and complications such as chest pain, transient fever, and empyema are rare or very are which are almost exclusively related to the therapeutic procedure itself.

[Early diagnosis of chronic obstructive pulmonary disease (COPD)]. / Frühdiagnostik der chronisch obstruktiven Lungenerkrankung. Wie lange reicht die Luft noch?

Since the early detection of COPD is problematic, nonobstructed smokers with a chronic productive cough are initially assigned to the COPD risk group o. Although there is still a lack of evidence that early pharmacological intervention is associated with benefits in terms of disease progression, the earliest possible diagnosis is still considered a desirable goal. For the sooner triggering noxae, such as cigarette smoke, are eliminated, the more positive are the effects on the subsequent course of the illness. When establishing the diagnosis, a careful case history is of particular importance. With the aid of various diagnostic pulmonary function tests, degrees of severity can be differentiated and the course of COPD can be determined. Since the end of 2004, structured therapeutic programs for COPD have become available.

[A connection between allergic rhinitis and allergic asthma? The "one-airway-one-disease"-hypothesis]. / Gemeinsamkeiten der allergischen Rhinitis und des allergischen Asthma bronchiale? Teil 2: Klinik, Diagnostik und gemeinsame Therapieansätze.

As outlined in part 1, numerous data from immunologic, genetic and epidemiologic studies point to a systemic link between allergic asthma and rhinitis which can be seen as manifestations of a common atopic syndrome. In part 2 clinical manifestations, diagnostics and most importantly therapeutic options effecting on both nasal and bronchial symptoms will be discussed. Allergen avoidance is the first step in therapeutic management of allergic diseases. Specific immunotherapy (SIT), leukotriene modifying compounds (in Germany exclusively Montelukast), and corticosteroids inhibit inflammation in the epithelium of the upper and the lower airways. Although SIT has a widely accepted indication in the treatment of allergic rhinitis, it is just provisionally recommended for the treatment of asthmatic patients. Most recently Montelukast, a potent leukotriene receptor inhibitor, has been approved for the treatment of asthma as well as for allergic rhinitis. Local administration of corticosteroids requires that they be given both nasally and bronchially. Just on the i. v. or oral route corticosteroids may inhibit the allergic inflammation in both compartments. Newly developed IgE-inhibitor Omalizumab, which has no approval in Germany yet, has been reported to have similar effects. Thus, various therapeutic options are available to treat asthma and rhinitis at the same time. Furthermore, multilateral clinical efficacy of antiinflammatory drugs support the "One-Airway-One-Disease" hypothesis.

[A connection between allergic rhinitis and allergic asthma? The "one-airway-one-disease"-hypothesis]. / Gemeinsamkeiten der allergischen Rhinitis und des allergischen Asthma bronchiale? Die 'One-Airway-One-Disease"-Hypothese -- Teil 1: Epidemiologie und Pathophysiologie.

The nose and the lungs are anatomically and physiologically divided which lead to separated strategies in diagnostic and therapy. The upper airways, from the nose and lungs may account for the traditional division in upper and lower airways. Nonetheless a link between upper and lower respiratory tracts has been repeatedly observed in the past decades making the current division in two separate entities an arbitrary dichotomy. Once allergic rhinitis and asthma are two manifestation of the atopic syndrome it is logical to expect that allergy is not a disease confined to specific target organ rather to a broad spectrum of clinical manifestations. This hypothesis has been supported from various observations: Both, allergic asthma and allergic rhinitis are characterized by a similar if not an identical inflammatory process in which mast cells and eosinophils appear to be the major effector cells, high comorbidity of both allergic manifestations as shown in epidemiologic studies. Both diseases are caused by the interaction of genetic susceptibility with environmental factors. In this review, the latest developments in epidemiology and pathophysiology with regard to nasobronchial interaction in allergic airway disease will be discussed.

Pulmonary 15NO uptake in interstitial lung disease.

Because lung nitric oxide (NO) diffusing capacity (DL) represents alveolar-capillary gas diffusion, we queried as to whether disturbances of pulmonary gas exchange in interstitial lung disease (ILD) are appropriately reflected by using NO. In this pilot study, we applied the (15)N-labeled stable isotope (15)NO (relative abundance 0.37% of total NO) in order to ignore the endogenous NO production. In 10 ILD-outpatients, we measured DL (15)NO by performing the single-breath method. Lung function parameters as well as arterial oxygen partial pressure (PaO(2)) were also tested. Values of DL (15)NO ranged within 50-151 ml (15)NO/(mmHg min). Ratios of DL (15)NO/reference were between 43 and 108% of predicted data as taken from our previous work on healthy volunteers [Eur. J. Physiol. 446 (2003) 256]. We found a significant reduction of DL (15)NO/reference in five patients. Additionally, values of PaO(2) were significantly correlated to ratios of DL (15)NO/reference (adjusted R2 +/-SEE=0.407+/-8.051). In conclusion, (15)NO represents an appropriate indicator gas for reflecting an ILD-induced impairment of alveolar-capillary gas exchange.

Anti-inflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial.

Airway hypersecretion is mediated by increased release of inflammatory mediators and can be improved by inhibition of mediator production. We have recently reported that 1.8-cineol (eucalyptol) which is known as the major monoterpene of eucalyptus oil suppressed arachidonic acid metabolism and cytokine production in human monocytes. Therefore, the aim of this study was to evaluate the anti-inflammatory efficacy of 1.8-cineol by determining its prednisolone equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dosage during a 2 month run-in phase, subjects were randomly allocated to receive either 200 mg 1.8-cineol t. i.d. or placebo in small gut soluble capsules for 12 weeks. Oral glucocorticosteroids were reduced by 2.5 mg increments every 3 weeks. The primary end point of this investigation was to establish the oral glucocorticosteroid-sparing capacity of 1.8-cineol in severe asthma. Reductions in daily prednisolone dosage of 36% with active treatment (range 2.5-10 mg, mean: 3.75 mg) vs. a decrease of only 7% (2.5-5 mg, mean: 0.91 mg) in the placebo group (P = 0.006) were tolerated. Twelve of 16 cineol vs. four out of 16 placebo patients achieved a reduction of oral steroids (P = 0.012). Long-term systemic therapy with 1.8-cineol has asignificant steroid-saving effect in steroid-depending asthma. This is the first evidence suggesting an anti-inflammatory activity of the monoterpene 1.8-cineol in asthma and a new rational for its use as mucolytic agent in upper and lower airway diseases.

Human and rat alveolar macrophages express multiple EDG receptors.

Endothelial differentiation gene (EDG) receptors are a new family of eight G protein-coupled receptors for the lysophospholipids lysophosphatitic acid and sphingosine-1-phosphate. In the present experiments, the expression of EDG receptors in rat and human alveolar macrophages was studied by reverse transcription-polymerase chain reaction (RT-PCR). In alveolar macrophages of both species, mRNA for multiple EDG receptors could be detected, but the pattern of expression was different in both species. In human alveolar macrophages, mRNA for EDG1, EDG2, EDG4, EDG7 receptors and, to a lesser extent, for the EDG7 receptor was detected, whereas in rat macrophages, mRNA for EDG2, EDG5 receptors and, to a lesser extent, for the EDG6 receptor was found. In functional experiments, it was observed that lysophosphatitic acid and sphingosine-1-phosphate can stimulate O(2)(-) generation in rat and human alveolar macrophages suggesting that lysophosphatitic acid and sphingosine-1-phosphate possibly acting via EDG receptors may play a role in controlling the activation of macrophages.

Respimat (a new soft mist inhaler) delivering fenoterol plus ipratropium bromide provides equivalent bronchodilation at half the cumulative dose compared with a conventional metered dose inhaler in asthmatic patients.

BACKGROUND: Respimat, a possible alternative to the conventional metered dose inhaler (MDI), is a novel, reusable, propellant-free, multidose soft mist inhaler. Respimat slowly releases a metered dose of active substance as a soft mist with a high proportion of the dose in the fine particle fraction, leading to improved lung deposition following inhalation when compared with the conventional MDI. OBJECTIVES AND METHODS: The equipotent bronchodilating efficacy and safety of a combination of fenoterol hydrobromide and ipratropium bromide (F/I) in cumulative doses delivered by either Respimat or pressurised MDI was assessed in a randomised, controlled, double-blind (within device) 4-way crossover study. Forty-three patients with stable asthma (mean FEV(1) 62% predicted) responsive to F/I inhaled cumulatively 16 puffs on each of 4 test days (1 + 1 + 2 + 4 + 8 puffs at 50-min intervals) via Respimat delivering 50/20, 25/20 or 25/10 microg F/I per puff or via MDI delivering 50/20 microg F/I per puff. RESULTS: Cumulative doses of 400/160 and 400/320 microg F/I via Respimat produced bronchodilation (evaluated by average increase in FEV(1) 45-245 min after first inhalation) equivalent to that achieved with a cumulative 800/320 microg F/I via MDI (mean increase in FEV(1) above baseline 0.76, 0.73 and 0.71 litres, respectively). The tolerability of the F/I combination via Respimat was also comparable to that of twice the dose delivered via MDI. CONCLUSION: Therefore, a fenoterol hydrobromide/ipratropium bromide combination delivered by Respimat is as safe and effective as the MDI at half the cumulative dose, on acute administration to patients with asthma.