pulmicort and Pulmonary-Edema

Acute lung injury (ALI) usually has a high morbidity and mortality rate, but the current treatment is relatively scarce. Both budesonide (Bud) and N-acetylcysteine (NAC) exhibit protective effects in ALI, so we further investigated whether they have a synergistic effect on ALI when used together.. Establishment of a rat model of ALI with Lipopolysaccharide (LPS). Bud and NAC were administered by nebulized inhalation alone or in combination. Subsequently, HE staining was performed to observe the pathological changes in lungs of rat. Evans blue staining was implemented to assess alveolar permeability, and the pulmonary edema was assessed by measuring the ratio of wet to dry weight of the lung. Moreover, a TUNEL kit was served to test apoptosis in lung tissues. Western blot and immunohistochemistry were analyzed for expression of scorch-related proteins and NLRP3 in lung tissue, respectively. ELISA was implemented to detect inflammatory factor levels in BALF. and RT-qPCR was utilized to assess the expression level of miR-381. After stable transfection of miR-381 inhibitor or OE-NLRP3 in BEAS-2B treated with LPS, Bud and NAC, miR-381 expression was assessed by RT-qPCR, scorch death-related protein expression was measured by western blot, cell proliferation/viability was assayed by CCK-8, apoptosis was measured by flow cytometry, and ELISA was implemented to assess inflammatory factor levels. Furthermore, the Dual-luciferase assay was used to verify the targeting relationship.. Bud and NAC treatment alone or in combination with nebulized inhalation attenuated the increased alveolar permeability, pulmonary edema, inflammatory response and scorching in LPS-induced ALI rats, and combined treatment with Bud and NAC was the most effective. In addition, combined treatment with Bud and NAC upregulated miR-381 expression and inhibited NLRP3 expression in cellular models and LPS-induced ALI rats. Transfection of the miR-381 inhibitor and OE-NLRP3 partially reversed the protective effects of Bud and NAC combination treatment on BEAS-2B cell proliferation inhibition, apoptosis, focal death and the inflammatory response.. Combined Bud and NAC nebulization therapy alleviates LPS-induced ALI by modulating the miR-381/NLRP3 molecular axis.

Topics: Acetylcysteine; Acute Lung Injury; Animals; Budesonide; Lipopolysaccharides; Lung; MicroRNAs; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Edema; Rats; Signal Transduction

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

Topics: Acetamides; Administration, Inhalation; Aged; Animals; Dose-Response Relationship, Drug; Humans; Indazoles; Mass Spectrometry; Powders; Proton Magnetic Resonance Spectroscopy; Pulmonary Edema; Rats; Receptors, Glucocorticoid

Meconium aspiration syndrome (MAS) is a serious condition, which can be treated with exogenous surfactant and mechanical ventilation. However, meconium-induced inflammation, lung edema and oxidative damage may inactivate delivered surfactant and thereby reduce effectiveness of the therapy. As we presumed that addition of anti-inflammatory agent into the surfactant may alleviate inflammation and enhance efficiency of the therapy, this study was performed to evaluate effects of surfactant therapy enriched with budesonide versus surfactant-only therapy on markers of oxidative stress in experimental model of MAS. Meconium suspension (25 mg/ml, 4 ml/kg) was instilled into the trachea of young rabbits, whereas one group of animals received saline instead of meconium (C group, n = 6). In meconium-instilled animals, respiratory failure developed within 30 min. Then, meconium-instilled animals were divided into 3 groups according to therapy (n = 6 each): with surfactant therapy (M + S group), with surfactant + budesonide therapy (M + S + B), and without therapy (M group). Surfactant therapy consisted of two bronchoalveolar lavages (BAL) with diluted surfactant (Curosurf, 5 mg phospholipids/ml, 10 ml/kg) followed by undiluted surfactant (100 mg phospholipids/kg), which was in M + S + B group enriched with budesonide (Pulmicort, 0.5 mg/ml). Animals were oxygen-ventilated for additional 5 hours. At the end of experiment, blood sample was taken for differential white blood cell (WBC) count. After euthanizing animals, left lung was saline-lavaged and cell differential in BAL was determined. Oxidative damage, i.e. oxidation of lipids (thiobarbituric acid reactive substance (TBARS) and conjugated dienes) and proteins (dityrosine and lysine-lipoperoxidation products) was estimated in lung homogenate and isolated mitochondria. Total antioxidant capacity was evaluated in lung homogenate and plasma. Meconium instillation increased transmigration of neutrophils and production of free radicals compared to controls (P < 0.05). Surfactant therapy, but particularly combined surfactant + budesonide therapy reduced markers of oxidative stress versus untreated animals (P < 0.05). In conclusion, budesonide added into surfactant enhanced effect of therapy on oxidative damage of the lung.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Budesonide; Disease Models, Animal; Female; Free Radicals; Inflammation; Lung; Lung Injury; Male; Meconium; Meconium Aspiration Syndrome; Neutrophils; Oxidative Stress; Pulmonary Edema; Pulmonary Surfactants; Rabbits; Trachea

Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury.

Topics: Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Budesonide; Chlorine; Glucocorticoids; Mice; Mice, Inbred Strains; Mometasone Furoate; Neutrophil Infiltration; Pneumonia; Pregnadienediols; Pulmonary Edema

Inflammation, oxidation, lung edema, and other factors participate in surfactant dysfunction in meconium aspiration syndrome (MAS). Therefore, we hypothesized that anti-inflammatory treatment may reverse surfactant dysfunction in the MAS model. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg; Mec) or saline (Sal). Thirty minutes later, meconium-instilled animals were treated by glucocorticoids budesonide (0.25 mg/kg, i.t.) and dexamethasone (0.5 mg/kg, i.v.), or phosphodiesterase inhibitors aminophylline (2 mg/kg, i.v.) and olprinone (0.2 mg/kg, i.v.), or the antioxidant N-acetylcysteine (10 mg/kg, i.v.). Healthy, non-ventilated animals served as controls (Con). At the end of experiments, left lung was lavaged and a differential leukocyte count in sediment was estimated. The supernatant of lavage fluid was adjusted to a concentration of 0.5 mg phospholipids/ml. Surfactant quality was evaluated by capillary surfactometer and expressed by initial pressure and the time of capillary patency. The right lung was used to determine lung edema by wet/dry (W/D) weight ratio. Total antioxidant status (TAS) in blood plasma was evaluated. W/D ratio increased and capillary patency time shortened significantly, whereas the initial pressure increased and TAS decreased insignificantly in Sal vs. Con groups. Meconium instillation potentiated edema formation and neutrophil influx into the lungs, reduced capillary patency and TAS, and decreased the surfactant quality compared with both Sal and Con groups (p > 0.05). Each of the anti-inflammatory agents reduced lung edema and neutrophil influx into the lung and partly reversed surfactant dysfunction in the MAS model, with a superior effect observed after glucocorticoids and the antioxidant N-acetylcysteine.

Topics: Acetylcysteine; Acute Lung Injury; Aminophylline; Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Budesonide; Dexamethasone; Disease Models, Animal; Humans; Imidazoles; Infant, Newborn; Leukocyte Count; Lung; Meconium; Meconium Aspiration Syndrome; Neutrophils; Oxidative Stress; Phosphodiesterase Inhibitors; Pulmonary Edema; Pulmonary Surfactants; Pyridones; Rabbits

Acute exacerbations of chronic obstructive pulmonary disease (COPD), which are often associated with respiratory infections, are defined as a worsening of symptoms that require a change in medication. Exacerbations are characterized by a reduction in lung function, quality of life and are associated with increased pro-inflammatory mediators in the lung. Our aim was to develop an animal model to mimic aspects of this exaggerated inflammatory response by combining key etiological factors, tobacco smoke (TS) and bacterial lipopolysaccharide (LPS).. Rats were exposed to TS for 30 min twice a day for 2 days. On day 3 animals were exposed to LPS for 30 min followed by exposure to TS 5 h later. Inflammation, mucus and lung function were assessed 24 h after LPS.. Neutrophils, mucus, oedema and cytotoxicity in lung and/or bronchoalveolar lavage was increased in animals exposed to combined LPS and TS, compared with either stimulus alone. Lung function was impaired in animals exposed to combined LPS and TS. Inflammatory cells, oedema and mucus were unaffected by pretreatment with the corticosteroid, budesonide, but were reduced by the phosphodiesterase 4 selective inhibitor roflumilast. Additionally, lung function was improved by roflumilast.. We have established an in vivo model mimicking characteristic features of acute exacerbations of COPD including lung function decline and increased lung inflammation. This model may be useful to investigate molecular and cellular mechanisms underlying such exacerbations, to identify new targets and to discover novel therapeutic agents.

Topics: Adrenal Cortex Hormones; Aminopyridines; Animals; Anti-Inflammatory Agents; Benzamides; Bronchoalveolar Lavage Fluid; Budesonide; Cyclopropanes; Disease Models, Animal; Inflammation Mediators; Lipopolysaccharides; Lung; Male; Mucus; Neutrophil Infiltration; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pneumonia; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Time Factors; Tobacco Smoke Pollution

It has been suggested that intratracheal administration of the immunomodulator, FTY720, could have anti-inflammatory effects without causing a decrease in blood lymphocyte counts. However, the receptor responsible for this effect has not been defined.. We have described, in a mouse model of allergen-induced inflammation, the use of proton magnetic resonance imaging to non-invasively assess lung fluid accumulation and inflammation. Here, we used this model to investigate the sphingosine-1-phosphate (S1P) receptor responsible for the anti-inflammatory effect of FTY720.. When given intranasally, FTY720 (3 and 10 microg.kg(-1)) inhibited by approximately 50% the allergen-induced accumulation of fluid in the lung detected by magnetic resonance imaging, but had no effect on the cellular inflammation in the airway space or on circulating blood lymphocytes. Inhibition of the infiltration of inflammatory cells into the airways was only observed at a dose of FTY720 that induced lymphopenia (100 microg.kg(-1)). Similar results were observed in S1P(3)-deficient mice. The effect of FTY720 was mimicked by intranasal treatment of wild-type mice with a S1P(1)-specific agonist, AUY954.. Thus, in contrast to previously published work, our results suggest that systemic exposure of FTY720 is necessary to obtain an airway anti-inflammatory effect. On the contrary, inhibition of the allergen-induced accumulation of fluid in the lung, via activation of the S1P(1) receptor, is obtainable without systemic effects.

Topics: Administration, Intranasal; Allergens; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; beta-Alanine; Budesonide; Capillary Permeability; Dose-Response Relationship, Drug; Female; Fingolimod Hydrochloride; Immunologic Factors; Lung; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumonia; Propylene Glycols; Pulmonary Edema; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Thiophenes

Allergen-induced airways oedema in actively sensitized rats has been studied earlier by magnetic resonance imaging (MRI). We used MRI to follow the consequences of non-immunological mast cell activation induced by compound 48/80 in the rat lungs in vivo.. Male naïve rats were scanned by MRI prior to and at several time points following intratracheal administration of the mast cell secretagogue, compound 48/80. The effects of a range of drugs on the response induced by compound 48/80 were studied.. Strong fluid signals were detected by MRI in the lungs at 24 h after compound 48/80, correlating with increased protein concentration and inflammatory cell infiltration in bronchoalveolar lavage, and with perivascular oedema observed histologically. Pharmacological intervention demonstrated that the increase in MRI signal volume induced by compound 48/80 24 h after challenge was blocked by disodium cromoglycate and the glucocorticoid, budesonide. Pretreatment with wortmannin, capsazepine, DNK333 (a dual neurokinin (NK) 1 and NK2 antagonist) or the anti-allergy drug CGS8515, but not indomethacin, resulted in partial inhibition.. Compound 48/80 induced a complex inflammatory reaction which did not solely involve mast cell degranulation but also activation of sensory nerves and was qualitatively similar to allergen challenge. Changes observed by MRI correlated with decreases in protein concentration in BAL fluid. However, the magnitude of the changes detected was greater using MRI. Our results demonstrate that MRI is a sensitive and efficient tool to assess the effects of drugs on lung inflammation.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Aza Compounds; Benzamides; Bronchoalveolar Lavage Fluid; Budesonide; Capsaicin; Cell Degranulation; Cromolyn Sodium; Disease Models, Animal; Drug Evaluation, Preclinical; Indomethacin; Lung; Magnetic Resonance Imaging; Male; Mast Cells; Naphthoquinones; ortho-Aminobenzoates; p-Methoxy-N-methylphenethylamine; Proteins; Pulmonary Edema; Rats; Rats, Inbred BN; Respiratory System Agents; Time Factors; Wortmannin

Local administration of corticosteroids may diminish acute lung injury associated with meconium aspiration. Budesonide was given intratracheally in 2 doses of 0.25 mg/kg each by means of inpulsion effect of high-frequency jet ventilation 0.5 and 2.5 hours after meconium instillation to oxygen-ventilated adult rabbits. Within 5 hours after the first dose, budesonide significantly improved gas exchange and decreased right-to-left pulmonary shunts, central venous pressure, and ventilatory pressures. In addition, budesonide reduced the meconium-induced lung edema formation, airway hyperreactivity to histamine, count of neutrophils in bronchoalveolar lavage fluid associated with higher total white blood cell and neutrophil counts in the blood, and diminished oxidative modifications of proteins and lipids in lung tissue compared to non-treated meconium-instilled group. The intratracheally administered corticosteroid budesonide effectively improved pulmonary functions and alleviated changes associated with inflammation in meconium-instilled rabbits.

Topics: Adrenal Cortex Hormones; Animals; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Budesonide; Central Venous Pressure; Disease Models, Animal; Histamine; Humans; Infant, Newborn; Intubation, Intratracheal; Lipid Peroxidation; Lung; Meconium Aspiration Syndrome; Neutrophil Infiltration; Oxidative Stress; Pneumonia, Aspiration; Protein Carbonylation; Pulmonary Circulation; Pulmonary Edema; Pulmonary Gas Exchange; Pulmonary Ventilation; Rabbits; Respiratory System Agents

1. Magnetic resonance imaging (MRI) was used to study noninvasively the effects of compounds to resolve inflammation induced by ovalbumin (OVA) challenge in the lungs of actively sensitised rats. 2. Marked oedematous signals were detected between 24 and 96 h following OVA in vehicle-treated animals. When administered 24 h after OVA, budesonide, a glucocorticosteroid, or 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), a selective phosphodiesterase 4 inhibitor, increased the rate of resolution of established oedematous signals detected by MRI. The effect was evident 3 h after drug administration and the signals were nearly fully resolved at 96 h postchallenge. 3. The drug-induced rapid resolution of MRI signals was not accompanied by changes in parameters of inflammation in the bronchoalveolar lavage fluid, but was associated with perivascular oedema detected histologically. 4. In conclusion, the effects of anti-inflammatory drugs on a component of allergic inflammation can be monitored by following with MRI the rate of resolution of the associated oedematous signals.

Topics: Animals; Bronchoalveolar Lavage Fluid; Budesonide; Inflammation; Leukocytes; Lung; Magnetic Resonance Imaging; Male; Naphthyridines; Ovalbumin; Oxadiazoles; Peroxidase; Pulmonary Edema; Rats; Rats, Inbred BN; Respiratory Hypersensitivity

A detailed analysis has been carried out of the correlation between the signals detected by MRI in the rat lung after allergen or endotoxin challenge and parameters of inflammation determined in the broncho-alveolar lavage (BAL) fluid. MRI signals after allergen correlated highly significantly with the BAL fluid eosinophil number, eosinophil peroxidase activity and protein concentration. Similar highly significant correlations were seen when the anti-inflammatory glucocorticosteroid, budesonide, manifested against allergen. In contrast, following endotoxin challenge, mucus was the sole BAL fluid parameter that correlated significantly with the long lasting signal detected by MRI. Since edema is an integral component of pulmonary inflammation, MRI provides a noninvasive means of monitoring the course of the inflammatory response and should prove invaluable in profiling anti-inflammatory drugs in vivo. Further, the prospect of noninvasively detecting a sustained mucus hypersecretory phenotype in the lung brings an important new perspective to models of chronic obstructive pulmonary diseases.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Budesonide; Eosinophil Peroxidase; Inflammation; Lipopolysaccharides; Lung; Magnetic Resonance Imaging; Male; Mucus; Ovalbumin; Peroxidases; Pulmonary Disease, Chronic Obstructive; Pulmonary Edema; Pulmonary Eosinophilia; Rats; Rats, Inbred BN; Respiration

The course of pulmonary edema formation after an intratracheal (i.t.) instillation of ovalbumin was followed noninvasively by magnetic resonance imaging (MRI) in actively sensitized Brown Norway (BN) rats. Changes in edema volume assessed by MRI mimicked the results from the analysis of the number and activation of inflammatory cells recovered from the broncho-alveolar lavage (BAL) fluid. Rats treated with budesonide did not develop edema following challenge with ovalbumin, and these animals showed a significant decrease in BAL fluid inflammatory cell numbers and eosinophil peroxidase and myeloperoxidase activities. Thus, following lung edema formation by MRI provides a reliable means of assessing pulmonary inflammation after allergen challenge. Unlike BAL fluid analysis, which requires killing animals at each time point, this method is noninvasive. MRI could be of importance for the noninvasive profiling of anti-inflammatory drugs in animal models of asthma and in the clinic. Magn Reson Med 45:88-95, 2001.

Topics: Allergens; Animals; Bronchoalveolar Lavage Fluid; Budesonide; Eosinophil Peroxidase; Eosinophils; Glucocorticoids; Image Enhancement; Magnetic Resonance Imaging; Male; Ovalbumin; Peroxidase; Peroxidases; Proteins; Pulmonary Edema; Rats; Rats, Inbred BN; Respiratory Hypersensitivity

Glucocorticoids (GCs) are the mainstay of asthma therapy; however, major side effects limit their therapeutic use. GCs influence the expression of genes either by transactivation or transrepression. The antiinflammatory effects of steroids are thought to be due to transrepression and the side effects, transactivation. Recently, a compound, RU 24858, has been identified that demonstrated dissociation between transactivation and transrepression in vitro. RU 24858 exerts strong AP-1 inhibition (transrepression), but little or no transactivation. We investigated whether this improved in vitro profile results in the maintenance of antiinflammatory activity (evaluated in the Sephadex model of lung edema) with reduced systemic toxicity (evaluated by loss in body weight, thymus involution, and bone turnover) compared with standard GCs. RU 24858 exhibits comparable antiinflammatory activity to the standard steroid, budesonide. However, the systemic changes observed indicate that transactivation events do occur with this GC with similar potency to the standard steroids. In addition, the GCs profiled showed no differentiation on quantitative osteopenia of the femur. These results suggest that in vitro separation of transrepression from transactivation activity does not translate to an increased therapeutic ratio for GCs in vivo or that adverse effects are a consequence of transrepression.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Bone Diseases, Metabolic; Budesonide; Desoximetasone; Dextrans; Femur Head; Gene Expression Regulation; Glucocorticoids; Growth Plate; Hydroxycorticosteroids; Immunosuppressive Agents; Intubation, Intratracheal; Male; Osteocalcin; Prednisolone; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Transcriptional Activation

Spontaneous or steroid-induced eosinophil apoptosis occurring in vitro has not been demonstrated in lung tissues in vivo. This study examines cell apoptosis in rat lungs using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) technique and transmission electron microscopy (TEM). After establishing sustained lung edema and eosinophilia by challenge with Sephadex beads intratracheally, budesonide treatment was started intratracheally. Sephadex alone increased the total number of apoptotic cells, which were not efficiently engulfed by macrophages or other cells, in vivo. Yet apoptotic tissue eosinophils were exceedingly rare (1 of 360 TEM-analyzed eosinophils). By contrast, approximately 20% of eosinophils in the airway lumen were apoptotic, and unengulfed. Budesonide promptly inhibited edema but 3 d of steroid treatment were required to reduce the established tissue eosinophilia. Not at any time point did budesonide induce eosinophil apoptosis (0 of 318 TEM-analyzed tissue eosinophils). We conclude that (1) eosinophil apoptosis can occur but is a rare event in vivo in respiratory tract tissues; (2) airway tissue eosinophils, rather than undergoing apoptosis, are eliminated by migration into airway lumen followed by apoptosis and mucociliary clearance; (3) anti-inflammatory steroid treatment may not increase eosinophil apoptosis in vivo nor may it affect the luminal entry of eosinophils; (4) steroids permit elimination of eosinophils into airway lumen and slowly resolve established lung eosinophilia.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Budesonide; Dextrans; Disease Models, Animal; Drug Evaluation, Preclinical; In Situ Nick-End Labeling; Inflammation; Leukocyte Count; Male; Microscopy, Electron, Scanning Transmission; Mucociliary Clearance; Pulmonary Edema; Pulmonary Eosinophilia; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.

Topics: Androstanes; Animals; Asthma; Cell Line; Humans; Liver; Magnetic Resonance Spectroscopy; Male; Organ Size; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Structure-Activity Relationship; Thymus Gland; Tyrosine Transaminase

1. A single i.p. injection of bacterial endotoxin in rats (3.5 mg kg-1) caused lung injury assessed as changes in lung dry:wet weight ratio and leukopaenia over the subsequent 28 h. 2. This treatment also slowed the efflux of 14C from [14C]-prostaglandin E2 (PGE2), i.e., increased t1/2 and increased the survival of PGE2 in isolated perfused lungs over the same period. 3. These effects of endotoxin were reversed by methylprednisolone (30 mg kg-1), given 30 min after the endotoxin. 4. Another synthetic corticosteroid, budesonide (1.2 mg kg-1) given 1 h before endotoxin partially prevented the lung injury and leukopaenia but did not affect the increased t1/2 for PGE2 nor its survival. 5. The reversal by methylprednisolone of both the physical signs of lung injury and the changes in PGE2 pharmacokinetics caused by endotoxin suggests that changes in PGE2 pharmacokinetics could serve as an index of acute lung injury following sepsis.

Topics: Animals; Anti-Inflammatory Agents; Budesonide; Dinoprostone; Endotoxins; Escherichia coli; In Vitro Techniques; Injections, Intraperitoneal; Leukocytes; Lung; Male; Methylprednisolone; Pregnenediones; Prostaglandins E; Pulmonary Edema; Rats; Rats, Inbred Strains; Steroids

Topics: Adrenal Glands; Animals; Anti-Inflammatory Agents; Budesonide; Disease Models, Animal; Glucocorticoids; Lung; Male; Organ Size; Pregnenediones; Pulmonary Edema; Rats