dinoprost and Lung-Diseases

Isoprostanes are produced during peroxidation of membrane lipids by free radicals and reactive oxygen species. Initially, they were recognized as being valuable markers of oxidative stress, and in the past 10 years, dozens of disease states and experimental conditions with diverse etiologies have been shown to be associated with marked increases in urinary, plasma, and tissue levels of isoprostanes. However, they are not just mere markers; they evoke important biological responses on virtually every cell type found within the lung, and these responses exhibit compound-, tissue-, and species-related variations. In fact, the isoprostanes may mediate many of the features of the disease states for which they are used as indicators. In this review, I describe the chemistry, metabolism, and pharmacology of isoprostanes, with a particular emphasis on pulmonary cell types, and the possible roles of isoprostanes in pulmonary pathophysiology.

Topics: Animals; Arachidonic Acid; Cell Membrane; Dinoprost; F2-Isoprostanes; Humans; Lipid Peroxidation; Lung; Lung Diseases; Muscle, Smooth; Oxidative Stress; Reactive Oxygen Species

Most of the traditional methods used to assess oxidative stress in clinical setting are non specific, unreliable or inaccurate. Recently, a novel family of prostaglandin F2 isomers, called F2-isoprostanes, produced in vivo by a free radical peroxidation of arachidonic acid, has been described. These compounds may produce physiological or pathological effects due to their ability to alter smooth muscle and platelet functions. The quantification of the two major isoforms (isoprostaglandin F2 alpha type-III and VI) in biological fluids and tissues as markers of lipid peroxidation appears to be an important advance in our ability to explore the role of free radicals in the pathogenesis of human disease.. Urinary excretion of F2-isoprostanes is correlated with age, indicating increased oxidative stress during the normal aging process. High F2-isoprostanes concentration has been described in diseases such as ischemic heart disease, diabetes, Alzheimer's disease and hepatic cirrhosis. The correlation of F2-isoprostane concentrations and human diseases severity in hepatic cirrhosis, cardiac failure and diabetes suggest that these compounds may be of interest as predictive markers.. Preliminary studies suggest the use of F2-isoprostanes as prognosis markers. In addition, F2-isoprostanes quantification offers promising potential as intermediate endpoints for clinical studies of antioxidant therapies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antioxidants; Biomarkers; Cardiovascular Diseases; Child; Diabetes Mellitus; Dinoprost; Female; Free Radicals; Humans; Hypercholesterolemia; Infant, Newborn; Kidney Transplantation; Lipid Peroxidation; Liver Diseases; Lung Diseases; Male; Middle Aged; Nervous System Diseases; Oxidative Stress; Prognosis; Risk Factors; Smoking

Topics: Anaphylaxis; Animals; Asthma; Bronchi; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Guinea Pigs; Humans; In Vitro Techniques; Lung; Lung Diseases; Models, Biological; Muscle, Smooth; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; SRS-A; Thromboxane A2

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Asthma; Bronchitis; Dinoprost; Dinoprostone; Epoprostenol; Humans; Leukotriene B4; Lung; Lung Diseases; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins D; Prostaglandins E; Prostaglandins F; Prostaglandins G; Prostaglandins H; Pulmonary Circulation; Pulmonary Ventilation; SRS-A

Topics: Adrenergic beta-Agonists; Alcohol Drinking; Anti-Anxiety Agents; Anti-Bacterial Agents; Anti-Infective Agents; Aspirin; Asthma; Barbiturates; Coffee; Cromolyn Sodium; Dinoprost; Drug Interactions; Female; Fetal Alcohol Spectrum Disorders; Histamine H1 Antagonists; Humans; Iodine; Lung Diseases; Maternal-Fetal Exchange; Nasal Decongestants; Parasympatholytics; Prednisone; Pregnancy; Pregnancy Complications; Prostaglandins F; Smoking; Theophylline

Topics: Adenylyl Cyclases; Anaphylaxis; Animals; Asthma; Bronchi; Chemical Phenomena; Chemistry; Dinoprost; Guinea Pigs; Lung; Lung Diseases; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins E; Prostaglandins F; Structure-Activity Relationship; Trachea

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Alprostadil; Combined Modality Therapy; Cyclic AMP; Cyclic GMP; Dinoprost; Dinoprostone; Female; Humans; Laser Therapy; Lung Diseases; Male; Middle Aged; Pneumonectomy; Preoperative Care; Prostaglandin D2; Thoracoplasty; Thromboxane B2

Exhaled breath condensate (EBC) has been increasingly used as a new and non-invasive method to study airway inflammation. In this study we have compared the concentrations of lipid mediators in EBC with concentrations in bronchoalveolar lavage fluid (BALF). We included 37 patients undergoing bronchoscopy (12 sarcoidosis, 12 COPD, 6 lung cancer, 5 chronic cough, 1 Wegener's granulomatosis, 1 sclerodermia). Patients were not allowed to have exacerbation or any change in concomitant medication for at least 4 weeks prior to the study. In all patients, EBC was collected immediately prior to the bronchoscopy. The levels of cys-LTs, LTB_{4}, 8-isoprostane were significantly higher in BALF compared to EBC (p < 0.0001, p< 0.001, p< 0.0001 for cys-LTs, LTB4, 8-isoprostane respectively). Moreover, there was a strong positive correlation between both leukotriene B_{4} and 8-isoprostane in BALF and EBC (r=0.53 and r=0.79, p< 0.01, respectively) in patients with sarcoidosis and COPD but there was no correlation between eicosanoids BALF and EBC in patients with chronic cough and lung cancer. This is the first study to compare EBC and BALF in different lung diseases which demonstrated significant correlations between the levels of eicosanoids in BALF and EBC in patients with COPD and sarcoidosis. EBC may be useful in measuring inflammation in several inflammatory lung diseases.

Topics: Adult; Aged; Biomarkers; Blood Cell Count; Breath Tests; Bronchoalveolar Lavage Fluid; Bronchoscopy; Case-Control Studies; Cysteine; Dinoprost; Dinoprostone; Female; Humans; Leukotrienes; Lung Diseases; Male; Middle Aged

Asbestos induces generation of reactive oxygen and nitrogen species in laboratory studies. Several such species can be measured non-invasively in humans in exhaled breath condensate (EBC) but few have been evaluated. This study aimed to assess oxidative stress and lung inflammation in vivo.. Eighty six men were studied: sixty subjects with asbestos-related disorders (asbestosis: 18, diffuse pleural thickening (DPT): 16, pleural plaques (PPs): 26) and twenty six age- and gender-matched normal individuals.. Subjects with asbestosis had raised EBC markers of oxidative stress compared with normal controls [8-isoprostane (geometric mean (95% CI) 0.51 (0.17-1.51) vs 0.07 (0.04-0.13) ng/ml, p<0.01); hydrogen peroxide (13.68 (8.63-21.68) vs 5.89 (3.99-8.69) microM, p<0.05), as well as increased EBC total protein (17.27 (10.57-28.23) vs 7.62 (5.13-11.34) microg/ml, p<0.05), and fractional exhaled nitric oxide (mean+/-SD) (9.67+/-3.26 vs 7.57+/-1.89ppb; p<0.05). EBC pH was lower in subjects with asbestosis compared with subjects with DPT (7.26+/-0.31 vs 7.53+/-0.24; p<0.05). There were no significant differences in exhaled carbon monoxide, EBC total nitrogen oxides and 3-nitrotyrosine between any of the asbestos-related disorders, or between these and controls.. In asbestos-related disorders, markers of inflammation and oxidative stress are significantly elevated in subjects with asbestosis compared with healthy individuals but not in pleural diseases.

Topics: Aged; Asbestos; Asbestosis; Biomarkers; Dinoprost; Forced Expiratory Volume; Humans; Lung Diseases; Male; Nitric Oxide; Oxidative Stress; Prognosis; Tyrosine

Sensitive assay method was developed for a parallel, rapid and precise determination of the most prominent oxidative stress biomarkers: 8-iso-prostaglandin F(2alpha), malondialdehyde and 4-hydroxynonenal. The method consisted of a pre-treatment part a solid-phase extraction, for rapid and effective isolation of biomarkers from body fluids (exhaled breath condensate, plasma and urine) and the detection method LC-ESI-MS/MS, where the selected reaction monitoring mode was used for its extremely high degree of selectivity and the stable-isotope-dilution assay for its high precision of quantification. The developed method was characterized by the following parameters: the imprecision was below 14.3%, the mean inaccuracy was determined to be lower than 13.1%. The method was tested on samples obtained from patients diagnosed with asbestosis, pleural hyalinosis or silicosis, i.e. occupational lung diseases caused by fibrogenic dusts, inducing oxidative stress in the respiratory system, and then compared to samples from healthy subjects. The difference in concentration levels of biomarkers between the two groups was perceptible in all the body fluids (the difference observed in an exhaled breath condensate was statistically most significant).

Topics: Aged; Aldehydes; Asbestos; Biomarkers; Body Fluids; Case-Control Studies; Chromatography, High Pressure Liquid; Dinoprost; Humans; Lung Diseases; Malondialdehyde; Middle Aged; Oxidative Stress; Silicon Dioxide; Solid Phase Extraction; Tandem Mass Spectrometry

The mechanisms involved in the fall of exhaled nitric oxide (NOe) concentration occurring in normal, anesthetized open chest rabbits with prolonged mechanical ventilation (MV) at low lung volume have been investigated. NOe, pH of exhaled vapor condensate, serum prostaglandin E(2), and F(2alpha), tumor necrosis factor (TNF-alpha), PaO(2), PaCO(2), pHa, and lung mechanics were assessed before, during, and after 3-4h of MV at zero end-expiratory pressure (ZEEP), with fixed tidal volume (9 ml kg(-1)) and frequency, as well as before and after 3-4h of MV on PEEP only. Lung histology and wet-to-dry ratio (W/D), and prostaglandin and TNF-alpha in bronchoalveolar lavage fluid (BALF) were also assessed. While MV on PEEP had no effect on the parameters above, MV on ZEEP caused a marked fall (45%) of NOe, with a persistent increase of airway resistance (45%) and lung elastance (12%). Changes in NOe were independent of prostaglandin and TNF-alpha levels, systemic hypoxia, hypercapnia and acidosis, bronchiolar and alveolar interstitial edema, and pH of exhaled vapor condensate. In contrast, there was a significant relationship between the decrease in NOe and bronchiolar epithelial injury score. This indicates that the fall in NOe, which occurs in the absence of an inflammatory response, is due to the epithelial damage caused by the abnormal stresses related to cyclic opening and closing of small airways with MV on ZEEP, and suggests its use as a sign of peripheral airway injury.

Topics: Airway Resistance; Animals; Bronchoalveolar Lavage Fluid; Carbon Dioxide; Dinoprost; Dinoprostone; Lung Diseases; Nitric Oxide; Oxygen Consumption; Positive-Pressure Respiration; Pulmonary Gas Exchange; Rabbits; Respiration, Artificial; Respiratory Mechanics; Single-Blind Method; Tidal Volume; Tumor Necrosis Factor-alpha

Exhaled breath condensate (EBC) is increasingly studied as a noninvasive research method of sampling the lungs, measuring several biomarkers. The exact site of origin of substances measured in EBC is unknown, as is the clinical applicability of the technique. Special techniques might be needed to measure EBC biomarkers.. To assess biomarker concentrations in clinical disease and investigate the site of origin of EBC, we compared EBC and bronchoalveolar lavage (BAL) biomarkers in 49 patients undergoing bronchoscopy for clinical indications.. We measured exhaled nitric oxide, 8-isoprostane, hydrogen peroxide, total nitrogen oxides, pH, total protein, and phospholipid (n = 33) and keratin (n = 15) to assess alveolar and mucinous compartments, respectively. EBC was collected over 10 min using a refrigerated condenser according to European Respiratory Society/American Thoracic Society recommendations, and BAL performed immediately thereafter.. 8-Isoprostane, nitrogen oxides, and pH were significantly higher in EBC than in BAL (3.845 vs. 0.027 ng/ml, 28.4 vs. 3.8 microM, and 7.35 vs. 6.4, respectively; p < 0.001). Hydrogen peroxide showed no difference between EBC and BAL (17.5 vs. 20.6 microM, p = not significant), whereas protein was significantly higher in BAL (33.8 vs. 183.2 microg/ml, p < 0.001). Total phospholipid was also higher in EBC, but keratin showed no difference. No significant correlation was found between EBC and BAL for any of the biomarkers evaluated either before or after correction for dilution.. In clinical disease, markers of inflammation and oxidative stress are easily measurable in EBC using standard laboratory techniques and EBC is readily obtained. However, EBC and BAL markers do not correlate.

Topics: Biomarkers; Breath Tests; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Dinoprost; Exhalation; Female; Humans; Hydrogen Peroxide; Inflammation; Keratins; Lung Diseases; Male; Middle Aged; Nitric Oxide; Phospholipids

Increased levels of 8-isoprostane were found in various human lung diseases suggesting 8-isoprostane as a marker of pulmonary oxidative stress in vivo. The exact role in pediatric lung diseases has not been defined yet. The goal of this study was to clarify the role of 8-isoprostane in nasally exhaled breath condensate as possible marker of oxidative stress in children with different lung diseases.. Levels of 8-isoprostane were measured in nasally exhaled breath condensate of 29 cystic fibrosis patients, 19 children with a history of wheezing episodes, 8 infants with acute respiratory tract infection and 53 healthy subjects using a specific enzyme immunoassay.. Levels of 8-isoprostane did neither discriminate between different disease groups nor correlate with lung function in cystic fibrosis patients.. Levels of 8-isoprostane in nasally exhaled breath condensate do not reflect oxidative stress in children with different lung diseases.

Topics: Adolescent; Adult; Age Factors; Biomarkers; Breath Tests; Child; Child, Preschool; Dinoprost; Humans; Immunoassay; Infant; Lung Diseases; Oxidative Stress; Respiratory Function Tests; Statistics, Nonparametric

Multiorgan failure is a major cause of late morbidity and mortality after trauma. Reactive oxygen species generated during shock/resuscitation contribute to tissue injury by priming the immune system for an exaggerated response to subsequent inflammatory stimuli such as LPS. Stilbazulenyl nitrone (STAZN) is a novel second-generation azulenyl nitrone that has been shown to have potent antioxidant properties in a rat model of brain ischemia. We hypothesized that STAZN may confer protection against lung injury after shock/resuscitation and LPS by reducing oxidative stress and lowering the production of NF-kappaB-dependent pro-inflammatory cytokines. Sprague-Dawley rats were submitted to a two-hit model of lung injury involving hemorrhagic shock/resuscitation and subsequent intratracheal LPS injection, with and without intraperitoneal injections of STAZN. STAZN reduced overall lung injury in response to LPS alone and also after shock/resuscitation plus LPS. STAZN also reduced plasma levels of 8-isoprostane, a proxy measure of oxidative stress, indicating its antioxidant activity in vivo. The effect of STAZN was, at least in part, related to its effect on nuclear translocation of NF-kappaB and generation of the pro-inflammatory cytokine TNF-alpha. Azulenyl nitrones such as STAZN represent a promising novel class of antioxidants for treating organ injury.

Topics: Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Dinoprost; Enzyme-Linked Immunosorbent Assay; Lipopolysaccharides; Lung; Lung Diseases; Male; NF-kappa B; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resuscitation; Sesquiterpenes; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

A prostaglandin F2-like compound, 8-epi-PGF2alpha, formed from oxidation of arachidonate, has been proposed as an indicator of lipid peroxidation. We determined whether tracheal aspirate or urinary 8-epi-PGF2alpha levels would differ over time or between infants in a control group and infants with severe respiratory failure. We correlated tracheal aspirate 8-epi-PGF2alpha levels with the fraction of inspired oxygen and with mean airway pressures at 24 and 48 hours of life. Levels in tracheal aspirates were in the range of 0 to 36 pg/microg of fSC of IgA and were higher in infants with severe pulmonary disorders compared with those in infants in the control group (p < 0.02). Urinary concentrations did not discriminate between sick infants and infants in the control group.

Topics: Biomarkers; Dinoprost; Exudates and Transudates; F2-Isoprostanes; Humans; Immunoenzyme Techniques; Infant, Newborn; Lipid Peroxidation; Lung Diseases; Respiratory Distress Syndrome, Newborn; Trachea

We hypothesized that endotoxin injection in rats would stimulate in vivo nuclear factor-kappa B (NF-kappa B) activation in lung tissue and that antioxidant treatment before endotoxin injection would attenuate endotoxin-induced NF-kappa B activation, chemokine gene expression, and neutrophilic lung inflammation. We studied NF-kappa B activation in rat lung tissue following a single i.p. injection of endotoxin (6 mg/kg). After in vivo endotoxin treatment, lung NF-kappa B activation peaked at 2 h and temporally correlated with the expression of cytokine-induced neutrophil chemoattractant mRNA in lung tissue. Treatment with the antioxidant N-acetylcysteine (NAC) 1 h before endotoxin resulted in decreased lung NF-kappa B activation in a dose-dependent manner (from 200-1000 mg/kg) and diminished cytokine-induced neutrophil chemoattractant mRNA expression in lung tissue. Treatment with NAC significantly suppressed endotoxin-induced neutrophilic alveolitis. The average total lung lavage neutrophil count was 5.5 x 10(6) with endotoxin treatment vs 0.9 x 10(6) with NAC treatment before endotoxin. The NF-kappa B pathway represents an attractive therapeutic target for strategies to control neutrophilic inflammation and lung injury.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Base Sequence; Chemokines, CXC; Chemotactic Factors; Chemotaxis, Leukocyte; Dinoprost; Disease Models, Animal; Drug Evaluation, Preclinical; Endotoxins; F2-Isoprostanes; Gene Expression Regulation; Glutathione; Growth Substances; Inflammation; Intercellular Signaling Peptides and Proteins; Leukocyte Count; Lung; Lung Diseases; Male; Molecular Sequence Data; Neutrophils; NF-kappa B; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; RNA, Messenger; Sepsis

We evaluated the effect of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) on pig cardiopulmonary function by intravenously infusing each cytokine individually or in combination (0.5 microgram/kg from 0 to 0.5 h + 5 ng.kg-1 x min-1 from 0.5 to 6 h for each cytokine). The role of eicosanoids in mediating the TNF-alpha + IL-1 alpha-induced cardiopulmonary dysfunction was also investigated by pretreating cytokine-infused pigs with CGS 8515 (5-lipoxygenase inhibitor) or indomethacin (cyclooxygenase inhibitor). Coinfusion of TNF-alpha with IL-1 alpha caused additive increases (P < 0.05) in total peripheral resistance and plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha). The increases in mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), alveolar-arterial O2 gradient (AaDO2), alveolar dead space-to-tidal volume ratio (VD/VT), and plasma concentrations of thromboxane B2 were either additive or synergistic. CGS 8515 blocked the TNF-alpha + IL-1 alpha-induced increases (P < 0.05) in mean aortic pressure, total peripheral resistance (4-6 h), VD/VT (5-6 h), and, at 6 h, attenuated the increases in Ppa, PVR, and AaDO2. Indomethacin blocked or attenuated the cytokine-induced increases (P < 0.05) in Ppa, PVR, AaDO2, VD/VT, and plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. The 1-to 2-h systemic hypotension, caused by TNF-alpha + IL-1 alpha, was not abrogated by either indomethacin or CGS 8515. The cytokines did not alter plasma concentrations of leukotriene B4 or 5-hydroxyeicosatetraenoic acid. We conclude that coinfusion of TNF-alpha with IL-1 alpha induces physiological responses that are additive or synergistic and that cyclooxygenase and 5-lipoxygenase products (other than leukotriene B4 and 5-hydroxyeicosatetraenoic acid) importantly mediate cardiopulmonary dysfunction in pigs infused with TNF-alpha + IL-1 alpha.

Topics: 6-Ketoprostaglandin F1 alpha; Albumins; Animals; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Cyclooxygenase Inhibitors; Cytokines; Dinoprost; Drug Synergism; Eicosanoids; Heart; Heart Diseases; Hydroxyeicosatetraenoic Acids; Indomethacin; Injections, Intravenous; Interleukin-1; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Lung Diseases; Naphthoquinones; ortho-Aminobenzoates; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance

We treated a 68-year-old man with cirrhosis of the liver associated with moderate hypoxemia. Contrast-enhanced echocardiography revealed late opacification of the left ventricle, and pulmonary perfusion imaging with 99mTc macroaggregated albumin showed evidence of a significant uptake in both lungs and in the liver, spleen, and kidneys. Right cardiac catheterization revealed pulmonary hypotension, low pulmonary vascular resistance, and high cardiac output. We administered prostaglandin F2 alpha intravenously (0.2 microgram/kg/min for 30 minutes) and indomethacin orally (75 mg/day for three days). There was some degree of resolution of the hypoxemia and increases in both pulmonary arterial pressure and pulmonary vascular resistance. These findings suggest that the pathophysiology of hepatogenic pulmonary angiodysplasia is a reversible intrapulmonary vascular dilatation. These conditions can to some extent be modulated by vasoactive substances such as prostaglandins or other eicosanoids.

Topics: Aged; Dilatation, Pathologic; Dinoprost; Drug Therapy, Combination; Hemodynamics; Humans; Indomethacin; Liver Cirrhosis; Lung Diseases; Male; Pulmonary Artery; Pulmonary Circulation; Vascular Diseases

The in vitro reactivity of the smooth musculature of the trachea and lungs to PGF2 alpha, was studied in control cats and cats with experimental airway inflammation induced by turpentine oil. No changes were found in the reactivity of the tracheal smooth muscle, but the reactivity of the pulmonary tissue was significantly raised compared with the controls. The results indicate that PGF2 alpha may play a role in the pathogenesis of bronchial hyperreactivity after airway inflammation.

Topics: Animals; Cats; Dinoprost; Female; Inflammation; Lung Diseases; Male; Muscle Contraction; Muscle, Smooth; Respiratory Muscles; Trachea

We evaluated the role of sulfidopeptide leukotrienes as mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of LY171883, a specific leukotriene D4 (LTD4)/LTE4 receptor antagonist. Endotoxin caused hemoconcentration, granulocytopenia, decreased cardiac index, systemic hypotension, pulmonary hypertension, increased pulmonary vascular resistance, bronchoconstriction, hypoxemia, increased permeability of the alveolar-capillary membrane, pulmonary edema, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha), and 6-keto-PGF1 alpha. LY171883 did not modify endotoxin-induced cardiopulmonary and hematologic abnormalities, except for a modest attenuation of pulmonary hypertension (at 1 h) and increased pulmonary vascular resistance (at 1-2 h). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2, PGF2 alpha, and LTB4. These increases were not significantly modified in blood derived from pigs treated with LY171883, indicating no inhibition of cyclooxygenase or 5-lipoxygenase. We conclude that LTD4 and LTE4 are not important mediators of endotoxin-induced lung injury in anesthetized pigs, although they may contribute modestly to pulmonary vasoconstriction.

Topics: Acetophenones; Animals; Autacoids; Blood Gas Analysis; Calcimycin; Capillary Permeability; Cyclooxygenase Inhibitors; Dinoprost; Endotoxins; Hemodynamics; Infusions, Intravenous; Leukotriene B4; Lung Diseases; Organ Size; Radioimmunoassay; Respiration; Swine; Tetrazoles; Thromboxane B2

Dopexamine hydrochloride is a new analog of dopamine that lowers systemic vascular resistance and has positive inotropic and chronotropic properties, but lacks the alpha-adrenoceptor agonist activity of dopamine. The effects of dopexamine on hypoxic pulmonary vasoconstriction (HPV) are not known. We investigated this using an isolated, blood-perfused, and ventilated rat lung model. To study HPV, the ventilating gas was changed from an FIO2 of 0.21 to 0.03 and dopexamine hydrochloride was added. At blood concentrations of 100, 200, and 300 ng/ml, dopexamine caused a significant decrease in HPV of 22 +/- 3%, 31 +/- 4%, and 58 +/- 4% (mean +/- SEM, p less than .05), respectively. This effect was blocked completely by pretreatment of the preparation with propranolol (0.5 mg/kg, p less than .05). Dopexamine also induced significant (p less than .05) vasodilation of the pulmonary circulation preconstricted under normoxic conditions with prostaglandin F2 alpha, suggesting that the effects of the drug were not specific to hypoxia. We conclude that dopexamine inhibits HPV and vasodilates the pulmonary circulation by stimulation of beta 2 adrenoceptors.

Topics: Animals; Dinoprost; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Hypoxia; Lung; Lung Diseases; Male; Propranolol; Rats; Rats, Inbred Strains; Respiration, Artificial; Vasoconstriction; Vasodilator Agents

1. The role of prostanoids in 3-methylindole (3MI)-induced lung disease was investigated. Goats were infused with 3MI in propylene glycol at a dose of 35 mg 3MI/kg body weight. Control goats were infused with propylene glycol alone. 2. Blood was collected at regular intervals starting 24 hr before and ending 72 hr following 3MI infusion. In a second experiment, 3MI-treated goats were killed at 2, 6, 12, 24, 48 and 72 hr post-infusion. The concentrations of PGF2 alpha, PGE, 6-keto PGF1 alpha and TXB2 in plasma and lung of 3MI-infused and control goats were determined by radioimmunoassay. 3. Comparison of individual prostanoid concentrations showed that 3MI-infused and control goats exhibited similar plasma profiles for all four prostanoids measured. 4. In addition, prostanoid concentrations in lungs did not seem to be affected by 3MI infusion. 5. Thus, plasma and lung prostaglandin and TXB2 concentrations do not appear to be altered in 3MI-induced lung disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Goats; Indoles; Lung; Lung Diseases; Male; Prostaglandins; Prostaglandins E; Radioimmunoassay; Skatole; Thromboxane B2

We investigated transpulmonary enzymatic conversion of prostaglandin F2 alpha (PGF) to the 13,14-dihydro-15-keto metabolite (PGFM) in normal and acutely lung injured sheep. PGF was infused directly into the right ventricle. Sequential, simultaneous blood samples were drawn from the pulmonary artery (PA) and aorta (A). PGF and PGFM plasma concentrations were quantitated by double antibody radioimmunoassay (RIA). The pulmonary conversion rate of PGF in normal lung was established over a wide range of concentrations in intubated, normoxic, and hemodynamically stable sheep. Both zero and first order kinetics were present. PGF had no physiological effects on either pulmonary or systemic hemodynamics at any infusion rate studied. Acute lung injury was produced by intravenous injections of oleic acid into the PA until the resting mean pulmonary artery pressure doubled. Infusions were then repeated and fractional metabolism of PGF across the lung was assessed. PGF, at infusion rates of 2 micrograms/kg/min and 8 micrograms/kg/min, was metabolized greater than 70% respectively. Thus, there was no difference between control or experimental groups in PGF conversion. We conclude that the in vivo sheep lung has an extensive substrate-dependent capacity to metabolize PGF and this mechanism is resistant to severe acute oleic acid lung injury.

Topics: Animals; Dinoprost; Female; Kinetics; Lung; Lung Diseases; Male; Oleic Acids; Radioimmunoassay; Sheep

1. Based on the findings in the preceding paper we investigated the ability of pulmonary endothelial cells to metabolize prostaglandin F2 alpha (PGF2 alpha) and angiotensin I (AI), and to produce endothelium-derived relaxing factor (EDRF) following lung vascular injury induced by monocrotaline in rats. The isometric tension of pulmonary artery rings isolated from rats 3-5 weeks after an injection of monocrotaline or saline was measured. For comparison the responses to drugs of the artery denuded of endothelium by rubbing were tested. 2. Acetylcholine-induced relaxation of the rings precontracted by noradrenaline was diminished in the artery from monocrotaline-treated rats, depending on the duration after treatment. The diminution was comparable to that in the control artery denuded of endothelium. 3. The contractile response to PGF2 alpha was significantly augmented in the artery injured by monocrotaline. The similar augmentation was observed after the mechanical removal of endothelium in the control artery. Decrease of EDRF was not involved in the enhancement of contractile response to PGF2 alpha in the monocrotaline-injured artery. 4. AI caused a contraction, which was sensitive to captopril, in control rings, and also in monocrotaline-injured rings to a similar degree. Removal of endothelium from the control artery did not modify the response to AI or to AII. 5. These results suggest that the monocrotaline treatment of rats suppresses the ability of pulmonary endothelium to produce EDRF and to degrade prostaglandins. The relative resistance of the AI response to endothelial injury suggests that the existence of converting enzyme is not restricted to the endothelium.

Topics: Acetylcholine; Angiotensin I; Angiotensin II; Animals; Dinoprost; Endothelium, Vascular; In Vitro Techniques; Lung; Lung Diseases; Male; Monocrotaline; Muscle Relaxation; Potassium Chloride; Pulmonary Artery; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains

Topics: Adolescent; Adult; Cyclic AMP; Cyclic GMP; Dinoprost; Humans; Lung Diseases; Middle Aged; Postoperative Period; Preoperative Care; Prostaglandins E; Prostaglandins F

We investigated direct histamine release and its effects in edema formation following paraquat (PQ) injury in a blood-free, perfused rat lung preparation. Under control conditions, perfusate histamine levels from the lung averaged 9.5 +/- 1.4 ng/ml. Lungs perfused with paraquat (1 mM) showed marked increases in pulmonary arterial pressure (133%), airway pressure (74%), alveolarcapillary protein flux (200%), and lung weight (38%). Prior to any detectable lung weight or pressure changes, PQ caused a 300% increase in perfusate histamine. Diphenhydramine (1.0 X 10(-5) M), a specific H1-histamine receptor antagonist, blocked the increased protein flux that followed PQ administration and significantly delayed edema. Furthermore, diphenhydramine attenuated the rise in PGF2 alpha. Conversely, histamine release was partially attenuated by the cyclooxygenase inhibitor, ibuprofen, at 2.4 X 10(-5) M, the same level that we had previously shown to block an early rise in PGF2 alpha and the onset of edema after PQ. These data show that the increased alveolar-capillary protein flux that occurred with PQ injury was attenuated by an H1-receptor antagonist and suggest that histamine is a primary mediator in paraquat-induced injury and that histamine subsequently stimulates prostaglandin release.

Topics: Animals; Capillary Permeability; Dinoprost; Diphenhydramine; Histamine; In Vitro Techniques; Lung; Lung Diseases; Male; Paraquat; Perfusion; Prostaglandins F; Pulmonary Alveoli; Rats; Rats, Inbred Strains

Topics: Dinoprost; Dinoprostone; Humans; Lung Diseases; Macrophages; Prostaglandins; Prostaglandins E; Prostaglandins F; Pulmonary Alveoli; Radioimmunoassay; Sarcoidosis; Smoking

Topics: Animals; Dinoprost; Dogs; Lung; Lung Diseases; Oleic Acids; Prostaglandins F; Pulmonary Artery

Plasma concentrations of 13,14,dihydro-15-keto prostaglandin F2 alpha were measured (1) serially in six healthy young adults over 24-25 h; (2) in 62 male and 61 female subjects aged 3 to 64 years; (3) before and after a 12-h volley ball marathon in eight players and eight controls, and (4) in 41 geriatric in-patients aged 65 years and over. There was a small diurnal variation in plasma PGF2 alpha M concentration, levels being highest around 08.00 to 09.00 h. Concentrations did not change with age in fit subjects up to 64 years. Significantly increased concentrations were found in elderly sick patients, high levels in men being associated most often with pulmonary symptoms. Concentrations were not increased significantly by 12 h of competitive sport.

Topics: Adolescent; Adult; Aged; Aging; Child; Child, Preschool; Circadian Rhythm; Dinoprost; Female; Humans; Lung Diseases; Male; Middle Aged; Physical Exertion; Prostaglandins F