15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Pulmonary-Edema

Acute lung injury (ALI), hallmarked with alveolar epithelial barrier impairment and pulmonary edema induced by acute inflammation, presents a severe health burden to the public, due to the limited available interventions. Oxyberberine (OBB), having improved anti-inflammatory activity and safety, is a representative component with various activities derived from berberine, whereas its role against ALI with alveolar epithelial barrier injury remains uncertain. To investigate the influence and underlying mechanisms of OBB on ALI, we induced acute inflammation in mice and A549 cells by using lipopolysaccharide (LPS). Changes in alveolar permeability were assessed by analyzing lung histopathology, measuring the dry/wet weight ratio of the lungs, and altering proinflammatory cytokines and neutrophils levels in the bronchoalveolar lavage fluid (BALF). Parameters of pulmonary permeability were assessed through ELISA, western blotting, quantitative real-time PCR, and immunofluorescence analysis. U46619, the agonist of RhoA/ROCK, was employed to further investigate the mechanism of OBB on ALI. Unexpectedly, we found OBB mitigated lung impairment, pulmonary edema, inflammatory reactions in BALF and lung tissue, reduction in ZO-1, and addition of connexin-43. Besides, OBB markedly reduced the expression of RhoA in association with its downstream factors, which are linked to the intercellular junctions and permeability both in vivo and in vitro. Nevertheless, U46619 abolished the benefits obtained from OBB in A549 cells. In conclusion, these outcomes indicated that OBB exerted RhoA/ROCK inhibitor-like effect to moderate alveolar epithelial barrier impairment and permeability, ultimately preventing ALI progression.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acute Lung Injury; Animals; Inflammation; Lipopolysaccharides; Lung; Mice; Pulmonary Edema; Signal Transduction

Pulmonary capillary pressure (Ppc), the major factor responsible for pulmonary edema, cannot be directly measured in intact subjects but may be estimated by analysis of the pressure decay profile after pulmonary artery catheter balloon inflation. We compared three different methods of pulmonary artery occlusion pressure (Ppao) decay profile analysis to estimates of Ppc derived from lymph flow measurements in halothane-anesthesized sheep. The relationship between Ppc and lymph flow was first determined by increasing Ppc by left atrial balloon inflation, and was then used to determine Ppc during pulmonary hypertension produced by infusion of a thromboxane analog. All three methods of Ppao decay profile analysis demonstrated a correlation with Ppc estimated from lymph flow. However, the method using a single exponential analysis significantly overestimated Ppc, and none of the methods reliably estimated changes in the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension. These results suggest that Ppao decay profile analysis as currently performed has limited application.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia, Inhalation; Animals; Capillaries; Cardiac Catheterization; Catheterization; Halothane; Hypertension, Pulmonary; Lymph; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Edema; Pulmonary Wedge Pressure; Reproducibility of Results; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

Endothelium-derived nitric oxide (NO) is an important regulator of vascular resistance. Low concentrations of NO have been recorded in the exhaled breath of spontaneously breathing animals and humans. To determine whether NO synthesis in the lung contributes to the NO measured in the breath, we measured the concentration of NO in the exhaled air of isolated perfused and ventilated porcine lungs by using a chemiluminescence method. With NO-free normoxic ventilation (21% O2-5% CO2-74% N2) of eight porcine lungs perfused with a Krebs-dextran and albumin perfusate, baseline exhaled NO was 5.8 +/- 1.8 parts per billion (ppb) and pulmonary vascular resistance (PVR) was 8.9 +/- 1.8 mmHg.l-1.min. Hypoxic ventilation (5% O2-5% CO2-90% N2) caused a fall in NO to 3.6 +/- 1.8 ppb and a rise in PVR to 13.6 +/- 3.6 mmHg.l-1.min. Vasoconstriction with the thromboxane analogue U-46619 (10(-9) M) raised PVR to 31.7 +/- 6.8 mmHg.l-1.min but did not decrease NO levels from baseline. Subsequent addition of acetylcholine (10(-6)M) lowered PVR to 22.1 +/- 4.5 mmHg.l-1.min and increased exhaled NO to 7.0 +/- 2.0 ppb. Addition of a NO synthase inhibitor, NG-nitro-L-arginine methyl ester (10(-5) M), to four lungs caused a rise in PVR to 43.0 +/- 7.0 mmHg.l-1.min and a decrease in NO to 1.5 +/- 1.0 ppb. Addition of autologous blood to the perfusate of four lungs caused no change in PVR from baseline but decreased exhaled NO to 2.7 +/- 0.5 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Arginine; Female; Hemoglobins; In Vitro Techniques; Indomethacin; Luminescent Measurements; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pulmonary Edema; Swine; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

We postulated that tumor necrosis factor-alpha (TNF) "primes" the lung for the development of pulmonary vasoconstriction and edema by activating protein kinase C (PKC). Guinea pigs were injected with TNF (1.6 x 10(5) U/kg i.p.), and the lungs were isolated 4 h later. Compared with controls, TNF pretreatment resulted in greater increases in pulmonary vascular resistance and pressure and lung weight, in response to the thromboxane A2 mimetic, U-46619 (122 pmol/min). Treatment with TNF resulted in 1) pulmonary arterial endothelial PKC activation, 2) increased lung polymorphonuclear neutrophil (PMN) sequestration, 3) increased levels of superoxide radical (O2.) in lung effluent, and 4) decreased nitrite levels (NO2-, oxidation product of nitric oxide) in lung effluent. Intraperitoneal treatment with calphostin C (3 microM, 15 min prior to treatment with TNF) prevented the effects of TNF on 1) PKC activation, 2) the hemodynamic responses to U-46619, and 3) the levels of NO2- and O2(.). PKC activation does not mediate TNF-induced lung sequestration of PMN, since calphostin C had no effect on lung myeloperoxidase activity. The data suggest that PKC activation mediates TNF-induced 1) increases in O2., 2) decreases in NO2-, and 3) increases in vasoreactivity and edema in response to U-46619.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Enzyme Activation; Guinea Pigs; Neutrophils; Nitrites; Prostaglandin Endoperoxides, Synthetic; Protein Kinase C; Pulmonary Artery; Pulmonary Edema; Superoxides; Thromboxane A2; Tissue Distribution; Tumor Necrosis Factor-alpha; Vasoconstriction; Vasoconstrictor Agents

Perfusion redistribution (PR) after acute oleic acid (OA) lung injury may be the result of changes in the tissue concentration ratio of thromboxane (Tx) and prostacyclin (A. H. Stephenson et al. J. Appl. Physiol. 73: 2126-2134, 1992). We tested this hypothesis by determining whether the Tx mimetic U-46619 would mimic PR caused by cyclooxygenase inhibition with meclofenamate and whether the Tx receptor antagonist ONO-3708 would inhibit PR even in the presence of meclofenamate. Measurements of regional pulmonary blood flow (PBF) and lung water concentration were made with the nuclear medicine imaging technique of positron emission tomography. Measurements were made at baseline and 2 h after OA. At baseline, the spatial distribution of PBF was similar in all experimental groups. Two hours after OA, fractional PBF was reduced to the edematous lung in all groups given OA, but the magnitude of change was greater in those groups receiving meclofenamate or U-46619 compared with the change in the group given OA only. Thus, although the Tx mimetic produced the same amount of PR as meclofenamate, Tx inhibition did not prevent PR after meclofenamate. Therefore, the ratio of Tx to prostacyclin per se is not the critical determinant of PR.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase Inhibitors; Dogs; Extravascular Lung Water; Image Processing, Computer-Assisted; Lung; Meclofenamic Acid; Oleic Acid; Oleic Acids; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pulmonary Edema; Pulmonary Gas Exchange; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2; Tomography, Emission-Computed; Vasoconstriction

1. Rabbit isolated lungs were perfused via the pulmonary artery with Tyrode solution containing 4.5% Ficoll and 0.1% bovine serum albumin at a constant rate of 20 ml min-1. Lung perfusate was drawn for alternating 5 min periods from two reservoirs, one containing 125I-albumin and the other unlabelled albumin to wash out the intravascular label. Microvascular 125I-albumin leakage was determined from the count remaining at the end of the washout phase with an external gamma scintillation probe. In addition, perfusion pressure was monitored continuously. Each experiment comprised 6 cycles over a total period of 60 min. 2. Infusion of platelet activating factor (PAF, 3 nmol min-1 for 10 min) resulted in microvascular 125I-albumin leakage, whereas lyso-PAF was without effect. During PAF infusions there was also an increase in perfusion pressure. Both the permeability and pressor effects of PAF were inhibited by the PAF antagonist L-652731. 3. Infusion of the thromboxane analogue U-46619 (0.6 nmol min-1 for 10 min) caused an increase in perfusion pressure but protein accumulation was not significantly different from that observed with control infusions. 4. Bolus injections of PAF (1 nmol) caused increases in perfusion pressure which were reduced by indomethacin, dazmegrel and BW 755C. Bolus injections of PAF, repeated at 30 min intervals caused reproducible pressor responses; however, repeated injections at 60 min intervals resulted in augmented responses. This augmentation did not occur in the presence of indomethacin. 5. Retrograde perfusion of PAF via the pulmonary vein induced increased perfusion pressure and microvascular 125I-albumin leakage. The observed increase in leakage when compared with forward perfusion suggests that PAF produces predominantly arteriolar constriction i.e. proximal to the site of leakage during forward perfusion. 6. These results indicate that PAF is a vasoconstrictor in the rabbit pulmonary circulation and augmented responses occur with repeated injections at 60 min intervals. Cyclo-oxygenase inhibition abolished this vascular hyperresponsiveness induced by PAF. PAF also caused protein accumulation in the lungs. Both these actions of PAF appear to be receptor-mediated because they were inhibited by PAF antagonists. Another pulmonary vasoconstrictor, U-46619 did not cause protein accumulation suggesting that the extravasation of protein with PAF is not merely secondary to changes in vascular tone.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Proteins; Capillary Permeability; Furans; In Vitro Techniques; Male; Microcirculation; Perfusion; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pulmonary Edema; Rabbits; Serum Albumin, Radio-Iodinated; Vascular Resistance; Vasoconstriction