6-ketoprostaglandin-f1-alpha and Pneumonia

Chronic inflammation, imbalance of proteolytic and anti-proteolytic activities, oxidative stress, and apoptosis of lung structural cells contribute to the pathogenesis of COPD. Prostacyclin protects cells against apoptosis, has anti-inflammatory properties, partially prevents cigarette smoke extract (CSE)-induced apoptosis of the pulmonary endothelium, and thus may be relevant in the pathogenesis of emphysema. We determined whether a synthetic stable prostacyclin analog, beraprost sodium (BPS), attenuates the development of CSE-induced emphysema and elucidated the molecular mechanisms involved in its effect. Sprague-Dawley rats were treated with BPS and injected with CSE once a week for 3 wk. We measured the DNA damage of cells, the expression of caspase-3, and the activity of matrix metalloproteinase (MMP)-2 and MMP-9. We also analyzed TNFalpha and IL-1beta concentrations and the serum antioxidant activity. BPS prevented the development of CSE-induced emphysema, resulting in significant attenuation in alveolar enlargement and pulmonary parenchymal destruction. BPS inhibited pulmonary apoptosis and induction of MMP-2 and MMP-9 activity. Moreover, the protective effect of BPS was associated with a reduction of the expression of proinflammatory cytokines including TNFalpha and IL-1beta and a normalized biological oxidant activity. BPS introduces all these events, probably by activating cAMP signaling through acting specific prostacyclin receptors. In conclusion, BPS protects against the development of CSE-induced emphysema by attenuating apoptosis, inhibiting proteolytic enzyme activity, reducing inflammatory cytokine levels, and augmenting antioxidant activity. BPS may potentially represent a new therapeutic option in the prevention of emphysema in humans in prospect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Apoptosis; Caspase 3; Cyclic AMP; Cytokines; Enzyme Activation; Epithelial Cells; Epoprostenol; In Situ Nick-End Labeling; Lung; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pneumonia; Protective Agents; Pulmonary Emphysema; Rats; Rats, Sprague-Dawley; Smoking

An inflammatory response accompanies the reversible pneumotoxicity caused by butylated hydroxytoluene (BHT) administration to mice. Lung tumor formation is promoted by BHT administration following an initiating agent in BALB/cByJ mice, but not in CXB4 mice. To assess the contribution of inflammation to this differential susceptibility, we quantitatively characterized inflammation after one 150 mg/kg body weight, followed by three weekly 200 mg/kg ip injections of BHT into male mice of both strains. This examination included inflammatory cell infiltrate and protein contents in bronchoalveolar lavage (BAL) fluid, cyclooxygenase (COX)-1 and COX-2 expression in lung extracts, and PGE(2) and PGI(2) production by isolated bronchiolar Clara cells. BAL macrophage and lymphocyte numbers increased in BALB mice (P<0.0007 and 0.02, respectively), as did BAL protein content (P<0.05), COX-1 and COX-2 expression (P<0.05 for each), and PGI(2) production (P<0.05); conversely, these indices were not perturbed by BHT in CXB4 mice. BALB mice fed aspirin (400 mg/kg of chow) for two weeks prior to BHT treatment had reduced inflammatory cell infiltration. Our results support a hypothesis that resistance to BHT-induced inflammation in CXB4 mice accounts, at least in part, for the lack of effect of BHT on lung tumor multiplicity in this strain.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Aspirin; Bronchoalveolar Lavage Fluid; Butylated Hydroxytoluene; Carcinogens; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Immunoblotting; Immunoenzyme Techniques; Immunohistochemistry; Isoenzymes; Lung; Lung Neoplasms; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Pneumonia; Prostaglandin-Endoperoxide Synthases; Statistics, Nonparametric

We determined the time course of the oxidant-induced systemic lipid peroxidation seen after burn injury. Twelve sheep were given a 15% of total body surface third-degree burn and monitored for 3 or 5 days. Circulating lipid peroxides were monitored by both malondialdehyde (MDA) and conjugated dienes (CD). Lung and liver tissue MDA was also measured and compared to controls. A significant but transient increase in circulating MDA and CD was noted several hours after burn. Venous plasma levels increased again 3-5 days postburn with onset of wound inflammation. Oxygen consumption, VO2, also increased by 35 +/- 12% at this time. Lung MDA, which increased to 64 +/- 5 from a control of 45 +/- 4 nMol/gm, at 12 hours after burn was still increased 3 days after injury. Marked lung inflammation was present early after injury and persisted for the 5-day study period. Liver MDA also increased from control value of 110 +/- 20 to 252 +/- 25 at 12 hours and remained increased over the 5-day period. Serum alkaline phosphatase was also increased. Burn biopsies revealed no infection to explain the ongoing lipid peroxidation process, i.e., bacterial content was less than 10(5) organisms/gram burn tissue. We conclude that an initial system lipid peroxidation occurs immediately after burn injury, and that this process continues well into the post-resuscitation period, corresponding in time with increased VO2, lung inflammation, and evidence of liver dysfunction. The ongoing oxidant changes with the presence of a burn may explain the accentuated organ dysfunction seen with an additional septic insult in burned patients.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Burns; Inflammation; Lipid Peroxidation; Liver; Lung; Malondialdehyde; Oxygen Consumption; Pneumonia; Sheep; Thromboxane B2; Time Factors

Chronic pulmonary infection/colonization caused by Pseudomonas aeruginosa accounts for much of the morbidity and mortality in cystic fibrosis (CF). The effect of chronic pulmonary P. aeruginosa infection on the pulmonary circulation has not been studied. Therefore, we investigated the effect of chronic P. aeruginosa infection on pulmonary hemodynamics in a rat model. Two groups of rats were inoculated with either agar beads containing 1.0 x 10(4) colony-forming units of P. aeruginosa (infected) or an equal volume of sterile beads alone (control). In vivo, pulmonary vasoreactivity measured as the percent change in total pulmonary resistance during hypoxia was decreased at 1 wk (22 +/- 7% versus 57 +/- 3%), 2 wk (29 +/- 5% versus 73 +/- 17%), 3 wk (41 +/- 8% versus 77 +/- 14%), and 6 to 9 wk (23 +/- 10 versus 53 +/- 7; p less than 0.05 all time points; mean +/- SEM) postinoculation in infected animals when compared with that in time-matched control animals. At 6 to 9 wk postinoculation, pulmonary artery pressure was significantly elevated in infected rats (25.8 +/- 1.6 versus 21.0 +/- 1.0 mm Hg; p less than 0.05) when compared with that in control animals. Histopathologic findings were characterized by bronchiectasis as well as by chronic bronchial, parenchymal, and perivascular inflammation at all time points in infected animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Lung; Male; Pneumonia; Pseudomonas Infections; Pulmonary Circulation; Pulmonary Wedge Pressure; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Acute bilateral Pseudomonas aeruginosa pneumonia was induced in 10 anesthetized dogs, after which five dogs received intravenous indomethacin (2 mg/kg) (indomethacin group), whereas five others were infused with saline (2 ml/kg) (control group). Plasma levels of 6-ketoprostaglandin F1 alpha(6-keto-PGF1 alpha) and thromboxane B2 (TxB2), stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), respectively, were measured by radioimmunoassay. Although TxB2 levels were not different before and after inoculation in either group, 6-keto-PGF1 alpha levels increased from their base-line value in each animal as pneumonia developed (indomethacin group: less than 100 to 330 +/- 90 pg/ml; control group: less than 100 to 630 +/- 300 pg/ml). Both prostaglandins fell to less than 100 pg/ml in each dog after indomethacin infusion, whereas they remained elevated in the control group after infusion of normal saline. Perfusion of consolidated lung regions (Qp/QT), measured with radioactive microspheres and expressed as a percent of total pulmonary blood flow, was dramatically reduced after indomethacin (35 +/- 3 to 16 +/- 1%) with consequent improvement in pulmonary shunt (Qs/QT: 30 +/- 8 to 18 +/- 6%) and arterial O2 tension (PaO2: 123 +/- 25 to 274 +/- 77 Torr). These parameters remained unchanged or deteriorated further in the control group after infusion of saline. Three additional dogs with Pseudomonas pneumonia were studied in which the indomethacin-induced reduction in Qp/QT was substantially but not completely reversed by intravenous infusion of PGI2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carbon Monoxide; Dogs; Epoprostenol; Hemodynamics; Indomethacin; Lung; Pneumonia; Pseudomonas Infections; Pulmonary Gas Exchange; Regional Blood Flow; Thromboxane B2; Vasoconstriction

In chronic P. aeruginosa infection, lung tissue damage is induced by either the microorganism or the inflammatory response. We investigated, in an animal model, whether a non-steroidal anti-inflammatory drug, ibuprofen, reduced lung inflammation produced by P. aeruginosa. Lung lavages, pulmonary clearance of P. aeruginosa and lung pathology were studied in CD-1 mice injected with sodium ibuprofenate. A single dose of the drug, injected immediately after 30 min exposure to the P. aeruginosa aerosol, decreased the recruitment of granulocytes into airways in a dose-dependent manner. Pretreatment with 2 doses of the drug 18 and 6 h before the P. aeruginosa challenge was even more effective. The kinetics of changes in prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in lung lavage fluids after P. aeruginosa aerosol were also modified by ibuprofen. Moreover, ibuprofen treatment did not impair lung clearance of the challenge microorganisms, and the animals had less inflammation of the lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Ibuprofen; Inflammation; Kinetics; Lung; Male; Mice; Neutrophils; Pneumonia; Prostaglandins E; Pseudomonas Infections; Therapeutic Irrigation; Thromboxane B2

We tested the hypothesis that monocrotaline would activate arachidonic acid metabolism in rats. If activation occurred before the pulmonary hypertension developed, arachidonate metabolites could play a role in the hypertensive monocrotaline injury. We found that 1 wk after monocrotaline administration 6-ketoprostaglandin F1 alpha and leukotriene C4 were increased in lung lavages. At 3 wk when pulmonary hypertension was well developed, lung lavage contained increased 6-ketoprostaglandin F1 alpha and thromboxane B2. In addition, the number and activity of white blood cells in the lavages was increased, and abnormal alveolar macrophages were present. The lung extract contained slow-reacting substances including leukotriene D4. Indomethacin administration inhibited the formation of cyclooxygenase metabolites but did not prevent pulmonary hypertension. Diethylcarbamazine administration reduced the numbers and activity of inflammatory cells, increased pulmonary hypertension, prevented right ventricular hypertrophy, and inhibited the formation of slow-reacting substances. We concluded that arachidonate metabolism was activated before pulmonary hypertension developed, that the inflammatory cells in the alveolus accompanied the hypertensive process, and that diethylcarbamazine attenuated both the monocrotaline-induced inflammatory response and the pulmonary hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Biological Assay; Diethylcarbamazine; Enzyme Activation; Guinea Pigs; Hypertension, Pulmonary; Indomethacin; Leukocyte Count; Lipoxygenase; Male; Monocrotaline; Muscle Contraction; Pneumonia; Prostaglandin-Endoperoxide Synthases; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains; SRS-A; Therapeutic Irrigation; Thromboxane B2; Time Factors