Acute cigarette smoke exposure causes lung injury in rabbits treated with ibuprofen

We studied lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA), plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2, and pulmonary edema as indices of lung injury in rabbits exposed to cigarette smoke (CSE). Forty-six rabbits were randomly assigned to 4 groups: control sham smoke exposure (SS, N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), sham smoke exposure ibuprofen-pretreated (SS-I, N = 10), CSE (N = 9), and CSE ibuprofen-pretreated (CSE-I, N = 19). Ibuprofen (cyclooxygenase eicosanoid inhibitor) was administered as a single daily intramuscular injection (25 mg/kg) for 7 days before the experiment. Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 15-min counting period between each subset of breaths to determine 99mTcDTPA biological half-life (T1/2). In the ibuprofen pretreated group, CSE caused significant decreases in 99mTcDTPA T1/2 and dynamic lung compliance. Furthermore, these changes in lung function were accompanied by severe injury to type I alveolar cell epithelium, pulmonary edema, and frequently death of the rabbits. These findings suggest that inhibition of the cyclooxygenase pathway before CSE exacerbates lung injury in rabbits.     

Effect of aging on 6-keto-PGF1 alpha levels in normotensive and essential hypertensive males

Prostacyclin (PGI2) is produced in the vessel wall and acts as a vasodilator hormone. Measurement of plasma 6-keto-PGF1 alpha is considered to be an index of PGI2 production. In the present study the effects of aging on the plasma 6-keto-PGF1 alpha levels were studied in 64 normotensive and 48 essential hypertensive males. The subjects were divided into 3 groups, i.e., young (24-39 years), middle-aged (40-55 years) and elderly (over 56 years) groups. Plasma 6-keto-PGF1 alpha was measured by specific radioimmunoassay after silicic acid column chromatographic purification. The 6-keto-PGF1 alpha levels were lower in elderly normotensive males (10.3 +/- 1.4 pg/ml, mean +/- SE, n = 12) than in normotensive young males (15.3 +/- 2.3, n = 30, p less than 0.05). The plasma 6-keto-PGF1 alpha levels in hypertensive elderly males (10.6 +/- 1.3 pg/ml, n = 10) is lower than in hypertensive young males (19.8 +/- 2.2, n = 17, p less than 0.01). These results indicate that the plasma 6-keto-PGF1 alpha levels decreased with age in both normotensive and hypertensive groups. Thus, PGI2 production may decrease with age.     

Increased lung permeability following long-term use of free-base cocaine (crack)

The clearance of inhaled 99mTc DTPA aerosol from the lungs is used as an index of lung epithelial permeability. Using the radioaerosol method, we investigated the effects of long-term "crack" (free-base cocaine) inhalation on lung permeability in 23 subjects. Eighteen control subjects (12 nonsmokers and 6 cigarette smokers) with no history of drug use were also studied. Subjects inhaled approximately 150 muCi (approximately 5.6 MBq) of 99mTc DTPA aerosol and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 minutes. Regions of interest (ROIs) were selected to include the following: (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc DTPA lung clearance was determined from the slopes of the respective time-activity plots for the different RIOs. Radioaerosol clearance half-times (T1/2) for the seven nonsmoking crack users (61.5 +/- 18.3 minutes) were longer than for the seven cigarette-smoking crack users (27.9 +/- 16.9 minutes) and nine cigarette-smoking crack plus marijuana users (33.5 +/- 21.6 minutes). T1/2 for the nonsmoking crack users was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 minutes). T1/2 for the cigarette-smoking drug users was similar to that of the cigarette-smoking control group (33.1 +/- 17.8 minutes), suggesting a similar mechanism of damage from the smoke of crack and tobacco. From these groups, one nonsmoker and 11 cigarette smokers displayed biexponential 99mTc DTPA clearances, indicative of greater lung injury than found in the usual cases of monoexponential clearance. The upper lungs of all crack users groups cleared faster than the lower lungs. The faster and biexponential clearance properties of inhaled 99mTc DTPA aerosol were the principal functional abnormalities found in all the drug users. In contrast, 19 of 23 crack users had normal spirometry and gas exchange. These results indicate that 99mTc DTPA may provide a sensitive and useful assay to evaluate the physiologic effects of cocaine inhalation in the lung.     

Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke

RATIONALE: Impaired endothelial cell-dependent vasodilation, inflammation, apoptosis, and proliferation are manifestations of endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Prostacyclin (PGI(2)) is a major product of the cyclooxygenase pathway with potent vasodilatory and antimitogenic properties and may be relevant to endothelial dysfunction in COPD. OBJECTIVES: To determine if PGI(2) expression is altered in smoking-related lung disease and if it may be protective in COPD-associated endothelial dysfunction. METHODS: We evaluated, by immunohistochemistry, Western blotting, and polymerase chain reaction, human emphysema tissue compared with normal tissue for expression of prostacyclin synthase (PGI(2)S). We examined the effects of cigarette smoke extract (CSE) and aldehyde components on eicosanoid expression in primary human pulmonary microvascular endothelial cells. Finally, we used a murine model of lung-specific PGI(2)S overexpression and in vitro studies to determine if PGI(2) expression has protective effects on cigarette smoke-induced endothelial apoptosis. MEASUREMENTS AND MAIN RESULTS: Human emphysema lung tissue exhibited lower PGI(2)S expression within the pulmonary endothelium than in normal lung. In vitro studies demonstrated that CSE, and in particular the alpha,beta unsaturated aldehyde acrolein, suppressed PGI(2)S gene expression, whereas CSE significantly induced the upstream mediators COX-2 and cytosolic phospholipase A2 in human pulmonary microvascular endothelial cells. Mice with lung-specific PGI(2)S overexpression exhibited less endothelial apoptosis after chronic smoke exposure. In vitro, iloprost exhibited protective effects on CSE-induced apoptosis. CONCLUSIONS: PGI(2) has protective effects in the pulmonary vasculature after acute and chronic cigarette smoke exposure. An imbalance in eicosanoid expression may be important to COPD-associated endothelial dysfunction.     

Value of technetium-99m diethyltriamine pentaaceticacid radioaerosol inhalation lung scintigraphy for the stage of amiodarone-induced pulmonary toxicity

BACKGROUND: Amiodarone is a potent antiarrhythmic agent that is limited in clinical use by its adverse effects, including potentially life threatening amiodarone-induced pulmonary toxicity (AIPT). The alteration of technetium-99m diethyltriaminepentaaceticacid (Tc-99m DTPA) radioaerosol lung clearance in AIPT was experimentally investigated. METHODS: Eighteen white New Zealand rabbits (initial weight 4.1+/-0.2 kg) were divided into two groups. AIPT group (n=13) was administered amiodarone (20 mg/kg BW) ip as a 5% aqueous solution for 6 week. The controls (n=5) were administered the same amount of 0.9% saline ip. Four rabbits of AIPT group died due to AIPT. The reminders of AIPT group (n=9) and controls underwent Tc-99m DTPA radioaerosol lung scintigraphy at the end of the treatment period. AIPT group was divided into two subgroups according to histopathologic evaluation. AIPT-I had interstitial pneumonitis (n=4) and AIPT-II had interstitial pneumonitis with fibrosis (n=5). RESULTS: The mean T(1/2) values of in control, AIPT-I, and AIPT-II groups were found 54+/-4.4, 39.2+/-11.7 and 114.6+/-16.7 min, respectively. The mean T(1/2) values of Tc-99m DTPA significantly differ than other groups (X(2)=11.78, P=0.02). The significantly increased T(1/2) values was noted in AIPT-II group when compared with control (P=0.001). In contrast, AIPT-I group has significantly lower T(1/2) values than control group (P=0.03). CONCLUSION: We suggested that Tc-99m DTPA radioaerosol inhalation lung scintigraphy provides an accurate evaluation about stage of lung toxicity and therefore may be a useful tool for the monitoring of AIPT.     

Cyclooxygenase products and cyclic nucleotide levels with infusion of arachidonic acid, PGI2, PGE2, PGF2, and 6-keto-PGF1 in an isolated dog lung

Arachidonic acid (AA) was infused into the pulmonary artery of an isolated dog lung perfused with a physiologic salt solution. This led to elevations in pulmonary cyclic AMP and prostaglandins (PGs) including PGE2, PGF2 alpha, TXB2 (a metabolite of TXA2), and 6-keto-PGF1 alpha (a metabolite of PGI2). The elevations were prevented by PG synthesis inhibitors. A dose of PGI2 comparable to that produced from AA led to elevations in cyclic AMP. These elevations were not reduced by PG synthesis inhibitors; this indicated that the inhibitors did not reduce cyclic AMP except by inhibiting metabolism of AA. The PGE2 led to lesser elevations in cyclic AMP than did PGI2; PGF2 alpha and 6-keto-PGF1 alpha did not increase cyclic AMP. Levels of cyclic AMP were not elevated. We conclude that some of the elevation in cyclic AMP from AA was most likely from production of PGs since elevations in both were prevented by the inhibitors. However, the possibility remains that AA metabolites other than PGs also contributed to elevations in cyclic AMP. We also conclude that PGI2 most likely accounted for some of the cyclic AMP elevation from AA since PGI2 could be readily produced in amounts that elevate cyclic AMP. However, the possibility remains that PGE2, the less consistent cyclic AMP stimulators (l.e., PGF2 alpha and 6-keto-PGF1 alpha), TXA2 or TXB2, or PGs not measured in this study also contributed to the elevations in cyclic AMP from AA.     

Stimulatory activity on prostacyclin production decreases in sera from streptozotocin-induced diabetic rats

We recently reported that serum stimulatory activity on prostacyclin (PGI2) production by cultured bovine aortic endothelial cells decreased in noninsulin-dependent diabetic patients. In the present study, this activity was compared in streptozotocin-induced (STZ) diabetic rats and controls. Platelet-poor plasma-derived serum (PDS) from Wistar male rats stimulated 6-keto-PGF1 alpha production (a stable metabolite of PGI2) by cultured bovine aortic endothelial cells, rat lung fibroblasts, and rat aortic rings in a time- and dose-dependent manner. Namely, PDS from rats has a stimulatory activity on PGI2 production (PGI2 stimulatory activity; PSA). Furthermore, PSA in PDS from STZ diabetic rats (n = 12) significantly decreased as compared with that from control rats (n = 10) using three types of in vitro systems. The reduction in PDS-stimulated PGI2 production by the vascular wall may lead to platelet hyperaggregation and thrombus formation in diabetics, which is considered to be involved in the pathogenesis of diabetic macro- or microangiopathy.     

Acute cigarette smoke exposure increases alveolar permeability in rabbits

We measured lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA) as an index of alveolar epithelial permeability in rabbits exposed to cigarette smoke. Eighteen rabbits were randomly assigned to 3 equal-size groups: control, all smoke exposure (ASE), and limited smoke exposure (LSE). Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 20-min counting period between each subset of breaths to determine 99mTcDTPA biologic half-life (T1/2). Mean T1/2 minimum (i.e., the smallest T1/2 observed) was significantly lower (p less than 0.05) for ASE and LSE rabbits than by control rabbits. We observed a significant difference at 20 and 30 breath exposures between the control and ASE group mean values (% baseline) for T1/2, arterial blood pressure, and peak airway pressure. A combination of light and electron microscopy showed focal alveolar edema and hemorrhage in the ASE and LSE groups but no alveolar-capillary membrane damage. In summary, acute cigarette smoke exposure increases alveolar permeability as measured by 99mTcDTPA clearance, but there was no detectable ultrastructural alteration of the alveolar-capillary membrane.     

Relation of arachidonate metabolites to abnormal control of the pulmonary circulation in a child

To evaluate the role of arachidonate metabolites in regulating pulmonary vascular tone, we performed multiple studies on a 17-month-old girl with idiopathic pulmonary hypertension, systemic arterial hypoxemia (due to ventilation-perfusion mismatching), and an elevated thromboxane A2 (TXA2) to prostacyclin (PGI2) ratio due to increased TXA2 (measured as their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively). Intravenous infusions of PGI2 reduced mean pulmonary arterial pressure (from 80 to 47 mmHg), increased cardiac output (from 3.43 to 3.97 L/min), increased systemic arterial oxygen saturation (from 60 to 72 percent), and decreased the TXB2 to 6-keto-PGF1 alpha ratio (from 5.9 to 0.2); mean systemic arterial pressure was unchanged. Pharmacologically decreasing the TXB2 to 6-keto-PGF1 alpha ratio with administration of nifedipine or diltiazem also reduced pulmonary hypertension and increased systemic arterial oxygen saturation in this patient. Nifedipine and diltiazem decreased the ratio by decreasing TXB2. Prostacyclin decreased the ratio by increasing 6-keto-PGF1 alpha. These studies support the hypothesis that the balance between TXA2 and PGI2 is an important influence on pulmonary vascular tone.     

Liposyn infusion increases plasma prostaglandin concentrations

To determine whether Liposyn infusion results in increased plasma prostaglandin (PG) concentrations, the following study was performed in 33 adult rabbits with chronically implanted arterial and venous catheters. Plasma PG concentrations were determined by radioimmunoassay for two vasodilators, PGE2 and PGI2 (as measured by its metabolite 6-keto-PGF1 alpha), and two vasoconstrictors, thromboxane (TX) A2 and PGF2 alpha, as measured by their metabolites TXB2 and PGF2 alpha-M, respectively. A 1-hour infusion of Liposyn at 4 ml per kg resulted in statistically significant increases in arterial and venous concentrations of PGE2 and 6-keto-PGF1 alpha (p less than 0.001) and of TXB2 (p less than 0.04). There were no significant changes in PGF2 alpha-M plasma concentrations. Liposyn infusion also resulted in a small but statistically significant increase in PaO2 of 4.7 +/- 1.5 torr (p less than 0.01). It is concluded that Liposyn infusion results in statistically significant increases in plasma concentrations of PGE2, 6-keto-PGF1 alpha, and TXB2.     

The observation of changes in plasma PGI2 and TXA2 levels and the therapeutic effect of tetramethylpyrazine in E. coli induced acute lung injury in rabbits

Thirty two rabbits were equally divided at random into 4 groups: A. control; B. E.coli; C. E.coli + ibuprofen; D. E.coli + tetramethylpyrazine. The plasma concentration of 6-keto-PGF1 alpha and TXB2, arterial blood gas as well as platelet aggregability were measured and the pathological changes of lung tissue were observed. The results suggest that TXA2 and PGI2 do take part in the pathogenesis of acute lung injury; that PGI2 may serve as an indicator in the evaluation of the degree of injury in the pulmonary endothelial cells and may also contribute to septic shock; and that both tetramethylpyrazine and ibuprofen possess therapeutic effects on the amelioration of acute lung injury, and the former is rather stronger than the latter in the inhibitory effect on granulocytic sequestration within the lung.     

Reduction of prostacyclin synthesis as a possible cause of transient flow reduction in a partially constricted canine coronary artery

Coronary blood flow decreases cyclically in a partially occluded coronary artery of anesthetized dogs. Spontaneous aggregation and deaggregation of platelet plugs in the constricted artery have been indicated to be responsible for this phenomenon. A current hypothesis is that platelet aggregation may be determined by a balance between proaggregatory platelet product, thromboxane A2 (TXA2), and antiaggregatory substance, prostacyclin (PGI2). To elucidate the relationship between the cyclical reduction of coronary flow (CRCF) and metabolic alterations of TXA2 and PGI2, we attempted to determine the plasma levels of their stable catabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in the coronary circulation of 69 dogs. Of 40 cases, 20 cases exhibited CRCF accompanying a significant increase in TXB2 in the coronary sinus (CS) (P less than 0.05) and constant levels of 6-keto-PGF1 alpha in the CS and aorta (Ao). Another 20 cases did not exhibit CRCF that accompanied a marked increase in 6-keto-PGF1 alpha (P less than 0.05) with virtually no change in TXB2 in the CS and Ao. A higher dose of indomethacin (10 mg/kg, i.v.) was capable of evoking CRCF in cases not exhibiting CRCF spontaneously. Under these conditions, a significant decrease in 6-keto-PGF1 alpha was seen both in the CS and Ao compared with lower doses of indomethacin (1 to 3 mg/kg, P less than 0.01), that produced less pronounced reduction of 6-keto-PGF1 alpha without CRCF. Intravenous infusion of PGI2 (0.1 microgram/kg/min.) completely abolished spontaneously and indomethacin-induced CRCF with a marked elevation of 6-keto-PGF1 alpha in the CS and Ao. Although OKY-1580, a TXA2 synthetase inhibitor, relieved spontaneously-evoked CRCF with a marked increase in 6-keto-PGF1 alpha and a slight reduction of TXB2, indomethacin-induced CRCF was not abolished by this agent. These results are consistent with the hypothesis that the reduction of endogenous PGI2 synthesis in the vascular wall is related to the occurrence of CRCF after partial constriction of coronary artery and indomethacin.     

Effects of tobacco smoke on respiratory epithelial clearance of DTPA and on lung histology in rats

The respiratory epithelial clearance of 99mTc-(DTPA) diethylenetriamine penta-acetate (RC-DTPA) was measured in rats before and after sham or cigarette smoke exposures. RC-DTPA was increased by cigarette smoke exposure (p less than 0.001); the amount and duration of the exposure had no significant effect. In smoker animals, the number of bronchoalveolar macrophages was decreased after one or five smoke exposures a day for one day (p less than 0.001) and the number of bronchoalveolar neutrophils was increased after five exposures a day for ten days (p less than 0.001). No abnormality was found in the lung parenchyma on light microscopy. We conclude that in rats RC-DTPA is increased by exposure to tobacco smoke, whatever the amount and duration of exposure; however, no gross parenchymal lung abnormality explains the increase in RC-DTPA.     

Crucial role of group IIA phospholipase A(2) in oleic acid-induced acute lung injury in rabbits.

Group IIA secretory phospholipase A(2) (sPLA(2)) has been implicated in a variety of inflammatory diseases including acute lung injury (ALI); however, the role of sPLA(2) in this disorder remains unclear. The aim of the present investigation was to examine the role of this enzyme in a model of ALI induced by oleic acid (OA) in rabbits by testing human group IIA phospholipase A(2) (PLA(2)) inhibitor, S-5920/LY315920Na. Experimental groups consisted of a saline control group (n = 8), an OA control group (n = 10) infused intravenously with OA (0.1 ml/kg/h for 2 h), and three groups given OA + S-5920/LY315920Na (three different doses, n = 8, respectively). Infusion of OA provoked pulmonary hemorrhage and edema formation, protein leakage, and massive neutrophil infiltration, resulting in severe hypoxemia and impaired lung compliance. PLA(2) activity was detected in the bronchoalveolar lavage fluid (BALF), but not plasma, which correlated well with severity of lung injury in this model. Pretreatment with S-5920/LY315920Na diminished the OA-induced PLA(2) activity in the BALF and dose-dependently attenuated the previously described lung injury induced by OA, accompanied by protection against lung surfactant degradation and production of thromboxane A(2) (TXA(2)) and leukotriene B(4) (LTB(4)). S-5920/LY315920Na also inhibited the OA-induced production of interleukin-8 (IL-8), both in plasma and BALF. Thus, sPLA(2) appears to play a key role in OA-induced lung injury, suggesting that the group IIA PLA(2) inhibitor may be a promising agent for patients with acute respiratory distress syndrome (ARDS).     

Vasoconstrictor response to prostacyclin in rabbit pulmonary circulation

We have determined the effect of prostacyclin (PGI2) on segmental vascular resistance in rabbit lungs. Lungs of 26 rabbits were isolated and perfused with blood; 16 adult, greater than 6 months old, five juvenile, 6-8 week old and five neonatal, 2-3-week old. Six of the adult lungs were pretreated with indomethacin to block cyclooxygenase, prior to infusion of PGI2. In all lungs, flow was adjusted initially to keep pulmonary artery pressure approximately 20 cmH2O, left atrial and airway pressures being 8 and 6 cmH2O, respectively (zone 3), and then kept constant. We measured pulmonary artery pressure continuously and in the 10 untreated adult lungs, in which a vasoconstrictor response to PGI2 was obtained, we also measured pressures in 20-50 microns diameter subpleural arterioles and venules by the micropipette-servonulling method. We found that in juvenile and neonatal rabbit lungs, PGI2 did not change total vascular resistance significantly but in untreated adult lungs, it caused a significant increase in total vascular resistance only after a dose of 10 micrograms/kg. This age-related difference in vasoconstrictor response to PGI2 was not related to baseline total vascular resistance in the three groups of lungs. In adult lungs, vasoconstriction occurred mainly in arteries with a small effect in veins. Circulating levels of thromboxane B2, leukotriene C4, and 6-keto-PGF1 alpha increased following PGI2 infusion in adult lungs, whereas in neonatal lungs, only 6-keto-PGF1 alpha increased significantly. Indomethacin pretreatment completely abolished the vasoconstrictor response to PGI2. We conclude that PGI2-induced vasoconstriction is age and dose dependent in isolated rabbit lungs and that a cyclooxygenase product, such as thromboxane A2, may play a role in mediating the vasoconstriction.     

Some short-term effects of changing to lower yield cigarettes

The rate of clearance from the lung of the hydrophilic tracer molecule 99mTc DTPA was used to investigate the short-term effects on lung epithelial function when smokers switched to cigarettes with lower yields of tobacco smoke constituents. Two separate studies were performed. In the first study, subjects smoked conventional mid- and low-tar cigarettes. The second study used two specially manufactured cigarettes with similar tar and nicotine yields, but differing carbon monoxide yields. Neither study demonstrated any significant improvement in 99mTc DTPA clearance. The yields of carbon monoxide determined under standard machine smoking conditions implied that there would be a 44 percent reduction in exposure to carbon monoxide when subjects switched from smoking conventional mid-tar to low-tar cigarettes. However, measurements of carboxyhemoglobin showed that the smokers compensated for the lower yields and their exposure was reduced by only 11 percent. Similarly, in the second study, the subjects reduced their exposure by 7 percent instead of the expected 44 percent. Urine nicotine/cotinine excretion measurements in this study indicated that there was no complimentary increase in nicotine absorption suggesting the possibility that subjects may be able to regulate their intake of individual components of the cigarette smoke. Thus, the unexpected result from this study was the finding that cigarette smokers could, in some way, regulate their intake of smoke from cigarettes of different composition so as to maintain a constant exposure of smoke constituents.     

The hypertensive response to vasopressor agents stimulates the release of thromboxane A2 in hypercholesterolaemic rabbits

The production of thromboxane A2 (TXA2) and prostacyclin (PGI2) is altered in hypercholesterolaemia. The purpose of this study was to investigate the effect of an acute rise in arterial pressure produced by pressor agents on the release of TXA2 and PGI2 in hypercholesterolaemic rabbits. Hypercholesterolaemia was induced in rabbits by feeding pellet food containing 1% cholesterol for 3 months. Administration of pressor agents (ergonovine 0.5-2.0 mg.kg-1, noradrenaline 5.0-20.0 micrograms.kg-1 and angiotensin-II 0.5-2.0 micrograms.kg-1) increased arterial pressure dose dependently, accompanied by a pressure dependent increase in the plasma concentrations of both TXB2 and 6-keto-PGF1 alpha (stable metabolites of TXA2 and PGI2) in control rabbits, but only of TXB2 in hypercholesterolaemic rabbits. In control rabbits the maximum increase in TXB2 was 51% with ergonovine, 73% with noradrenaline, and 51% with angiotensin-II; and the maximum increase in 6-keto-PGF1 alpha was 48% with ergonovine, 76% with noradrenaline, and 198% with angiotensin-II. In hypercholesterolaemic rabbits the maximum increase in TXB2 was 130% with ergonovine, 144% with noradrenaline, and 128% with angiotensin-II. The pressor induced increase in TXB2 was suppressed when the increase in arterial pressure was counteracted by the concomitant administration of vasodilators (glyceryl trinitrate 40 micrograms.kg-1.min-1 and verapamil 20 micrograms.kg-1.min-1) in both control and hypercholesterolaemic rabbits. Neither TXB2 biosynthesis nor phospholipase A2 activity in platelets was affected by ergonovine, noradrenaline or angiotensin-II in vitro. These results suggested that the acute rise in arterial pressure caused by these pressor agents increased TXA2 release in vivo and that the increase was greater in hypercholesterolaemic than in control rabbits.     

Effects of smoking on the synthesis of leukotriene B4 by rat alveolar macrophages

Leukotriene B4 (LTB4) is a potent chemotactic factor for polymorphonuclear leukocytes. It was reported recently that pulmonary macrophages from some mammalian species synthesize and release LTB4. Laviolette et al. reported the decrease of LTB4 synthesis in smokers' alveolar macrophages (AM). In this paper, we report the chronic effects of passive smoking on the production of LTB4 by rat AM. Some rats inhaled tobacco smoke and some inhaled smoke which did not contain nicotine. LTB4 production from AM from these rats was compared. In the tobacco-smoking group (n = 12), LTB4 production was 8.0 +/- 2.4 ng/10(6) cells. This value was significantly lower than in the nonsmoking (NS) group (n = 12; 16.5 +/- 4.5 ng/10(6) cells; p less than 0.01) and in the non-nicotinized cigarette smoking (NNCS) group (n = 8; 18.5 +/- 3.5 ng/10(6) cells; p less than 0.01). There were no significant differences between the NS and the NNCS group. These data may suggest that chronic inhalation of nicotine in tobacco smoke decreases LTB4 production activity of rat AM. The precise mechanism of decreased synthesis of LTB4 is not clear but it may have some immunological effects on the lung.     

A comparison of 99mTc-DTPA and 113mIn-DTPA aerosol clearances in humans. Effects of smoking, hyperinflation, and in vitro oxidation

As an index of permeability of the alveolar epithelium, the clearance of an inhaled aerosol of 99mTc-DTPA is increased in several disease states. However, the usefulness of the test to assess the severity of disease is limited because healthy smokers also have abnormally rapid rates of clearance. Because the stability of the 99mTc-DTPA bond might be a contributory factor, we tested the affinity of 99mTc for DTPA in vitro, and in groups of healthy smokers (n = 13) and nonsmokers (n = 7) we measured the clearances of 99mTc-DTPA and 113mIn-DTPA, which have a similar molecular shape and charge. In vitro, sodium hypochlorite or hydrogen peroxide released as much as 98% of free 99mTc from the 99mTc-DTPA complex. When incubated with human neutrophils stimulated with phorbol myristate acetate, between 4 and 7% of free 99mTc-DTPA was released after 30 min, and 12% was released after 60 min. In vivo, the clearances of both 99mTc-DTPA and 113mIn-DTPA in the smokers (n = 13) were faster than in the nonsmokers (n = 7) (p less than 0.05). Within the smokers, the mean 99mTc-DTPA clearance (T1/2 25 +/- 4 min) was faster than the mean 113mIn-DTPA clearance (34 +/- 6 min), (p less than 0.05). For nonsmokers, the difference was smaller (T1/2 99mTc-DTPA, 56 +/- 6; T1/2 113mIn-DTPA, 62 +/- 6) and not significant. During hyperinflation, smokers (n = 8) and nonsmokers (n = 8) both demonstrated an increase in 113mIn-DTPA clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endotoxin-induced production of thromboxane and prostacyclin by equine peritoneal macrophages

Equine peritoneal macrophages were isolated and cultured in vitro to assess their ability to produce thromboxane (TxA2) and prostacyclin (PGI2) in response to endotoxin. Peritoneal macrophages (2.5 x 10(6)/ml) were incubated in tissue culture media, containing 1) no additive (nonstimulated control), 2) endotoxin (0.5 to 100 ng/ml) or 3) the calcium ionophore, A23187 (0.95 microM) for two and six h. Concentrations of the stable metabolites of TxA2 and PGI2 thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in the incubation media were determined by radioimmunoassay. The concentrations of both metabolites increased from two to six h incubation. Endotoxin increased the production of TxA2 and PGI2 over the nonstimulated control values at both two and six h and endotoxin-induced concentrations of 6-keto-PGF1 alpha were higher at six than at two h. The response of macrophages to A23187 was similar to endotoxin. Mean eicosanoid concentrations did not differ among the range of endotoxin concentrations at either time; however there was significant curvilinear regression between endotoxin concentration and TxB2 at both times, and between endotoxin and 6-keto-PGF1 alpha at two h. The results indicate that equine macrophages may be a significant source of TxA2 and PGI2 during endotoxemia.