Hyperbaric oxygen toxicity: role of thromboxane.

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary hypertension after postlavage lung injury in rabbits: possible role of polymorphonuclear leukocytes.

Previous studies showed that repeated lung lavage leads to a severe lung injury with very poor gas exchange, a substantial protein leak into the alveoli with hyaline membrane formation, pulmonary hypertension, and migration of granulocytes (PMN) into the alveolar spaces. Depletion of PMN leads to a better gas exchange and a markedly decreased protein leak with only scanty hyaline membranes. In this study we show that there is sustained pulmonary hypertension after the lung lavage, but in PMN-depleted rabbits there is no postlavage increase in pulmonary arterial pressure. Changing the shunt fraction by manipulating mean airway pressure still leads to a hypoxic vasoconstriction with increase of pulmonary arterial pressure. Thus, after lung lavage, pulmonary reactivity to hypoxia is still preserved. Comparisons between high-frequency ventilation and conventional mechanical ventilation at the same mean airway pressures showed that equal mean airway pressure in these two very different modes of ventilation do not translate into the same mean functional lung volumes.     

Ibuprofen attenuates cardiopulmonary dysfunction by modifying vascular tone in endotoxemia.

Ibuprofen, a cyclooxygenase inhibitor, improves pulmonary and cardiovascular injury in endotoxemia. We studied the mechanism of the beneficial effects of ibuprofen in relation to production of inflammatory mediators which influence vascular tone in endotoxemia. Rats were randomly assigned to one of three groups: (1) control, (2) endotoxemia alone; and (3) ibuprofen pretreatment and endotoxemia. Plasma and lung lavage concentrations of tumor necrosis factor, thromboxane B2 (TXB2), leukotriene (LT) C4,D4,E4 and nitric oxide (NO) were determined over a 2 h period. Pretreatment with ibuprofen resulted in increased survival, and attenuation of pulmonary and cardiovascular dysfunction when compared to the rats receiving endotoxin alone. The marked elevation in plasma TXB2 concentration in endotoxemic rats was prevented by pretreatment with ibuprofen. Similarly, pretreatment with ibuprofen prevented the decrease in lung lavage NO levels in endotoxemic rats. The improved survival and cardiopulmonary protection in endotoxemic rats pretreated with ibuprofen appears to be related to decreased thromboxane production and preservation of endothelial production of nitric oxide.     

Thromboxane does not mediate pulmonary hypertension in phorbol ester-induced acute lung injury in dogs

Thromboxane (Tx) has been suggested to mediate the pulmonary hypertension of phorbol myristate acetate- (PMA) induced acute lung injury. To test this hypothesis, the relationship between Tx and pulmonary arterial pressure was evaluated in a model of acute lung injury induced with PMA in pentobarbital sodium-anesthetized male mongrel dogs. Sixty minutes after administration of PMA (20 micrograms/kg iv, n = 10), TxB2 increased 10-fold from control in both systemic and pulmonary arterial blood and 8-fold in bronchoalveolar lavage (BAL) fluid. Concomitantly, pulmonary arterial pressure (Ppa) increased from 14.5 +/- 1.0 to 36.2 +/- 3.5 mmHg, and pulmonary vascular resistance (PVR) increased from 5.1 +/- 0.4 to 25.9 +/- 2.9 mmHg.l-1.min. Inhibition of Tx synthase with OKY-046 (10 mg/kg iv, n = 6) prevented the PMA-induced increase in Tx concentrations in blood and BAL fluid but did not prevent or attenuate the increase in Ppa. OKY-046 pretreatment did, however, attenuate but not prevent the increase in PVR 60 min after PMA administration. Pretreatment with the TxA2/prostaglandin H2 receptor antagonist ONO-3708 (10 micrograms.kg-1.min-1 iv, n = 7) prevented the pressor response to bolus injections of 1-10 micrograms U-46619, a Tx receptor agonist, but did not prevent or attenuate the PMA-induced increase in Ppa. ONO-3708 also attenuated but did not prevent the increase in PVR. These results suggest that Tx does not mediate the PMA-induced pulmonary hypertension but may augment the increases in PVR in this model of acute lung injury.     

Low-dose PGI2 prevents monocrotaline-induced thromboxane production and lung injury

In animals, monocrotaline induces an acute lung injury secondary to capillary endothelial damage. To date, no reports have appeared dealing with the role of prostaglandins in monocrotaline-induced injury. Our studies, in dogs, revealed that monocrotaline (30 mg/kg iv) caused an acute and persistent thrombocytopenia, lung platelet deposition, pulmonary hypertension, and increased extravascular lung water (EVLW). The pulmonary hypertensive response was biphasic. Thromboxane B2 levels were similarly biphasic, peaking at 5 min and 2 h. The levels of 6-keto-PGF1 alpha peaked at 30 min and returned to base line at 3 h. Pulmonary vascular resistance paralleled thromboxane levels. Infusion of prostacyclin (PGI2) at 50 ng X kg-1 X min-1 effectively prevented the thrombocytopenia, lung platelet deposition, pulmonary hypertension, and increased EVLW; and it decreased excess thromboxane production by 79%. These results suggest that platelet activation and lung sequestration play a role in acute lung injury due to monocrotaline, and that the resultant thromboxane production may contribute to the pulmonary hypertension. PGI2 ameliorates monocrotaline-induced injury, perhaps by preventing platelet activation.     

Effects of thromboxane synthase inhibition on air emboli lung injury in sheep

We tested the effects of OKY-046, a thromboxane synthase inhibitor, on lung injury induced by 2 h of pulmonary air infusion (1.23 ml/min) in the pulmonary artery of unanesthetized sheep with chronic lung lymph fistula so as to assess the role of thromboxane A2 (TxA2) in the lung injury. We measured pulmonary hemodynamic parameters and the lung fluid balance. The concentrations of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in plasma and lung lymph were determined by radioimmunoassay. Air infusion caused sustained pulmonary hypertension and an increase in pulmonary vascular permeability. The levels of TxB2 and 6-keto-PGF1 alpha in both plasma and lung lymph were significantly elevated during the air infusion. TxB2 concentration in plasma obtained from the left atrium was higher than that from the pulmonary artery at 15 min of air infusion. When sheep were pretreated with OKY-046 (10 mg/kg iv) prior to the air infusion, increases in TxB2 were prevented. The pulmonary arterial pressure, however, increased similarly to that of untreated sheep (1.8 X base line). The increase in lung lymph flow was significantly suppressed during the air infusion. Our data suggest that the pulmonary hypertension observed during air embolism is not caused by TxA2.     

Cecal ligation and puncture is associated with pulmonary injury in the rat: Role of cyclooxygenase pathway products

The present studies evaluated the role cyclooxygenase products play in bacterial sepsis induced pulmonary injury in the rat. Lung injury was assessed by determining the pulmonary capillary filtration coefficient (Kf) and the lung lavage protein concentration four and 18 hours after cecal ligation and puncture. Four hours after cecal ligation, the Kf was unchanged from control, however, by 18 hours, the Kf was increased 171% (p<.05). Similarly, lung lavage protein levels were unchanged four hours after cecal ligation but were significantly (p<.05) elevated at 18 hours. On the other hand, pulmonary lavage immunoreactive thromboxane B2 (iTXB2) levels were increased both four and 18 hours after the initiation of sepsis. In order to determine if cyclooxygenase products played a role in the sepsis associated lung injury, ibuprofen was administered prior to cecal ligation. Ibuprofen pretreatment prevented the sepsis associated increase in both Kf and lung lavage protein concentration. These studies suggest that bacterial sepsis in the rat is associated with pulmonary injury and that early administration of ibuprofen ameliorates this damage.     

Effects of thromboxane synthase inhibition on tumor necrosis factor-induced lung injury in sheep.

To examine the role of thromboxane (Tx) A2 in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we tested the effects of OKY-046, a selective thromboxane synthase inhibitor, on pulmonary hemodynamics, lung lymph balance, circulating leukocytes, arterial blood gas analysis, and TxA2 (as TxB2) and prostacyclin (as 6-keto-prostaglandin F1 alpha) levels in plasma and lung lymph after TNF infusion in awake sheep. Infusion of human recombinant TNF (3.5 micrograms/kg) into a chronically instrumented awake sheep caused a transient increase in pulmonary arterial pressure (Ppa). The Ppa peaked within 15 min of the start of TNF infusion from 23.3 +/- 1.1 (SE) cmH2O of baseline to 42.3 +/- 2.3 cmH2O and then decreased toward baseline. The pulmonary hypertension was accompanied by transient hypoxemia, peripheral leukopenia, and the increases in TxB2 in plasma and lung lymph. These changes were followed by an increase in flow of protein-rich lung lymph, consistent with an increase in pulmonary microvascular permeability. OKY-046 significantly prevented the rises of Ppa and TxB2 concentrations in plasma and lung lymph during early phase after TNF infusion. OKY-046, however, did not attenuate the increase of lung lymph flow, transient hypoxemia, and leukopenia. From these data, and by comparison with our previous studies of OKY-046-pretreated sheep during endotoxemia, we conclude that TxA2 has an important role of the increase in the early pulmonary hypertension, but it is not related to the early hypoxemia, leukopenia, and lung lymph balances in TNF-induced lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interleukin 1 bioactivity in the lungs of rats with monocrotaline-induced pulmonary hypertension

A single subcutaneous injection of monocrotaline in rats provokes lung injury, inflammation, and progressive pulmonary hypertension. The specific mediators of the lung injury and inflammation and the relation of these events to the ensuing hypertensive pulmonary vascular disease are not understood. Since the monokine interleukin 1 (IL-1) has been implicated in acute inflammatory reactions, the present study tested the hypotheses that monocrotaline promotes the appearance of IL-1 in the bronchoalveolar spaces of treated rats and that accumulation of the monokine coincides temporally with development of lung injury, inflammation, and/or pulmonary hypertension. As expected, monocrotaline administration was associated with an early phase of pulmonary edema, manifest at Day 7 post-treatment as an increase in the lung wet-to-dry weight ratio, followed at Day 14 post-treatment by development of pulmonary hypertension as evidenced by progressive right ventricular hypertrophy. Lung inflammation also was present at Days 14 and 21 after monocrotaline as indicated by the accumulation of leukocytes in the bronchoalveolar lavage fluid and by an increase in the lung tissue activity of the granulocyte-specific enzyme myeloperoxidase. Interleukin 1, bioassayed in bronchoalveolar lavage fluid using the standard D10 T-cell assay system, was increased slightly at Day 4 postmonocrotaline, returned to baseline at Day 7, and was markedly elevated at Days 14 and 21 after monocrotaline treatment. These observations indicate that increases in the bronchoalveolar lavage fluid content of IL-1 bioactivity are temporally related to the evolution of monocrotaline-induced lung injury, inflammation, and pulmonary hypertension and suggest that the monokine may play a pathogenetic role in these events.     

Characterization of a postlavage,in situ pulmonary macrophage population

A postlavage in situ subpopulation of pulmonary macrophages (PM), biochemically distinct from the lavaged population, has recently been isolated from rats. After exhaustive bronchopulmonary lavage to extract the free lung cells, the lungs were excised, homogenized, and filtered, and the resultant cell suspension was allowed to form a monolayer on plastic Petri dishes. Electron microscopic morphometry failed to indicate any morphologic differences in the two populations. The postlavage in situ PM were more active metabolically during phagocytosis of zymosan particles or stimulation by phorbol myristate acetate (PMA) than the corresponding lavage population, as evidenced by greater superoxide generation. Macrophages prepared by either method became more avidly phagocytic when incubated with cell-free medium isolated in the preparation of the in situ population. Peroxidase, an enzyme absent from the granules of PM separated by lavage techniques, was found in a granule-rich fraction of the in situ macrophage. Catalase activity was found in similar amounts in both supernatants and granule-rich fractions of both populations. The results support the concept of subpopulations of PM and suggest that these subpopulations are distinguished by their biochemical properties and their functional abilities.     

Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion

Glutathione is a tripeptide important in a number of diverse cellular functions including enzymatic reactions involved in prostaglandin endoperoxide metabolism. We have previously reported that cyclophosphamide administration to rats results in acute lung injury manifested by increased bronchoalveolar lavage albumin concentrations. In the current study we examine whether cyclophosphamide treatment affects pulmonary glutathione stores or bronchoalveolar endoperoxide metabolic product levels and whether these effects may be related to acute lung injury caused by the drug. We show that cyclophosphamide treatment causes a dose-dependent reduction in pulmonary glutathione stores 4 h after drug administration. In addition, acute lung injury as the result of cyclophosphamide can be abrogated by coadministration of oxothiazolidine carboxylate, an intracellular cysteine delivery system that also reverses pulmonary glutathione depletion induced by cyclophosphamide in our study. Finally, cyclophosphamide treatment reduces prostaglandin E2 concentrations in bronchoalveolar lavage and alveolar macrophage culture supernatant in a dose-dependent fashion and increases bronchoalveolar thromboxane concentrations in low dose-treated animals. These effects are reversed to a variable degree by coadministration of oxothiazolidine carboxylate. Our study suggests in vivo pulmonary arachidonic acid metabolism and cyclophosphamide-induced acute lung injury are modulated by cellular glutathione stores. These findings may have important implications for the treatment of acute lung injury.     

PAF potentiates protamine-induced lung edema: role of pulmonary venoconstriction

We studied the synergistic interaction between platelet-activating factor (PAF) and protamine sulfate, a cationic protein that causes pulmonary endothelial injury, in isolated rat lungs perfused with a physiological salt solution. A low dose of protamine (50 micrograms/ml) increased pulmonary artery perfusion pressure (Ppa) but did not increase wet lung-to-body weight ratio after 20 min. Pretreatment of the lungs with a noninjurious dose of PAF (1.6 nM) 10 min before protamine markedly potentiated protamine-induced pulmonary vasoconstriction and resulted in severe lung edema and increased lung tissue content of 6-keto-prostaglandin F1 alpha, thromboxane B2, and leukotriene C4. Pulmonary microvascular pressure (Pmv), measured by double occlusion, was markedly increased in lungs given PAF and protamine. These potentiating effects of PAF were blocked by WEB 2086 (10(-5) M), a specific PAF receptor antagonist. Pretreatment of the lungs with a high dose of histamine (10(-4) M) failed to enhance the effect of protamine on Ppa, Pmv, or wet lung-to-body weight ratio. Furthermore, PAF pretreatment enhanced elastase-, but not H2O2-, induced lung edema. To assess the role of hydrostatic pressure in edema formation, we compared lung permeability-surface area products (PS) in papaverine-treated lungs given either protamine alone or PAF + protamine and tested the effect of mechanical elevation of Pmv on protamine-induced lung edema. In the absence of vasoconstriction, PAF did not potentiate protamine-induced increase in lung PS. On the other hand, mechanically raising Pmv in protamine-treated lungs to a level similar to that measured in lungs given PAF + protamine did not result in a comparable degree of lung edema. We conclude that PAF potentiates protamine-induced lung edema predominantly by enhanced pulmonary venoconstriction. However, a pressure-independent effect of PAF on lung vasculature cannot be entirely excluded.     

Evaluation of a leukotriene receptor antagonist in prevention of hyperoxic lung injury in newborn rabbits.

Prolonged exposure to hyperoxia can result in significant lung injury and has been associated with the development of bronchopulmonary dysplasia. Leukotrienes (LT) recruit polymorphonuclear leukocytes (PMN) to the lung, increase vascular permeability, and have therefore been postulated to play a role in the pathogenesis of hyperoxic lung injury. This study investigates ICI 198,615 (ICI), an LTD4 and LTE4 receptor antagonist in preventing hyperoxic lung injury in newborn rabbits. Matched littermates of 7-day-old rabbits received ICI (0.1 or 1.0 microM/kg/h) or vehicle alone, were exposed to greater than 95% O2, and sacrificed after 48, 72, 84 and 96 h of exposure. Bronchoalveolar alveolar lavage fluid (BAL) of the left lung was analyzed for white cell count, differential, absolute number of PMNs, total protein, and cyclooxygenase products 6-keto-PGF1 alpha, and thromboxane B2. Lung water was quantified utilizing the right lung. Results demonstrated no significant differences between the ICI groups or between the ICI groups and controls. In conclusion, the administration of the LTD4 and LTE4 receptor antagonist ICI 198,615 was insufficient to reduce the formation of pulmonary edema, reduce mortality or attenuate hyperoxic lung injury. These experiments suggest that a number of other mediators may be involved in the hyperoxic lung injury process and that the functional inhibition of a portion of the arachidonic acid cascade was not sufficient to either prevent or attenuate hyperoxic lung injury in newborn rabbits.     

Pulmonary endothelial dysfunction induced by unilateral as compared to bilateral thoracic irradiation in rats

Rats were sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung.     

Leukotriene B4 induces airway hyperresponsiveness in dogs

We studied the effect of leukotriene B4 aerosols on airway responsiveness to inhaled acetylcholine aerosols and on the cellular components and cyclooxygenase metabolites in bronchoalveolar lavage fluid in dogs. Inhalation of leukotriene B4 aerosols had no effect on resting total pulmonary resistance but increased airway responsiveness, an effect that was maximum in 3 h and that returned to control levels within 1 wk. Three hours after leukotriene B4, the number of neutrophils and the concentration of thromboxane B2 recovered in lavage fluid increased markedly. Pretreatment with the thromboxane synthase inhibitor OKY-046 prevented the increases in airway responsiveness and in thromboxane B2 but did not alter neutrophil chemotaxis. Thus we speculate that leukotriene B4 causes neutrophil chemotaxis and release of thromboxane B2, which increases airway responsiveness.     

Effects of U-46619 on pulmonary hemodynamics before and after administration of BM-573, a novel thromboxane A2 inhibitor

We studied the effects on pulmonary hemodynamics of U-46619, a thromboxane A2 (TXA2) agonist, before and after administration of a novel TXA2 receptor antagonist and synthase inhibitor (BM-573). Six anesthetized pigs (Ago group) received 6 consecutive injections of U-46619 at 30-min interval and were compared with six anesthetized pigs (Anta group) which received an increasing dosage regimen of BM-573 10 min before each U-46619 injection. Consecutive changes in pulmonary hemodynamics, including characteristic resistance, vascular compliance, and peripheral vascular resistance, were continuously assessed during the experimental protocol using a four-element Windkessel model. At 2 mg/kg, BM-573 completely blocked pulmonary hypertensive effects of U-46619 but pulmonary vascular compliance still decreased. This residual effect can probably be explained by a persistent increase in the tonus of the pulmonary vascular wall smooth muscles sufficient to decrease vascular compliance but not vessel lumen diameter. Such molecule could be a promising therapeutic approach in TXA2 mediated pulmonary hypertension as it is the case in pulmonary embolism, hyperacute lung rejection and endotoxinic shock.     

Lung eicosanoids in perinatal rats with congenital diaphragmatic hernia

Abnormal levels of pulmonary eicosanoids have been reported in infants with persistent pulmonary hypertension (PPH) and congenital diaphragmatic hernia (CDH). We hypothesized that a dysbalance of vasoconstrictive and vasodilatory eicosanoids is involved in PPH in CDH patients. The levels of several eicosanoids in lung homogenates and in bronchoalveolar lavage fluid of controls and rats with CDH were measured after caesarean section or spontaneous birth. In controls the concentration of the stable metabolite of prostacyclin (6-keto-PGF(1alpha)), thromboxane A(2) (TxB(2)), prostaglandin E(2) (PGE(2)), and leukotriene B(4) (LTB(4)) decreased after spontaneous birth. CDH pups showed respiratory insufficiency directly after birth. Their lungs had higher levels of 6- keto-PGF(1alpha), reflecting the pulmonary vasodilator prostacyclin (PGI(2)), than those of controls. We conclude that in CDH abnormal lung eicosanoid levels are present perinatally. The elevated levels of 6-keto-PGF(1alpha) in CDH may reflect a compensation mechanism for increased vascular resistance.     

Pulmonary inflammation induced by high-stretch ventilation is mediated by tumor necrosis factor signaling in mice

Although high-stretch mechanical ventilation has been demonstrated to induce lung inflammation, the roles of soluble mediators, in particular TNF, remain controversial. We have previously shown in mice that high-stretch ventilation, in the absence of preceding lung injury, induces expression of bioactive TNF in lung lavage fluid early in the course of injury, but the biological significance of this, if any, has yet to be determined. We therefore investigated the pulmonary inflammatory response to a transient period of high-stretch ventilation in anesthetized mice lacking TNF receptors and mice treated with anti-TNF antibodies. A standardized stretch-induced lung injury (assessed by lung mechanics, blood gases, and lavage protein content), followed by noninjurious low-stretch ventilation for 3 h, produced significant alveolar neutrophil infiltration in wild-type mice. However, neutrophil recruitment was substantially attenuated in TNF receptor double knockout mice and in wild-type mice treated with intratracheal anti-TNF antibody. This attenuation was not associated with decreased concentrations of neutrophil attractant CXC chemokines (macrophage inflammatory protein-2 and keratinocyte-derived chemokine) in lavage fluid. In contrast to intratracheal antibody, intravenous anti-TNF antibody did not reduce neutrophil infiltration, suggesting that the role of TNF signaling is localized within the alveolar space and does not require decompartmentalization of TNF into the circulation. These findings provide the first direct evidence that pulmonary inflammation induced by high-stretch ventilation without underlying lung injury possesses a significant TNF-dependent component. The results suggest a potential for regional anti-TNF treatment in attenuating stretch-induced pulmonary inflammation.     

Pulmonary response to group B streptococcal toxin in young lambs

Marked respiratory distress is seen in severe early onset group B beta-hemolytic streptococcal (GBS) disease in newborn infants. To investigate the pathophysiological effects of a polysaccharide toxin from GBS type III cultures, obtained from an infant who died from this disease, young chronically instrumented, unanesthetized lambs were studied with measurements of lung mechanics, lung volumes, ventilation, hemodynamics, and lung vascular permeability. Intravenously administered GBS toxin resulted in a biphasic response with an early threefold increase in total lung resistance, 40% decrease in dynamic lung compliance, and 30% increase in minute ventilation coinciding with hypoxemia, pulmonary hypertension, and fever. A second phase of the response followed consisting of less prominent changes in these variables as well as increased lung lymph protein clearance compatible with increased vascular permeability. The temporal close relationship between marked leukopenia and increased lung lymph thromboxane B2 concentrations to the simultaneously occurring pulmonary hypertension and changes in lung mechanics suggests that leukocytes and thromboxane A2 may be mediators of these GBS toxin-induced effects.     

Effects of ONO-6240, a platelet-activating factor antagonist, on endotoxin shock in unanesthetized sheep

To determine the role of platelet-activating factor (PAF) in endotoxin shock, we studied the effects of ONO-6240, a PAF antogonist, on endotoxin shock in unanesthetized sheep. Changes in hemodynamics, lung lymph balance, leukocyte and platelet counts, and arterial blood gas tensions were measured in four groups; (1) endotoxin alone; (2) endotoxin plus ONO-6240; (3) ONO-6240 alone; (4) vehicle control. Pretreatment with ONO-6240 in sheep given endotoxin significantly prevented the decreases in systemic arterial pressure, left atrial pressure and cardiac output observed in sheep given endotoxin alone. A partial effect on diminishing the magnitude of peripheral leukopenia was also noted. However, pretreatment with ONO-6240 had little effect on pulmonary hypertension and lung lymph balance. We conclude that endotoxin causes two different effects: vascular collapse and direct lung injury; and that PAF is involved only in the circulatory manifestations.