thromboxane-b2 and Pneumonia--Aspiration

Acid aspiration leads to lung injury characterized by polymorphonuclear neutrophil leukocytes (PMN) sequestration and edema. This study investigates whether localized acid aspiration leads to activation of circulating PMN and triggers both local and remote PMN sequestration and whether these cells are responsible for increase in pulmonary permeability and systemic organ edema.. Rats pretreated with intravenous saline solution or rendered neutropenic (nitrogen mustard or antineutrophil serum) underwent tracheostomy and insertion of a cannula into a lung segment. This was followed by instillation of either 0.1 N HCl or saline solution.. After 30 minutes leukopenia was noted (2650 white blood cells/mm3) in saline-treated, acid-lavaged rats, and circulating PMN produced H2O2 (20 femtomole dichlorofluorescein/PMN compared with 3 femtomole in control animals (both, p < 0.05). PMN were progressively sequestered in the nonaspirated lung, the heart, and kidney. Permeability and edema developed in the lungs and systemic organs. In neutropenic rats there was a reduction of aspiration-induced thromboxane B2 and leukotriene B4 synthesis (p < 0.05), decrease in lung wet to dry weight and protein level in bronchoalveolar lavage of the aspirated and nonaspirated lungs, and reduction in myeloperoxidase activity in the heart and kidney and in wet to dry weight of these organs (all, p < 0.05).. These data indicate that localized acid aspiration activates circulating neutrophils and promotes their sequestration in the lungs and systemic organs. These cells are largely responsible for the multisystem organ edema.

Topics: Animals; Edema; Hydrochloric Acid; Hydrogen Peroxide; Kidney; Leukopenia; Lung; Male; Mechlorethamine; Myocardium; Neutrophils; Peroxidase; Pneumonia, Aspiration; Rats; Rats, Sprague-Dawley; Thromboxane B2

Acid aspiration leads to thromboxane-dependent lung neutrophil sequestration associated with microvascular permeability increase. Leukotriene B4 (LTB4) is postulated to be a cofactor in the thromboxane-induced inflammatory response. This study tests the interaction between LTB4 and thromboxane, focusing on LTB4 induction of thromboxane-dependent lung neutrophil sequestration after acid aspiration. Anesthetized rats underwent tracheostomy and insertion of a cannula in a left lung segment. This was followed by instillation of either 0.1 ml 0.1N hydrochloric acid (n = 18) or 0.1 ml saline in control rats (n = 18). When assayed at 3 hours, acid aspiration led to increased plasma levels of LTB4 and thromboxane B2 (TxB2), higher than control values (p less than 0.05). The rise in plasma LTB4 was correlated (p less than 0.05; r = 0.83) with sequestration of neutrophils in the nonaspirated lung. The entrapment of thromboxane-dependent lung neutrophil was associated with an increase in protein concentration in bronchoalveolar lavage of the aspirated and nonaspirated sides and an increase in lung wet to dry weight ratio. Pretreatment of other rats (n = 18) with the lipoxygenase inhibitor diethylcarbamazine IV prevented an aspiration-induced rise in plasma LTB4 and TxB2. Further, there was an attenuation of lung leukosequestration and protein leak in bronchoalveolar lavage and lung edema (all p less than 0.05). Pretreatment of other rats (n = 12) with the leukotriene receptor antagonist FPL 55712 IV did not prevent the aspiration-induced rise in LTB4 or TxB2, but otherwise was as effective as diethylcarbamazine in preventing injury. Finally, other hydrochloric acid-aspirated rats (n = 8) were pretreated intravenously with the thromboxane synthetase inhibitor OKY 046 or the thromboxane receptor antagonist SQ 29548. Both agents limited the aspiration-induced rise in plasma LTB4 (p less than 0.05). The data indicate that localized acid aspiration induces synthesis of LTB4 and thromboxane A2. Inhibition of either leukotriene or thromboxane will limit PMN adhesion and increased lung permeability.

Topics: Animals; Leukotriene B4; Male; Neutrophils; Pneumonia, Aspiration; Pulmonary Edema; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

Acid aspiration leads to increased neutrophil (PMN) oxidative metabolism, an event associated with lung leukosequestration and permeability increase. Neutropenia protected the vascular barrier function against acid injury. This study tests whether active oxygen species and elastase (which are presumably released by adherent PMNs) affect the microvascular barrier. Anesthetized rats underwent tracheostomy and insertion of a cannula into a lung segment. This was followed by localized instillation of 0.1 N HCl (n = 18) or saline (n = 18). Sequestration of PMNs in acid-aspirated and nonaspirated segments was 77 and 46 PMNs/high-power field (HPF), respectively, which was higher than control values of 11 and 8 PMNs/10 HPF in saline-aspirated and nonaspirated regions (P less than 0.05). Acid aspiration was associated with increased protein concentration in bronchoalveolar lavage (BAL) fluid to 3,550 and 2,900 micrograms/ml in the aspirated and nonaspirated lungs, respectively, which were higher than control values of 420 and 400 micrograms/ml (P less than 0.05). Acid aspiration also led to increased lung wet-to-dry weight ratios (W/D) of 6.6 and 5.4, which were higher than control values of 3.4 and 3.3 (P less than 0.05). Intravenous treatment of rats (n = 18) 90 min after aspiration with scavengers of reactive oxygen species, superoxide dismutase (1,500 U/kg), and catalase (5,000 U/kg), both conjugated to polyethylene glycol, did not reduce PMN sequestration but attenuated acid aspiration-induced increase in protein accumulation in BAL fluid in the aspirated and nonaspirated segments (990 and 610 micrograms/ml) as well as the increased lung W/D (4.6 and 4.0; all P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Catalase; Evans Blue; Hydrochloric Acid; Lung; Male; Methacrylates; Neutrophils; Pancreatic Elastase; Permeability; Pneumonia, Aspiration; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Thromboxane B2; Thromboxane-A Synthase

To test the hypothesis that the effect of steroids on hydrochloric acid aspiration may be involved in the metabolism of eicosanoids, we investigated the effects of an iv bolus of prednisolone on the metabolism of 15-hydroxyeicosatetraenoic acid and 11-dehydrothromboxane B2 (11-dehydro-TxB2) in the rat model of acid aspiration. Wistar rats were randomly selected for three groups and treated with either a) an iv bolus of saline after intratracheal injection of saline (control group), b) an iv bolus of saline after intratracheal injection of acid (acid-saline group), or c) an iv bolus of prednisolone after intratracheal injection of acid (acid-prednisolone group). The concentrations of 15-hydroxyeicosatetraenoic acid and 11-dehydro-TxB2 in bronchoalveolar lavage fluid were measured by radioimmunoassay.. The concentration of 15-hydroxyeicosatetraenoic acid in bronchoalveolar lavage fluid of either acid-saline group (804 +/- 129 pg/mL) or acid-prednisolone group (748 +/- 112 pg/mL) was significantly greater than that of the control group (143 +/- 27 pg/mL, p less than .01) 1 hr after the administration. The iv bolus of prednisolone caused a significant decrease in 15-hydroxyeicosatetraenoic acid (acid-saline group 1027 +/- 43 pg/mL; acid-prednisolone group 514 +/- 62 pg/mL; p less than .01) and cell counts of bronchoalveolar lavage fluid 48 hrs after intratracheal injection of acid, while there was no significant change in 11-dehydro-TxB2.. These findings suggest that corticosteroid administration may contribute to the inhibition of the inflammatory process of lungs after acid aspiration by decreasing the release of 15-hydroxyeicosatetraenoic acid in the distal lung unit.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Hydroxyeicosatetraenoic Acids; Injections, Intravenous; Pneumonia, Aspiration; Prednisolone; Rats; Thromboxane B2

Acid aspiration may recruit a generalized inflammatory reaction that can potentiate the local injury. After surgical isolation of bronchi in a group of 15 dogs, 1 milliliter per kilogram of 0.37 normal hydrochloric acid was instilled into either side. After five minutes, platelet and white blood cell counts fell to 10,000 and 1,000 per cubic millimeter (p less than 0.05). Platelet aggregates were noted in blood smears. 111Indium-platelet activity doubled over both the aspirated and nonaspirated lung (p less than 0.05). Physiologic dead space rose from 18 to 67 per cent and to 46 per cent in the aspirated and nonaspirated lung (p less than 0.05). Physiologic shunt increased from 12 to 47 per cent and to 43 per cent (p less than 0.05) on the two sides. Plasma thromboxane B2 levels at 30 minutes rose from 0.28 to 0.93 nanograms per milliliter (p less than 0.05). Edema fluid from the aspirated lung had thromboxane B2 values of 2.87 nanograms per milliliter, indicating pulmonary synthesis. Within five minutes of aspiration, systemic effects were prominent; mean arterial pressure fell from 114 to 46 milliliters of mercury (p less than 0.05), and the cardiac index fell 24 per cent from 106 to 81 milliliters per kilogram per minute (p less than 0.05) along with an 18 per cent decrease in contractility of a rat papillary muscle bathed in plasma from the aspirated dog. Mean pulmonary arterial pressure rose from 12 to 18 millimeters of mercury (p less than 0.05). Despite fluid infusion at 36 milliliters per kilogram per hour to keep wedge pressure constant at 5.5 millimeters of mercury, and sampling of one-third the blood volume, hemoglobin concentration rose 0.9 grams per cent (p less than 0.05) indicating increased microvascular permeability. At autopsy, the aspirated and nonaspirated lung were indistinguishable with congestion, interstitial hemorrhage, and white blood cell infiltrates. Systemic organs showed vascular congestion and edema. These data demonstrate that local aspiration leads to generalized inflammatory sequelae with cardiopulmonary failure.

Topics: Animals; Blood Gas Analysis; Dogs; Female; Hemodynamics; Hydrochloric Acid; Hypoxia; Leukocyte Count; Lung; Lung Volume Measurements; Male; Platelet Count; Pneumonia, Aspiration; Respiratory Function Tests; Thromboxane B2