thromboxane-b2 and Fistula

The clinical use of interleukin-2 (IL-2) is limited by severe cardiopulmonary dysfunction. This study examines the mechanism of respiratory failure related to IL-2, using sheep with chronic lung lymph fistulae. Awake animals were infused with an intravenous (I.V.) bolus of IL-2 10(5) U/kg (n = 5) or its excipient (EXC) control (n = 3), every 8 hours for 4 to 5 days. Cardiopulmonary function was monitored daily for at least one 8-hour period. Within 2 hours after each IL-2 administration, mean pulmonary arterial pressure (MPAP) rose. On Day 1, the mean rise was from 13 to 26 mmHg (p less than 0.05), and on Day 5, to 29 mmHg (p less than 0.05). MPAP returned to baseline levels after 2-3 hours. Pulmonary arterial wedge pressure was unchanged from 4 mmHg. There were transient falls in arterial oxygen tension, from 88 to 77 mmHg on Day 1 and to 73 mmHg (p less than 0.05) on Day 5. Lung lymph flow (QL) rose from 2.4 to 6.8 ml/30 minutes (p less than 0.05) on Day 1, and from 4.7 to 10.2 ml/30 minutes (p less than 0.05) on Day 5, whereas the lymph/plasma protein ratio increased on Day 1 from 0.69 to 0.83 (p less than 0.05) and from 0.63 to 0.71 (p less than 0.05) on Day 5. This documents an increase in pulmonary microvascular permeability. Thromboxane (Tx)B2 levels increased transiently after each IL-2 injection in plasma from 195 to 340 pg/ml (p less than 0.05) and in lung lymph from 222 to 772 pg/ml (p less than 0.05) on Day 1, and to similar levels on Day 5. There was a progressive rise in cardiac output from 5.7 to 8.6 1/minute (p less than 0.05) during the 5 days of infusion. Systemic blood pressure did not change. Temperature rose from 39.1 to 41.2 C (p less than 0.05), and shaking chills were common. There was a progressive fall in leukocyte count, from 8.4 to 3.2 X 10(3)/mm3 (p less than 0.05) by Day 5, reflecting a 77% fall in lymphocytes. Lung lymph lymphocyte counts rose, and lymphocyte clearance increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillary Permeability; Disease Models, Animal; Female; Fistula; Hemodynamics; Interleukin-2; Leukocyte Count; Lung; Lymph; Lymph Node Excision; Lymphocytes; Proteins; Recombinant Proteins; Respiratory Insufficiency; Sheep; Thromboxane B2; Time Factors

Paraquat, a widely used herbicide, causes severe lung damage in humans and laboratory animals. Pulmonary edema is a common initial feature of paraquat toxicity, but its pathophysiology is not well understood. The purpose of this investigation was to determine the acute toxic effect of paraquat (30 mg/kg) on pulmonary transvascular protein and fluid fluxes, histologic features, and prostanoid production, using awake sheep with chronic lung lymph fistulas (n = 6). Lung lymph flow increased significantly 3.5 h after intravenous infusion of paraquat and rose to 2.6 times baseline within 8 h (from 4.4 +/- 0.4 to 11.4 +/- 1.5 ml/h, p less than 0.05). Lymph-plasma protein concentration ratio increased during the same time period (from 0.64 +/- 0.05 to 0.75 +/- 0.04, p less than 0.05). Lung lymph protein clearance also increased at 3.5 h and remained elevated throughout the duration of the experiment. Pulmonary arterial and left atrial pressure were only slightly altered. Plasma and lung lymph thromboxane A2 (as TXB2) concentrations were significantly increased at 30 min and continued so thereafter. Plasma and lung lymph prostacyclin (6-keto-PGF1 alpha) concentrations increased significantly at 3 h and were more than 5 times baseline by 7 h. The time course of the increase in 6-keto-PGF1 alpha concentrations seemed similar to that of lung lymph flow. The high flow of protein-rich lymph strongly suggested an increase in pulmonary vascular permeability, which may indicate pulmonary endothelial damage. Histologic studies of the lungs revealed only minor changes in perivascular cuffing, minimal alveolar hemorrhage, and slight neutrophilic alveolar wall infiltration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Cell Count; Body Fluids; Fistula; Hemodynamics; Lung; Lung Diseases; Lymph; Lymphatic Diseases; Paraquat; Prostaglandins; Sheep; Thromboxane B2; Time Factors; Wakefulness

We studied the effects of a burn injury on the response of the lung to endotoxin. Seventeen unanesthetized sheep with lung lymph fistulas were studied. Eight were given Escherichia coli endotoxin (1.5 micrograms/kg) alone and nine were given the same dose 72 hours after a 25% total body surface burn injury. At this time after burn, all physiologic parameters were at baseline levels. A characteristic two-phase lung injury was seen after administration of endotoxin with an initial hypertension phase, characterized by pulmonary artery hypertension, and a second or permeability phase, characterized by an increase in protein-rich lymph flow. all eight animals that underwent only endotoxin administration survived, whereas four of the nine burned animals died during the permeability phase in pulmonary edema. Major physiologic differences between the groups were noted during the permeability phase, including a more severe hypoxia, pulmonary hypertension, and increased postburn lymph flow. Major biochemical changes included significant increases in lymph thromboxane, thromboxane B2, and beta-glucuronidase activity in the burn group. We conclude that the lung is more sensitive to endotoxin after burn, probably as a result of an increased release of products of arachidonic acid metabolism and products of leukocyte activation caused by the body burn.

Topics: Animals; Burns; Endotoxins; Escherichia coli Infections; Fistula; Glucuronidase; Hypertension, Pulmonary; Hypoxia; Lung Diseases; Lymph; Sheep; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Burns; Fistula; Hemodynamics; Lung Diseases; Lymphatic Diseases; Lymphatic System; Prostaglandins; Sheep; Thromboxane A2; Thromboxane B2; Thromboxanes