Biomedical subjects

J M Hoeffel

Publications and source records attributed to J M Hoeffel.

At least 19 recordsLinked to original sources

PubMed1994

Neutralization of IL-8 inhibits neutrophil influx in a rabbit model of endotoxin-induced pleurisy.

Although the potent neutrophil chemotaxin, IL-8, is a known product of endotoxin-stimulated cells in vitro, the contribution of IL-8 to neutrophil recruitment in Gram-negative endotoxin inflammation in vivo is unknown. To determine whether neutralization of IL-8 would decrease endotoxin-induced neutrophil influx, we generated neutralizing mAbs to rabbit rIL-8 for use in our rabbit model of endotoxin-induced pleurisy. One mAb, ARIL8.2, specifically inhibited both rabbit rIL-8-induced chemotactic activity and activation of the rabbit IL-8 receptor transfected in 293 cells. Anesthetized rabbits with in-dwelling pleural catheters received either neutralizing mAb (ARIL8.2; 1 mg/kg) or irrelevant isotype-matched mAb (anti-HIV gp120) i.v. 1 h before as well as intrapleurally (20 micrograms/ml) at the time of intrapleural instillation of Escherichia coli endotoxin (200 ng bilaterally). ARIL8.2 blocked 77% of endotoxin-induced neutrophil influx (21 +/- 2 (SE) x 10(6) (ARIL8.2) vs 91 +/- 15 x 10(6) (anti-gp120) (p < 0.0001)). By Western analysis, a band corresponding to rabbit IL-8 was detected in the pleural liquid of rabbits in both groups. By ELISA, however, the concentration of free, unbound IL-8 in the pleural liquid was significantly less in the ARIL8.2 group than in the anti-gp120 group for at least 4 h, confirming that ARIL8.2 bound the IL-8 generated in vivo during that time. We conclude that neutralization of IL-8 profoundly inhibits neutrophil recruitment in endotoxin-induced pleurisy indicating that IL-8 is a major chemotactic factor in this model of acute inflammation.

Animals↗

PubMed1994

Interleukin-8 is a major component of pleural liquid chemotactic activity in a rabbit model of endotoxin pleurisy.

Gram-negative endotoxin induces production of the potent chemotactic factor interleukin-8 (IL-8) in vitro; however, the importance of IL-8 in endotoxin-induced inflammation in vivo is unknown. We asked whether IL-8 is an important contributor to chemotactic activity in acute inflammatory liquids formed in response to endotoxin, and, if present, what concentrations of IL-8 antigen are generated. For these studies, we cloned and expressed rabbit recombinant IL-8 (rrIL-8), developed specific anti-rabbit IL-8 monoclonal antibodies (mAb), and then used these reagents to develop assays to detect rabbit IL-8 bioactivity and measure rabbit IL-8 antigen. Escherichia coli endotoxin (20 ng/ml, n = 4, or 2,000 ng/ml, n = 4) was instilled into the pleural space of eight rabbits for 6 h. Rabbit IL-8 bioactivity in the endotoxin pleurisy samples was assayed by measuring the migration of rabbit neutrophils toward the pleural liquid under two different conditions: 1) after addition of an anti-IL-8 neutralizing mAb and 2) after desensitization of the neutrophils to rrIL-8. Addition of the anti-IL-8 mAb decreased neutrophil migration toward the pleural liquid by 65 +/- 13 and 75 +/- 22% (mean +/- SE, after 20 and 2,000 ng/ml endotoxin, respectively; P < 0.01 compared with a control mAb). Desensitization of neutrophils to rrIL-8 decreased their migration toward the pleural liquid by 72 +/- 5% (P = 0.03, compared with exposure of neutrophils to buffer alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effect of phenytoin on acute lung injuries in unanesthetized sheep.

OBJECTIVE: To determine if the intravenous administration of phenytoin attenuates or prevents acute experimental lung injury. DESIGN: Placebo-controlled, longitudinal animal investigative study. SETTING: University research laboratory. SUBJECTS: Sixteen yearling female lambs weighing 30 +/- 3 kg. INTERVENTION: After administration of anesthesia, the animals were endotracheally intubated and mechanically ventilated. Using sterile techniques, four thoracotomies were performed. Through the left fourth intercostal space, cannulas for pressure measurements were inserted directly into the main pulmonary artery and left atrium. An ultrasound flow cuff for determination of cardiac output was placed around the main pulmonary artery. Through the left tenth intercostal space, the diaphragmatic and mediastinal parietal pleura were widely cauterized. Through the right tenth intercostal space, the caudal mediastinal lymph node was identified and divided at the caudal margin of the right pulmonary ligament, and a 1- to 2-cm portion of the node distal to the ligament was resected. The diaphragmatic and mediastinal parietal pleura were widely cauterized. Through the right sixth intercostal space, the efferent duct (or ducts) was identified, ligated at the site of entry into the thoracic duct, and cannulated. The lymph cannula was brought to the outside of the thorax through a separate stab wound. MEASUREMENTS AND MAIN RESULTS: Unanesthetized sheep were studied 7 to 10 days after surgery. Hemodynamic, lung fluid balance, and arterial blood variables were measured in uninjured sheep and in sheep injured by intravenous infusions of Escherichia coli endotoxin (1 microgram/kg iv over 30 mins), air bubbles (0.056 to 0.074 mL/kg/min over 4 hrs), or oleic acid (0.06 mL/kg over 1 hr). The sheep were studied when untreated and after pretreatment with phenytoin. We found that the expected increase in protein-rich lung lymph flow with injuries, resulting from increased microvascular permeability in the lungs, was attenuated by phenytoin when the lungs were injured by endotoxin or air bubbles. In contrast, phenytoin had no effect on oleic acid-induced lung injury or on uninjured lungs. CONCLUSIONS: Phenytoin attenuates acute lung injuries in sheep that are thought to be caused by stimulation of host inflammatory responses (e.g., endotoxin and air bubbles), but has no effect on direct injuries to the lungs (e.g., oleic acid). A plausible mechanism for this finding is phenytoin inhibition of polymorphonuclear leukocyte function.

Animals↗

PubMed1992

Interleukin-8 is a major neutrophil chemotactic factor in pleural liquid of patients with empyema.

Interleukin-8 (IL-8), a potent neutrophil chemotactic peptide, has been found in association with human disease, but its contribution to chemotactic activity in humans is not yet known. We asked whether IL-8 is present in inflammatory human pleural effusions, and to what extent it contributes to pleural liquid neutrophil chemotactic activity. Because tumor necrosis factor alpha (TNF-alpha) is a strong inducer of IL-8, we also asked whether TNF-alpha was present. For this prospective study, we collected pleural liquid from 51 patients (empyema, 14; parapneumonic, four; tuberculous, eight; malignant, nine; miscellaneous exudative, seven; and transudative, nine), counted pleural neutrophils, and measured IL-8 and TNF-alpha concentrations in the supernatant. To determine the contribution of IL-8 to chemotactic activity in empyema, we measured the neutrophil migration induced by empyemic liquids before and after addition of anti-IL-8 F(ab')2 antibody fragments or control anti-IL-6 F(ab')2. We found that IL-8 concentrations were higher in empyema (61.3 +/- 21.0 ng/ml [SEM]) than in all other effusions (1.1 +/- 0.5 ng/ml) (p = 0.0001). All empyema liquids had IL-8 concentrations above 2.5 ng/ml, which was true for only three of the other 37 effusions (two parapneumonic, one tuberculous). IL-8 levels correlated with the pleural neutrophil count (r = 0.46; p = 0.007) and the neutrophil chemotactic activity of pleural liquid (r = 0.43; p = 0.008). Anti-IL-8 antibodies decreased chemotactic activity in empyema liquids by 65 +/- 5%, whereas the control antibody had no effect (0 +/- 5% decrease) (p = 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

Chemotaxis, Leukocyte↗

PubMed1992

Evidence of a role for mesothelial cell-derived interleukin 8 in the pathogenesis of asbestos-induced pleurisy in rabbits.

Although acute asbestos-induced pleurisy is characterized by an influx of neutrophils, the identity of the factors that attract these cells to the pleural space and the source of the factors are unknown. We found that instillation of crocidolite asbestos into the pleural space of rabbits led to the appearance in pleural liquid of chemotactic activity for neutrophils, and that this chemotactic activity was inhibited significantly by a neutralizing antibody to human interleukin 8 (IL-8). Cultured rabbit pleural mesothelial cells incubated with crocidolite asbestos also released chemotactic activity for neutrophils, which was inhibited significantly by the anti-IL-8 antibody. To determine whether rabbit pleural mesothelial cells synthesize IL-8, we generated a probe for rabbit IL-8 mRNA by amplifying cDNA prepared from stimulated pleural mesothelial cells using the polymerase chain reaction (PCR) and primers based on homologous sequences in human and sheep IL-8 cDNAs. Homology-based PCR yielded a single cDNA fragment with a nucleotide sequence 88% identical to that of a corresponding region of human IL-8 cDNA. With the radiolabeled PCR product as a probe, we demonstrated rapid induction of IL-8 mRNA expression in pleural mesothelial cells exposed to asbestos. As expected, tumor necrosis factor-alpha also led to the appearance of IL-8 in the rabbit pleural space and stimulated cultured pleural mesothelial cells to synthesize and release IL-8. We conclude that asbestos directly stimulates pleural mesothelial cells to synthesize IL-8 and that mesothelial cell-derived IL-8 may play an important role in mediating asbestos-induced pleural inflammation.

Animals↗

PubMed1990

Effects of aerosolized artificial surfactant on repeated oleic acid injury in sheep.

We studied the effects of an artificial surfactant, Exosurf, administered as an aerosol on respiratory system compliance (Crs), total respiratory resistance (RT), and gas exchange (PO2) in anesthetized, paralyzed sheep with oleic acid (OA)-induced lung injury. Paired experiments with OA were performed in 10 sheep, 5 of which received Exosurf in the first experiment and aerosolized 0.9% NaCl in the second; in the other 5 sheep the order of Exosurf and NaCl was reversed. Paired experiments without OA were performed in 6 additional sheep that served as controls. In the first set of experiments, OA caused significant abnormalities, compared to control and baseline values (p less than 0.02), in Crs, RT, and PO2; there was no difference between animals that received Exosurf and those that received NaCl. Baseline values for PO2 and Crs during the second set of experiments with OA were lower than controls (p less than 0.002), indicating that the animals had not fully recovered from their initial injury. After OA, the animals that received NaCl (i.e., the ones that received Exosurf the first time) had higher PO2 and Crs values (p less than 0.01) than those that received NaCl first and Exosurf second. There was no difference in postmortem lung water content between the animals that received Exosurf or NaCl first, both of which were higher than control (p less than 0.01). Studies in 3 additional sheep showed peripheral deposition of aerosol. Thus, we failed to show an acutely beneficial effect of aerosolized Exosurf in OA-induced lung injury; Exosurf did, however, appear to provide protection against some of the consequences of repeated lung injury.

Aerosols↗

PubMed1988

Pulmonary clearance of three aerosolized solutes in oleic acid-induced lung injury.

We studied the effects of oleic acid (OA) on pulmonary clearance of three aerosolized radioactive solutes: 99mTc-diethylenetriamine pentaacetate (99mTc-DTPA), 67Ga-desferoxamine (67Ga-DFOM), and 111In-transferrin (111In-TF). Either 0.09 ml/kg OA or an equivalent volume of 0.9% NaCl (controls) was administered intravenously to 48 anesthetized, paralyzed dogs. Each animal received one aerosolized solute either 60 min after (protocol A) or 30 min before (protocol B) the infusion of OA or NaCl. In protocol A clearances of all three solutes were similar in OA and control animals. In contrast, in protocol B clearances of all three solutes increased significantly during OA infusion; during the next 60 min clearances of 99mTc-DTPA and 67Ga-DFOM returned to control values but 111In-TF remained increased. We conclude that 1) in OA-induced permeability edema pulmonary clearance of aerosolized solutes is increased when the aerosol is delivered 30 min before but not 60 min after injury, and 2) increased clearance persists only for large molecules, presumably because smaller molecules cross injured epithelium quickly and completely. These phenomena are best explained by a nonhomogeneous distribution of OA-induced injury.

Aerosols↗

PubMed1988

Catalase prevents increased lung vascular permeability during air emboli in unanesthetized sheep.

We studied the effects of bovine catalase on increased lung vascular permeability to fluid and protein during air emboli in unanesthetized sheep. Pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, lymph and plasma protein concentrations, arterial PO2, and numbers of arterial leukocytes were measured in paired experiments in which each sheep served as its own control. We found an increase in protein-rich lung lymph flow during embolization in untreated sheep, indicating an increase in microvascular permeability. When sheep were pretreated with intraperitoneal injections of catalase (50 mg/kg divided over the 24 h before air infusion), vascular pressures, arterial PO2, and leukocyte counts were not different from when the sheep were untreated, but the expected increases in transvascular fluid and protein flow during emboli were significantly attenuated (by approximately 50%). This effect required catalase enzyme activity, as demonstrated by the failure of enzymatically inactivated catalase (by reaction in vitro with aminotriazole in the presence of H2O2) or catalase vehicle (0.1% thymol in water) to affect the lung lymph response to air emboli. We conclude that H2O2 plays a role in the pathogenesis of the acute lung injury caused by intravenous air infusions into unanesthetized sheep. Because both catalase and superoxide dismutase have protected sheep lungs from air emboli-induced increased vascular permeability, a possible specific cause of microvascular barrier injury could be hydroxyl radicals formed from reactions between H2O2 and superoxide anion.

Animals↗

PubMed1988

Effect of catalase on endotoxin-induced acute lung injury in unanesthetized sheep.

Administration of endotoxin intravenously to unanesthetized sheep causes an acute lung injury characterized by increased microvascular barrier permeability and subsequent pulmonary edema. Endotoxin-induced sheep lung injury can be attenuated by leukocyte depletion, and may be mediated by toxic metabolites of oxygen. We studied effects of administering catalase, which catalyzes conversion of hydrogen peroxide to oxygen and water, to sheep subsequently infused with endotoxin to test the hypothesis that hydrogen peroxide plays a role in the pathogenesis of lung injury. We found that infusions of endotoxin (1 microgram/kg) into untreated sheep caused the expected biphasic response, a transient, early, marked pulmonary arterial hypertension followed by a prolonged increase in protein-rich lung lymph flow characteristic of increased microvascular permeability filtration in the lungs. Intraperitoneal injections of catalase (50 mg/kg) prior to infusing endotoxin in these same sheep resulted in substantial catalase activity in plasma and in lung lymph, and attenuated the expected changes in pulmonary arterial pressure, lung lymph flow, and arterial leukocyte counts and oxygen tension after endotoxin infusions. Furthermore, mechanical elevation of hydrostatic pressure in the lungs of a catalase-treated sheep infused with endotoxin resulted in increased lung lymph flow with a decreased protein concentration, indicating that the microvascular barrier to fluid and protein was functionally intact. Administration of catalase that was inactivated by reaction with hydrogen peroxide in the presence of aminotriazole or administration of the catalase vehicle, thymol, had no effects on the sheep responses to endotoxin. We conclude that hydrogen peroxide plays a role in the pathogenesis of endotoxin-induced acute lung injury in sheep.

Acute Disease↗

PubMed1987

Respiratory clearance of aerosolized radioactive solutes of varying molecular weight.

To determine the influence of varying molecular weight (mol wt) on respiratory clearance of aerosolized solutes, we studied eight radiopharmaceuticals, each administered to four dogs: sodium 99mTc pertechnetate (TcO4), 99mTc glucoheptonate ([99mTc]GH), 51Cr-ethylenedinitrotetraacetate ([51Cr]EDTA), 99mTc diethylenetriaminepentaacetate ([99mTc] DTPA), 111In diethylenetriaminepentaacetate ([111In]DTPA), 67Ga desferoxaminemesylate ([67Ga]DFOM), 99mTc dextran ([99mTc]DX) and 111In transferrin ([111In]TF). After aerosolization (0.8 m MMD, 2.4 GSD), clearance was determined for 30 min and then corrected by intravenous injection for nonairspace radioactivity. In-TF clearance (0.11 +/- 0.10%/min) was lower than TcO4 (6.32 +/- 0.62%/min), [99mTc]GH (1.50 +/- 0.37%/min), [51Cr]EDTA (2.38 +/- 1.02%/min), [99mTc]DTPA (3.51 +/- 0.40%/min), [111In]DTPA (2.35 +/- 0.42%/min), [67Ga] DFOM (1.99 +/- 0.49%/min) and [99mTc]DX (1.81 +/- 0.75%/min) clearances (p less than 0.001). TcO4 clearance was higher than others (p less than 0.001). Technetium binding to DX was unsatisfactory; aerosolization caused unbinding from DTPA. We conclude that respiratory clearance of large mol wt solutes within 30 min is negligible and, that clearance of molecules between 347-5,099 daltons differs greatly, suggesting that binding and/or intrapulmonary retention affect transfer.

Animals↗

PubMed1986

Oleic acid lung injury in sheep.

Intravenous infusion of oleic acid into experimental animals causes acute lung injury resulting in pulmonary edema. We investigated the mechanism of oleic acid lung injury in sheep. In experiments with anesthetized and unanesthetized sheep with lung lymph fistulas, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and lymph and plasma protein concentrations. We injured the lungs with intravenous infusions of oleic acid at doses ranging from 0.015 to 0.120 ml/kg. We found that oleic acid caused reproducible dose-related increases in pulmonary arterial pressure and pulmonary vascular resistance, arterial hypoxemia, and increased protein-rich lung lymph flow and extravascular lung water. The lung fluid balance changes were characteristic of increased permeability pulmonary edema. Infusion of the esterified fat triolein had no hemodynamic or lung fluid balance effects. Depletion of leukocytes with a nitrogen mustard or platelets with an antiplatelet serum had no effect on oleic acid lung injury. Treatment of sheep before injury with methylprednisolone 30 mg/kg or ibuprofen 12.5-15.0 mg/kg also had no effects. Unlike other well-characterized sheep lung injuries, injury caused by oleic acid does not require participation of leukocytes.

Animals↗

PubMed1986

Rebreathing lung tissue volume of sheep with normal and edematous lungs.

To determine the accuracy of measurements of lung tissue volume (Vlt) by rebreathing acetylene in normal and edematous lungs, we compared gravimetric values of total lung weight (Ql) and extravascular lung water (Qwl) with Vlt in anesthetized control sheep (C) and sheep with hydrostatic pulmonary edema (HPE) or oleic acid-induced permeability pulmonary edema (PPE), five animals each. In eight additional sheep we determined that acetylene solubility in blood (0.117 +/- 0.010 ml X 100 ml-1 X Torr-1) differed significantly from that in lung-blood homogenates (0.095 +/- 0.009 ml X 100 ml-1 X Torr-1, P = 0.0017). The latter value was used in all calculations. In C, Vlt was 194% of Qwl and 98% of Ql; in HPE, Vlt was 144% of Qwl and 87% of Ql; and in PPE, Vlt was 112% of Qwl and 77% of Ql. We conclude that when the lungs are normal, Vlt reasonably measures Ql not Qwl. However in both HPE and PPE, Vlt progressively underestimates Ql and cannot differentiate between increased blood volume and increased Qwl.

Acetylene↗

PubMed1986

Reduction of total hemolytic complement activity with Naja haje cobra venom factor does not prevent endotoxin-induced lung injury in sheep.

We studied the effects of reducing total hemolytic complement activity with Naja haje cobra venom factor on the lung injury caused by intravenously infused endotoxin in 5 unanesthetized sheep with lung lymph fistulas. In normal sheep, infusions of lipopolysaccharide W from Escherichia coli (1.0 micrograms/kg) intravenously over 30 min caused increases in protein-rich lung lymph flow as well as the appearance in plasma and lung lymph of complement (C5)-derived chemotactic activity for polymorphonuclear leukocytes. Reduction of total hemolytic complement activity by treatment with Naja haje cobra venom factor (12 to 17 U/kg intraperitoneally) did not prevent the lung injury caused by endotoxin and also did not prevent the appearance in plasma and lung lymph of chemotactic activity. We conclude that although complement appears to be activated following intravenously infused endotoxin in sheep, a completely intact complement system is not necessary for endotoxin-induced lung injury.

Animals↗

PubMed1985

Factors affecting tissue volume measurements in normal and edematous dog lungs.

To characterize further some of the factors affecting lung tissue soluble-gas rebreathing volume (Vlt), we determined the solubility of acetylene in blood and lung tissue, the influence of the presence of pulmonary edema on tissue solubility, the effects of varying tidal volume (VT), and the tissue volume actually measured in two groups of six anesthetized paralyzed dogs: controls (C) and oleic acid-induced pulmonary edema (OA). Each animal's solubility was used to compute Vlt for comparison with gravimetric lung weight (Ql) and extravascular lung water content (Qwl). Solubility at 37.5 degrees C in blood (0.125 ml X 100 ml-1 X Torr-1) exceeded that in lung tissue (P less than 0.005): C = 0.118 and OA = 0.112 ml X 100 ml-1 X Torr-1 (NS). Vlt, expressed as %Ql, increased with increasing VT (20, 35, and 50 ml/kg) in OA (62.2, 78.9, and 94.7%, respectively, P less than 0.0001) but not in C (92.4, 94.4, and 99.3%, respectively). We conclude that solubility differs in blood and lung tissue but not in normal and edematous lungs, Vlt is not affected by VT in normal dogs but is in those with pulmonary edema, and Vlt measures Ql rather than Qwl.

Acetylene↗

PubMed1984

Accurate reference measurement for postmortem lung water.

To test the hypothesis that dry blood-free lung weight is increased during pulmonary edema, thereby leading to an underestimation of the ratio of extravascular lung water-to-dry lung weight, we measured postmortem lung water, dry mass, and hydroxyproline content in 33 sheep with normal lungs (n = 10), high-pressure edema (n = 9), or increased permeability edema (n = 14). Residual blood in the lung, measured using hemoglobin as the intravascular marker in all sheep, and also using 51Cr-tagged red blood cells in 24 sheep, was not different between the two methods or among the three groups of sheep. Extravascular lung water increased 64% in sheep with high-pressure edema and 82% in those with increased permeability edema compared with control values. Dry blood-free lung weight was significantly greater (33% more than control values) in sheep with increased permeability edema, causing the ratio of extravascular lung water-to-dry blood-free lung weight to underestimate accumulated lung water by about 50%. Because hydroxyproline content of the lung was not affected by edema, the ratio of extravascular lung water-to-lung hydroxyproline content was more accurate than the ratio of extravascular lung water-to-dry blood-free lung weight in the quantification of pulmonary edema.

Animals↗

PubMed1984

Site of deposition and factors affecting clearance of aerosolized solute from canine lungs.

We determined the influence of several factors on lung solute clearance using aerosolized 99mTc-diethylenetriaminepentaacetate. We used a jet nebulizer-plate separator-balloon system to generate particles with an activity median aerodynamic diameter of 1.1 micron, administered the aerosol in a standard fashion, and determined clearance half times (t1/2) with a gamma-scintillation camera. The following serial studies were performed in five anesthetized, paralyzed, intubated, mechanically ventilated dogs: 1) control, with ventilatory frequency (f) = 15 breaths/min and tidal volume (VT) = 15 ml/kg during solute clearance; 2) repeat control, for reproducibility; 3) increased frequency, with f = 25 breaths/min and VT = 10 ml/kg; 4) positive end-expiratory pressure (PEEP) of 10 cmH2O; 5) unilateral pulmonary arterial occlusion (PAO); and 6) bronchial arterial occlusion (BAO). Control t1/2 was 25 +/- 5 min and did not change in the repeat control, increased frequency, or BAO experiments. PEEP markedly decreased t1/2 to 13 +/- 3 min (P less than 0.01), and PAO increased it to 37 +/- 6 min (P less than 0.05). We conclude that clearance from the lungs by our method is uninfluenced by increased frequency, increases markedly with PEEP, and depends on pulmonary, not bronchial, blood flow.

Aerosols↗

PubMed1984

Effect of lung injuries on [14C]urea permeability-surface area product in dogs.

To determine whether [14C]urea permeability-surface area product (PS) is a reliable indicator of changes in permeability in various injuries and its relationship to indicator-dilution and gravimetric lung water contents, we studied six groups of anesthetized, paralyzed, and mechanically ventilated dogs (5 animals each). The groups consisted of control dogs, those injured by intravenous alloxan, oleic acid, or glass beads, and those exposed to acute hypoxia or increased left atrial pressure from volume loading (Pla). Interanimal variation of PS was large (3.0-15.0 ml/s), but successive hourly values in individual animals were stable for 2 h in experimental groups and for 4 h in controls. The PS increased after alloxan, elevated Pla, and 2 h of hypoxia; PS decreased after oleic acid and microemboli. The gravimetric lung water increased after alloxan, oleic acid, and microemboli, and indicator-dilution lung water increased only after alloxan. We conclude 1) that intersubject variability requires normalization to enable detection of significant deviation from base line, and 2) that decreased PS after oleic acid and microvascular injury occurred because vascular obstruction, which decreased surface area, masked probable coexisting increases in capillary permeability.

Alloxan↗

PubMed1983

Superoxide dismutase with heparin prevents increased lung vascular permeability during air emboli in sheep.

We studied the effects of bovine superoxide dismutase on the increased lung microvascular permeability to fluid and protein during air emboli in unanesthetized sheep. We measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and lymph and plasma protein concentrations. In air emboli experiments we continuously infused the same dose of air bubbles 1 mm in diameter into the right atrium of each sheep to increase pulmonary vascular resistance to 2-4 times base-line values. We did experiments in pairs so that each sheep served as its own control. We found an increase in protein-rich lymph flow from the lung during embolization in untreated sheep, indicating an increase in microvascular permeability to both fluid and protein. When we pretreated the sheep with heparin (300 U/kg) and infused them with intravenous bovine superoxide dismutase (1 mg X kg-1 X h-1 beginning before the air infusion), we found that vascular pressures and pulmonary vascular resistance were not different from untreated sheep but that the expected increases in transvascular fluid and protein flow during emboli were significantly decreased (P less than 0.0005). Heparin alone did not significantly attenuate the increased microvascular permeability but we found that it greatly enhanced the effectiveness of superoxide dismutase in preserving microvascular functional integrity during air emboli. We conclude that superoxide anion, probably produced and released by leukocytes, is a central factor in the microvascular injury that results in increased permeability in the lungs of sheep during air microembolization.

Animals↗