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W M Selig

Publications and source records attributed to W M Selig.

33 records · Page 2Linked to original sources
PubMed1988

Antigen-induced edema formation, bronchoconstriction, and pulmonary vasospasm in the isolated perfused guinea pig lung. Evidence for a secondary edemagenic response.

The effect of antigen (ovalbumin) challenge on pulmonary hemodynamics, bronchoconstriction, and fluid filtration was investigated in Ringer's-perfused (non-recirculating) lungs that had been passively sensitized in vitro. Bolus ovalbumin injection (30 micrograms) produced immediate increases in pulmonary arterial pressure, peak intratracheal pressure, and lung weight within 1 min and secondary marked increases in intratracheal pressure and lung weight from 120 to 200 min. Electron microscopy of antigen-challenged isolated lungs showed evidence of both septal and intraalveolar edema. Ionophore A23187 (100 micrograms) challenge of nonsensitized lungs produced immediate pulmonary responses similar to antigen, whereas secondary increases in lung weight were smaller. Arachidonic acid pretreatment (1 microM) potentiated immediate antigen-induced increases in intratracheal pressure but did not affect pulmonary responses to ionophore challenge. Putative mediators of anaphylaxis including histamine, leukotrienes B4, C4, D4, and E4, platelet-activating factor, and substance P produced immediate changes in pulmonary arterial and/or intratracheal pressure similar to antigen challenge. Only platelet-activating factor and substance P partially mimicked the secondary edema formation noted following antigen challenge. Thus, antigen challenge in in vitro sensitized guinea pig lungs produced both immediate and secondary responses characterized by increases in vascular pressure, airway pressure, and edema formation. This occurred in the absence of circulating blood-formed elements and without a massive influx of cells. Synergism between mediators such as histamine, the leukotrienes, platelet-activating factor, and substance P released following antigen challenge may be necessary to produce the complete pathophysiological sequelae associated with antigen challenge in the perfused guinea pig lung.

Anaphylaxis↗
PubMed1987

Role of lipids in bone marrow-induced pulmonary edema.

We examined the mechanism of the bone marrow-induced pulmonary edema in the isolated Ringer-perfused rabbit lung. Bone marrow administration (0.2 ml/kg body wt) increased pulmonary arterial pressure, capillary pressure, arterial resistance, and venous resistance within 2-4 min. Bone marrow also produced marked increases in lung wet weight and the capillary filtration coefficient but at later time points (90-120 min) during the perfusion. Only the triglyceride-containing lipid component of the bone marrow produced increases in pulmonary hemodynamics, lung wet weight, and the capillary filtration coefficient comparable to those observed after bone marrow. Bone marrow and the lipid component of bone marrow both produced increases in venous effluent lipoprotein lipase activity (the enzyme responsible for hydrolysis of triglycerides to free fatty acids). Bone marrow also stimulated the production of thromboxane B2 but not 6-ketoprostaglandin F1 alpha in the perfused lung. Both meclofenamate (1 microM), a cyclooxygenase inhibitor, and U-60,257 (10 microM), a lipoxygenase inhibitor, attenuated the bone marrow-induced pulmonary hemodynamic response, whereas only U-60,257 attenuated the increases in lung wet weight and the capillary filtration coefficient. In conclusion, pulmonary embolization induced by bone marrow results in increases in lung weight and the capillary filtration coefficient in the isolated Ringer-perfused rabbit lung. Pulmonary vasoconstriction is partially dependent on arachidonic acid metabolites but appears to be independent of circulating blood-formed elements. The lipid component of bone marrow or products derived from this component (e.g., free fatty acids and lipoxygenase products) may mediate the bone marrow-induced pulmonary edema.

Animals↗
PubMed1987

Measurement of albumin permeability across endothelial monolayers in vitro.

We have developed an experimental system to measure the permeability of the cultured endothelial monolayer. The luminal-to-abluminal flux of 125I-albumin across cultured pulmonary endothelium was expressed as a clearance rate equal to the permeability-surface area product. After clearance rate measurement for a 30-min base-line period, a test agent was added to the luminal side, and the clearance rate was remeasured during a 30-min experimental period. In control studies the base-line clearance rate was 0.343 +/- 0.017 microliter/min. After correction for the diffusional resistances of the filter and unstirred layers, the calculated permeability of the endothelial monolayer was 1.2 X 10(-5) cm/s. When culture medium was the test agent, the experimental clearance rate was unchanged from the base-line value. After addition of 4 mM oleic acid to the luminal chamber, the clearance rate was 0.528 +/- 0.017 microliter/min compared with a base-line value of 0.330 +/- 0.008 microliter/min (P less than 0.005). This method allows the calculation of endothelial permeability with correction for unstirred layers and the use of each monolayer as its own control.

Animals↗
PubMed1987

Effect of heparin on increased pulmonary microvascular permeability after bone marrow embolism in awake sheep.

We examined the alterations in pulmonary transvascular fluid and protein exchange after intravenous infusion of fat emboli, i.e., bone marrow suspension (BMS) in awake sheep prepared with chronic lung lymph fistulas and compared these changes with those observed in sheep pretreated with heparin. The BMS injection (0.2 ml/kg) over 15 min caused rapid, but transient, increases (p less than 0.05) in mean pulmonary artery pressure and pulmonary vascular resistance. These increases were accompanied by significant increases in the lymph concentrations of thromboxane B2 and 6-keto-PGF1 alpha. Pulmonary lymph flow increased by 3.9-fold (+/- 0.8) over baseline by 120 min after BMS with no change in the lymph-to-plasma protein concentration ratio (L/P ratio). Heparin pretreatment (700 U/kg) enhanced the BMS-induced increases in pulmonary artery pressure and pulmonary vascular resistance. Thromboxane B2 concentrations in the lymph increased, whereas there was no change in the concentration of 6-keto-PGF1 alpha. Lung lymph flow increased 4-fold (+/- 1.0) over baseline by 120 min after BMS without a change in L/P ratio. Changes in lung vascular permeability were evaluated by elevating pulmonary microvascular pressure (left atrial balloon catheter inflation) at 120 min after BMS. Lung lymph flow increased 7-fold (+/- 1.1) from baseline, whereas the L/P ratio decreased to a mean value of 0.48 +/- 0.03. The protein reflection coefficient (sigma = 1 - L/P ratio) decreased from a control mean of 0.69 +/- 0.02 to 0.52 +/- 0.03 after the BMS challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Cyclooxygenase metabolites contribute to oleic acid-induced lung edema by a pressure effect.

We investigated the role that lung-derived arachidonic acid metabolites play in the acute changes in pulmonary hemodynamics, airway function, and lung fluid balance following oleic acid-induced injury in the isolated blood free perfused lung. A bolus injection of oleic acid (OA) emulsion (12 mg) into the pulmonary artery caused a rapid increase in pulmonary arterial pressure, inspiratory pressure, and weight gain. These pathophysiologic changes were not due to emboli per se, but were correlated with release of the vaso- and broncho-constrictive prostanoids, thromboxane A2 (measured as thromboxane B2) and prostaglandin F2 alpha. The leukotrienes (C4, D4, and E4) and prostacyclin (measured as 6 keto-prostaglandin F1 alpha) were not released by OA injury. Ibuprofen, a cyclooxygenase inhibitor, blocked the release of the vasoconstrictive prostanoids and also attenuated the rise in pressures and the development of edema indicating an important functional role for the prostanoids in the fluid imbalance. Ibuprofen also attenuated the increase in bronchoalveolar lavage protein but the protein leak was not completely prevented, suggesting that OA-induced increases in protein permeability occurred independently of prostanoid or leukotriene action. These data indicate that OA-induced edema formation was greatly amplified by arachidonic acid mediated pressure increases.

Animals↗
PubMed1986

Pulmonary microvascular responses to arachidonic acid in isolated perfused guinea pig lung.

We examined the effects of arachidonic acid (AA) on pulmonary hemodynamics and fluid balance in Ringer- and blood-perfused guinea pig lungs during constant-flow conditions. Mean pulmonary arterial (Ppa), venous (Pv), and capillary pressures (Pcap, estimated by the double-occlusion method) were measured, and arterial (Ra) and venous resistances (Rv) were calculated. Bolus AA injection (500 micrograms) caused transient increases (peak response 1 min post-AA) in Ppa, Pcap, and Rv without affecting Ra in both Ringer- and blood-perfused lungs. The response was sustained in blood-perfused lungs. AA had no effect on the capillary filtration coefficient in either Ringer- or blood-perfused lungs. AA stimulated the release of thromboxane B2 and 6-ketoprostaglandin F1 alpha in both Ringer- and blood-perfused lungs, but the responses were sustained only in the blood-perfused lungs. Meclofenamate (1.5 X 10(-4) M), a cyclooxygenase inhibitor, abolished the AA-induced pulmonary hemodynamic responses in both Ringer- and blood-perfused lungs, whereas U-60257 (10 microM), a lipoxygenase inhibitor, attenuated the response only in the blood-perfused lungs. In conclusion, AA does not alter pulmonary vascular permeability to water in either Ringer- or blood-perfused lungs. AA mediates pulmonary venoconstriction and thus contributes to the rise in Pcap. The venoconstriction results from the generation of cyclooxygenase-derived metabolites from lung parenchymal cells and blood-formed elements. Lipoxygenase metabolites may also contribute to the vasoconstriction in the blood-perfused lungs.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Hyperthermia-induced pulmonary edema.

The effects of temperature (37-45 degrees C) on pulmonary edema formation and transendothelial albumin clearance were investigated using isolated perfused guinea pig lungs and bovine pulmonary arterial endothelial cells grown to confluency on a gelatinized membrane. Perfusion of isolated lungs with Ringer-albumin solution at 37 or 41 degrees C for 90 min produced no change in lung wet-to-dry weight ratios (W/D) or in pulmonary capillary pressure (measured by the double-occlusion method). When perfused at 43 degrees C, lung wet weight increased 0.8 +/- 0.4 g over base line (final W/D = 7.43 +/- 0.7) within 90 min. Perfusion at 45 degrees C increased lung weight by 2.7 +/- 0.9 g over base line (final W/D 11.8 +/- 2.3 vs. control value of 5.2 +/- 0.23 at 37 degrees C perfusion) within 60 min. The changes in pulmonary capillary pressure were small (from a base-line value of 4.3 +/- 0.8 to 4.9 +/- 0.4 at 43 degrees C and from a base-line value of 4.9 +/- 0.8 to 5.9 +/- 0.6 at 45 degrees C). The clearance of 125I-albumin (microliter/min) across the endothelial monolayer system increased threefold (from 0.295 +/- 0.035 to 1.048 +/- 0.107) at 45 degrees C, an effect comparable to positive controls of trypsin (from 0.272 +/- 0.046 to 1.595 +/- 0.138) or oleic acid (from 0.278 +/- 0.043 to 0.672 +/- 0.26). An increase in temperature from 37 to 45 degrees C had no effect on the permeability of the gelatinized membrane alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1986

Role of histamine in acute oleic acid-induced lung injury.

The action of histamine in oleic acid (OA)-induced injury was investigated using the isolated guinea pig lung perfused with blood-free media. OA infusion caused a significant increase in pulmonary arterial pressure, airway inspiratory pressure, lung weight, and protein flux across the alveolar-capillary barrier. These changes were dose dependent and caused injury regardless of the chemical form of OA (salt or free acid). Triolein (a neutral fat) infused at comparable emulsion particle size did not alter lung weight or bronchoalveolar lavage protein concentration in the perfused lung, suggesting that mechanical obstruction or emboli per se is not responsible for initiating early events in OA-induced injury. Infusion of OA caused a significant early histamine release into the venous effluent in the presence of aminoguanidine, a histamine catabolism inhibitor. Pretreatment with H1-receptor antagonists significantly attenuated OA-induced increase in lung weight and protein leak. These data support the link between OA-induced mast cell degranulation, histamine release, and OA-induced edema.

Animals↗
PubMed1986

Mechanism of peptidoleukotriene-induced increases in pulmonary transvascular fluid filtration.

We examined the effects of leukotrienes C4 (LTC4) and D4 (LTD4) (1 microgram) on the pulmonary vascular filtration coefficient, a measure of vessel wall conductivity to water, and the alterations in pulmonary vascular resistance (PVR) in isolated-perfused guinea pig lungs. We also assessed whether LTC4 and LTD4 increased the permeability to albumin in cultured monolayers of pulmonary artery endothelial cells. In Ringer-perfused and blood-perfused lungs, LTC4 resulted in increases in pulmonary arterial pressure (Ppa) and the pulmonary capillary pressure (Pcap) measured as the equilibration pressure after simultaneous pulmonary arterial and venous occlusions. Pulmonary venous resistance (Rv) increased to a greater extent than arterial resistance (Ra) in both Ringer-perfused and blood-perused lungs challenged with LTC4. The greater increase in PVR in blood-perfused lungs corresponded with a greater elevation of lung effluent thromboxane B2 (TxB2) concentration. The LTC4-stimulated increase in PVR was prevented by pretreatment with meclofenamate (10(-4) M). LTD4 also induced rapid increases in Ppa and Pcap in both Ringer-perfused and blood-perfused lungs; however, Ppa decreased before stabilizing at a pressure higher than base line. The increases in Rv with LTD4 were greater than Ra. The LTD4-stimulated increases in Ra and Rv also paralleled the elevation in TxB2 concentration. As with LTC4, the increases in Ppa, Pcap, PVR, and TxB2 concentration were greater in blood-perfused than in Ringer-perfused lungs. Pretreatment with meclofenamate reduced the magnitude of the initial increase in Ppa, but did not prevent the response.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Platelet-activating factor increases lung vascular permeability to protein.

We studied the effects of platelet-activating factor (PAF) on pulmonary hemodynamics and microvascular permeability in unanesthetized sheep prepared with lung-lymph fistulas. Since cyclooxygenase metabolites have been implicated in mediating these responses, we also examined the role of the cyclooxygenase pathway. PAF infusion (4 micrograms X kg-1 X h-1 for 3 h) produced a rapid, transient rise in pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), plasma thromboxane B2 concentration (TxB2), and pulmonary lymph flow (Qlym). The lymph-to-plasma protein concentration ratio (L/P) did not change from base line. Pretreatment with the cyclooxygenase inhibitor, sodium meclofenamate, prevented the generation of TxB2 and the hemodynamic changes but did not prevent the increase in Qlym. The estimated protein reflection coefficient decreased from a control value of 0.66 +/- 0.04 to 0.43 +/- 0.06 after PAF infusion. We also studied the effects of PAF on endothelial permeability in vitro by measuring the flux of 125I-albumin across cultured bovine pulmonary artery endothelial cells (EC) grown to confluency on a gelatinized micropore filter and mounted within a modified Boyden chemotaxis chamber. PAF (10(-8) to 10(-4) M) had no direct effect on EC albumin permeability, suggesting that the increase in permeability in sheep was not the direct lytic effect of PAF. In conclusion, PAF produces pulmonary vasoconstriction mediated by cyclooxygenase metabolites. PAF also increases pulmonary vascular permeability to protein that is independent of cyclooxygenase products and is not the result of a direct effect of PAF on the endothelium.

Animals↗
PubMed1986

Histamine action in paraquat-induced lung injury.

We investigated direct histamine release and its effects in edema formation following paraquat (PQ) injury in a blood-free, perfused rat lung preparation. Under control conditions, perfusate histamine levels from the lung averaged 9.5 +/- 1.4 ng/ml. Lungs perfused with paraquat (1 mM) showed marked increases in pulmonary arterial pressure (133%), airway pressure (74%), alveolarcapillary protein flux (200%), and lung weight (38%). Prior to any detectable lung weight or pressure changes, PQ caused a 300% increase in perfusate histamine. Diphenhydramine (1.0 X 10(-5) M), a specific H1-histamine receptor antagonist, blocked the increased protein flux that followed PQ administration and significantly delayed edema. Furthermore, diphenhydramine attenuated the rise in PGF2 alpha. Conversely, histamine release was partially attenuated by the cyclooxygenase inhibitor, ibuprofen, at 2.4 X 10(-5) M, the same level that we had previously shown to block an early rise in PGF2 alpha and the onset of edema after PQ. These data show that the increased alveolar-capillary protein flux that occurred with PQ injury was attenuated by an H1-receptor antagonist and suggest that histamine is a primary mediator in paraquat-induced injury and that histamine subsequently stimulates prostaglandin release.

Animals↗
PubMed1986

Integrated substrate utilization by perinatal lung.

The aims of this study were to examine the pattern and relative utilization of exogenously supplied substrates by the perinatal rat lung and to study their functional relationship at a key period of lung maturation (3 days before birth until one day after birth). Maximal incorporation of 14C-labeled substrates (glucose, lactate, glycerol, and beta-hydroxybutyrate) from the media into lung lipids occurred one day before birth and corresponded to maximal incorporation of 14C-choline into disaturated phosphatidylcholine (DSPC) (63 n moles X hr-1 X g-1), and to maximal increase in tissue DSPC concentration. Whereas, 14C-palmitate utilization for phospholipid synthesis was refractory to changes in DSPC synthesis. Lactate was shown to be a key substrate in fetal lung. When lactate and glucose were supplied at physiological concentrations, lactate: 1) provided 60% of the carbons for de novo fatty acid synthesis compared to only 9% from glucose, 2) produced 5 times more CO2 than glucose (23.9 vs. 4.9 u moles CO2 X hr-1 X g-1) and 3) altered the major fate of glucose incorporated into lung lipid from the fatty acid moiety to the glycerol moiety. Glycerol and palmitate were relatively unimportant energy fuels in the perinatal lung.

3-Hydroxybutyric Acid↗
PubMed1985

Effects of exogeneous leukotrienes on the pulmonary circulation.

This review illustrates the diverse effects of LTB4 and the peptidoleukotrienes (LTC4 and LTD4) on pulmonary hemodynamics and lung fluid balance. LTB4 had a lesser effect on pulmonary hemodynamics compared to the peptidoleukotrienes. The small increases in pulmonary artery pressure and pulmonary vascular resistance were the result of precapillary constriction associated with increases in effluent thromboxane concentration. On the other hand, peptidoleukotrienes resulted in marked increases in thromboxane concentrations, pulmonary artery pressure, pulmonary capillary pressure, and pulmonary vascular resistance. Increased thromboxane generation probably contributes to the noted hemodynamic alterations following peptidoleukotriene administration. Moreover, in the isolated perfused guinea pig lung, there was also a direct effect of LTD4 on pulmonary hemodynamics which was not blocked by cyclooxygenase inhibition. This latter, resistant vasoconstrictor response is analogous to the LTD4-mediated pulmonary vasoconstriction in some species which is not dependent on cyclooxygenase (Kadowitz et al., 1984). The primary site of vasoconstriction with LTD4 was in the postcapillary vessels in contrast to the LTB4 response. LTB4 increased lung vascular permeability directly (perhaps by a direct endothelial contracture) and may also contribute to increase in permeability via neutrophil activation. However, the neutrophil dependent permeability-increasing response could not be demonstrated in the isolated perfused guinea pig lung; thus, this response requires further study. In contrast, LTC4 and LTD4 had no effect on lung vascular permeability in the awake sheep, isolated perfused guinea pig lung, and the cultured bovine pulmonary endothelial monolayer system.

Animals↗
PubMedDate not supplied

Pathophysiologic changes induced by phospholipase A2 in the isolated, perfused guinea pig lung.

Pathophysiologic changes induced by phospholipase A2 (PLA2), a lipolytic enzyme implicated in a variety of pulmonary diseases, were examined in the isolated, perfused guinea pig lung. Thirty microliters of vehicle (saline) or 30 units of PLA2 suspended in saline was given as a bolus injection into either the trachea or pulmonary artery, and the lungs were examined by combined light and transmission electron microscopy at 1, 10, and 30 min following administration. Pulmonary morphologic and physiologic changes were observed only in animals that received PLA2 via the trachea. Initially, morphologic evidence of airway constriction was accompanied by a significant increase in intratracheal pressure. No morphologic change was observed in alveolar parenchymal cell populations at this time. Later there was marked swelling of airway epithelial cells accompanied by pronounced blebbing of the apical cytoplasm with a subsequent decrease in airway lumen size. Interalveolar septa were multifocally thickened by edema and alveolar spaces contained sparse fibrogranular material 10 min after intratracheal PLA2. Significant increases in lung weight were observed at this time. Morphologic features of vasoconstriction, characterized by undulating and convoluted endothelium with prominent cytoplasmic processes resulting in decreased luminal size were observed in small caliber vessels and occurred in conjunction with significant increases in pulmonary arterial pressure. There was pronounced injury to type I alveolar epithelium, including marked cell swelling and fragmentation, accompanied by lesser injury in type II alveolar epithelium. This study demonstrates that the airway epithelium was the initial cell population having morphologic change following intratracheal PLA2, and that the airway epithelium and type I alveolar epithelium were the cell populations most severely affected following intratracheal PLA2. Results further suggest that normal circulating levels of blood-formed elements are not essential for the development of PLA2-induced morphologic change in the isolated, perfused guinea pig lung.

Animals↗