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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 657-662, (2002)
© 2002 American Thoracic Society

Original Article

Platelet-Activating Factor–induced Pulmonary Edema Is Partly Mediated by Prostaglandin E2, E-Prostanoid 3-Receptors, and Potassium Channels

Rolf Göggel, Sven Hoffman, Rolf Nüsing, Suh Narumiya and Stefan Uhlig

Division of Pulmonary Pharmacology, Research Center Borstel, Borstel; Department of Pediatrics, Philipps-University of Marburg, Marburg, Germany; and Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan

Correspondence and requests for reprints should be addressed to Stefan Uhlig, Ph.D., Division of Pulmonary Pharmacology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. E-mail: suhlig{at}fz-borstel.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Platelet-activating factor (PAF) is an important endogenous mediator of pulmonary edema in many models of acute lung injury. PAF triggers edema formation by simultaneous activation of two independent pathways; one is mediated by a cyclooxygenase metabolite, and the other is blocked by quinine. We examined the hypothesis that the cyclooxygenase-dependent part of PAF-induced edema is mediated by prostaglandin E2 (PGE2). In isolated rat lungs, PAF administration stimulated release of PGE2 into the venous effluate and increased lung weight as a measure of edema formation. Perfusion with a neutralizing PGE2 antibody attenuated the PAF-induced edema formation. In vivo, E-prostanoid 3-receptor–deficient mice showed less pulmonary Evans blue extravasation in response to PAF injection than did mice deficient in EP1, EP2, or EP4 receptors. Perfusion of rat lungs with PGE2 caused pulmonary edema, which was largely prevented by inhibition of voltage-gated potassium channels (25 nM ß-dendrotoxin), but not by blocking calcium-dependent potassium currents (100 µM paxilline). In line with its effects on PGE2-induced edema formation, ß-dendrotoxin attenuated PAF-induced edema partly if given alone, and completely in combination with quinine. Our findings suggest that PAF-triggered edema is partly mediated by the release of PGE2, activation of EP3 receptors, and activation of voltage-gated potassium channels.

Key Words: adult respiratory distress syndrome • platelet-activating factor • prostaglandin E2 • pulmonary edema


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pulmonary edema is one of the hallmarks of acute lung injury. In experimental models of acute lung injury, platelet-activating factor (PAF) was identified as an important mediator of pulmonary edema (1, 2). For instance, treatment with PAF antagonists prevents pulmonary edema induced by endotoxin (3, 4), interleukin-2 (5), or intestinal ischemia–reperfusion (6), and PAF receptor-deficient mice show reduced edema formation in acid-induced lung injury (7). In addition to edema, PAF also causes contraction of airways and vessels in the lungs by the release of thromboxane and leukotrienes (8–10).

Although it is clear that PAF causes pulmonary edema by increasing vascular permeability (11, 12), the mediators and molecular mechanisms ultimately responsible have not been defined. We have shown that PAF induces edema by simultaneous activation of two independent pathways: one is sensitive to quinolines, whereas the other is blocked by cyclooxygenase inhibition (4). The cyclooxygenase metabolite that mediates PAF-induced edema is unknown. Thromboxane and prostacyclin, two cyclooxygenase metabolites that are known to be produced in response to PAF, do not increase vascular permeability and lung weight in isolated lungs (4, 13, 14). In addition, a thromboxane receptor antagonist had no effect on PAF-induced edema (4). Prostaglandin E2 (PGE2) is a mediator that has long been suspected of playing a critical role in many models of edema formation (15, 16). However, the lack of selective tools to interfere with PGE2 synthesis or E-prostanoid (EP)-receptors has complicated a detailed investigation of this hypothesis for a long time. Recently, a neutralizing PGE2 antibody was described that prevented carrageenan-induced paw edema in vivo (17), providing the first direct evidence for PGE2 as a mediator of edema formation.

It was the aim of this study to examine whether PAF-induced pulmonary edema formation is mediated by PGE2. This hypothesis was tested by using neutralizing PGE2 antibodies and other pharmacological tools in isolated perfused rat lungs, a model that permits monitoring the time course of edema formation (weight gain) under conditions in which hydrostatic edema is largely excluded by perfusion with constant pressure rather than constant flow (14, 18). In addition, we investigated the mechanisms by which PGE2 might elevate vascular permeability, in particular the EP receptor subtype involved and the role of potassium channels.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Material
Lungs were taken from 8-week-old female Wistar rats (220 ± 20 g) obtained from Harlan Winkelman (Borchen, Germany). The generation and maintenance of EP receptor knockout mice were reported previously (19). These mice and wild-type control mice have a genetic background similar to that of C57BL/6 mice. All experiments were performed in 10- to 12-week-old male mice.

The neutralizing PGE2 antibody (2B5) was kindly provided by Pharmacia (St. Louis, MO); the anti-lipid A antibody was provided by L. Brade (Borstel, Germany); all other agents were from Sigma (Deisenhofen, Germany).

Isolated Perfused Rat Lung Preparation
Rat lungs were prepared and perfused essentially as described (18, 20). Briefly, lungs were perfused at constant hydrostatic pressure (12 cm H2O) through the pulmonary artery, which resulted in a flow rate of approximately 30 ml/minute. As a perfusion medium we used Krebs–Henseleit buffer (37°C) that contained 1% autologous rat serum, 0.1% glucose, and 0.3% HEPES. The lungs were ventilated by negative pressure with 80 breaths/minute and a tidal volume of approximately 2 ml. A weight transducer was integrated into the chamber lid and allowed continuous assessment of lung weight (14). Vascular and airway conductance were measured by standard methods as described (21).

Measurement of PGE2
Samples taken from the perfusate were immediately stored at -80°C. PGE2 was assessed by enzyme immunoassay (Cayman, Ann Arbor, MI).

Experimental Design of Perfused Lung Studies
PAF was injected as a bolus of 5 nmol directly into the perfusate after 30 minutes of perfusion. All other agents were added to the buffer reservoir. PGE2 was given after 30 minutes of perfusion, all other substances 10 minutes before PAF or PGE2 administration; within these 10 minutes none of these agents caused any detectable changes in lung weight, vascular conductance, or airway conductance. Acetylsalicylic acid (ASA) was dissolved in bicarbonate solution. ß-Dendrotoxin (ß-Dtx), lidocaine, and quinine were prepared in H2O or perfusate buffer. Stock solutions of PAF, PGE2, misoprostol, sulprostone, butaprost, and RA-112 (SC-51322) were made up in absolute ethanol. Ethanol alone did not affect the responses to PAF (data not shown). In three separate lungs that were perfused for 40 minutes with ASA, the PGE2 antibody, and quinine together no effect on weight gain or any other parameter was noted (data not shown).

Experimental Design of In Vivo Studies
Edema was assessed by measuring the pulmonary extravasation of Evans blue (4). Evans blue (20 mg/kg) and PAF (4 µg/kg) (22) were injected into the tail vein. Seven minutes after the injection of Evans blue, the animals were killed. After the animals were killed, their lungs were perfused free of blood with ice-cold phosphate-buffered saline before the lung tissue was used to determine the Evans blue content (23).

Statistical Analysis
In vivo, we analyzed whether EP3-receptor–deficient mice had reduced Evans blue extravasation compared with the other EP-receptor–deficient mice; Tables 1–3 indicate whether the various treatments reduced the final weight gain induced by PAF (one-sided unpaired t test). In the case of heteroscedasticity, the Welch correction was applied (Prism 3; GraphPad, San Diego, CA). In all cases, the {alpha} error was corrected for multiple comparisons by applying the Finner step-down procedure (24). The concentration–response curves shown in Figure 3 were analyzed by a four-parameter logistic equation (Prism 3).


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  		TABLE 1. Role of prostaglandin e2 in platelet-activating factor–induced edema formation

 

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  		TABLE 3. Role of potassium channels in platelet-activating factor–induced edema formation

 

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  		TABLE 2. Prostaglandin e2–induced edema formation

 


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  		Figure 3. Concentration–response curves for the increase in lung weight 30 minutes after injection of PGE2 or misoprostol. PGE2 or misoprostol was given 30 minutes after the perfusion was started. Closed circles = PGE2 (n = 3–6); open circles = misoprostol (n = 3–6). Data represent means ± SEM.

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Isolated rat lungs were perfused for 30 minutes under control conditions before 5 nmol of PAF was injected into the pulmonary artery. This resulted in a rapid and brief increase in PGE2 concentrations in the perfusate (Figure 1) and a sustained elevation in lung weight (Figure 2) . Treatment with a neutralizing PGE2 antiserum attenuated the weight gain to the same extent as ASA (Table 1). Whereas the effects of antiserum and ASA were not additive, the PGE antiserum augmented the anti-edematogenous effect of quinine from 64 to 86% (Table 1 and Figure 2). If the PGE2 antiserum was inactivated by heating or if an antibody directed against another lipid (lipid A [25]) was used, there was no reduction in PAF-induced weight gain (data not shown). Specificity of the PGE2 antiserum is further indicated by the fact that it did not affect the PAF-induced alterations in airway and vascular conductance (Table 1), which are known to be mediated by thromboxane and leukotrienes (10).



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  		Figure 1. Effect of PAF on PGE2 release into the perfusate of isolated lungs. PAF was given as a bolus injection of 5 nmol 30 minutes after the perfusion was started. Closed circles = PAF (n = 5); open circles = control (n = 5). Data represent means ± SD.

 


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  		Figure 2. Effect of anti-PGE2 antibody ± quinine on PAF-induced weight gain in perfused rat lungs. PAF was given as a bolus injection of 5 nmol 30 minutes after the perfusion was started. The anti-PGE2 antibody was given 30 minutes and 10 minutes before injection of PAF; quinine (330 µM) was given 10 minutes before PAF. Closed circles = PAF (n = 45); closed squares = anti-PGE2 antibody plus PAF (n = 5); closed triangles = anti-PGE2 antibody/quinine plus PAF (n = 5); closed diamonds = quinine plus PAF (n = 8); open circles = control (n = 12). Data represent means ± SEM. For statistics, see Table 1.

 
These findings suggested that PGE2 is a mediator of PAF-induced edema formation. Therefore, we investigated whether PGE2 is able to induce edema by itself. PGE2 as well as the stable PGE1 analog misoprostol (an EP2, EP3, and EP4 agonist) increased lung weight in a concentration-dependent manner (Figure 3) , with a time course that was comparable to that observed after injection of PAF (data not shown). Misoprostol was about 10 times more potent (EC50, 3.8 ± 2.4 nM) than PGE2 (EC50, 34 ± 1.5 nM). To show that PGE2 increased vascular permeability, the capillary filtration coefficient was measured, which was significantly increased from 0.16 ± 0.07 ml·minute–1·100 g–1·cm H2O–1 before addition of 100 nM PGE2 to 0.40 ± 0.21 ml·minute–1·100 g–1·cm H2O–1 thereafter (n = 6, p = 0.007).

Next, we set out to identify the EP-receptor subtype that mediates PGE2-induced edema formation. The specific EP1 antagonist RA-112 (1 µM) was without any effect on edema triggered by PAF (Table 1). Unfortunately, no specific inhibitors for EP2 and EP3-receptors are currently available. We therefore investigated the effect of the EP2-receptor agonist butaprost and of the EP1/3-receptor agonist sulprostone on weight gain in perfused lungs. At 1 µM butaprost elicited only low-level weight gain (0.15 ± 0.05 g) compared with sulprostone (0.45 ± 0.05 g) (Figure 4) .



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  		Figure 4. Effect of butaprost and sulprostone on weight gain in perfused rat lungs. Both agonists (1 µM) were given 30 minutes after the perfusion was started. Closed circles = sulprostone (n = 3); closed squares = butaprost (n = 4); open circles = control (n = 12). Data represent means ± SEM. All three curves are significantly (p < 0.05) different from each other according to repeated measurement ANOVA from 30 to 60 minutes and orthogonal polynomials (JMP 4.05; SAS Institute, Cary, NC).

 
These data suggested that PGE2 mediates PAF-induced edema formation by activation of EP3-receptors. To further examine this hypothesis, EP-receptor–deficient mice were treated with PAF and edema formation was assessed by measuring Evans blue extravasation. Mice deficient in the EP3-receptor experienced significantly less pulmonary Evans blue extravasation than mice deficient in the EP1, EP2, or EP4-receptor (Figure 5) .



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  		Figure 5. PAF-induced edema formation in EP-receptor–deficient mice in vivo. Pulmonary protein extravasation was measured as the amount of Evans blue (EB) sequestered in lung tissue 7 minutes after PAF treatment (4 µg/kg). Four different mouse strains were used, that is, mice deficient in EP1 (EP1 KO, n = 3), EP2 (EP2 KO, n = 3), EP3 (EP3 KO, n = 5), and EP4-receptors (EP4 KO, n = 4). Data represent means ± SEM. The asterisk (*) indicates a smaller EB-seqnestration than in any of the other groups (p < 0.05). Please note the logarithmic scale of the ordinate.

 
Next we investigated the hypothesis that potassium channels contribute to PGE2-induced edema formation. Pretreatment with ß-Dtx, a specific inhibitor of voltage-dependent potassium channels, effectively reduced PGE2-induced edema formation (Table 2). The local anesthetic lidocaine—another substance modulating potassium currents—also reduced PGE2-induced edema formation (Table 2), but to a lesser extent than ß-Dtx. In contrast, paxilline, a specific inhibitor of calcium-activated potassium channels, had no effect on PGE2-induced edema formation (Table 2).

Finally, we investigated the effect of ß-Dtx, lidocaine, paxilline, and glibenclamide (an inhibitor of KATP channels), on PAF-induced edema formation. In these experiments, PAF-induced weight gain was markedly reduced by ß-Dtx (Figure 6) and lidocaine, but not by paxilline or glibenclamide (Table 3). The efficacy of ß-Dtx on both PGE2- and PAF-induced edema further supports our hypothesis that PGE2 contributes to PAF-induced edema formation. However, as repeatedly noted, release of PGE2 is only one mechanism by which PAF triggers edema, whereas the other mechanism is blocked by quinine. In line with this, PAF-induced edema was completely prevented if lungs were simultaneously treated with ß-Dtx and quinine (Figure 6). A similar additive effect, although not as pronounced, was also noted if quinine was combined with lidocaine (Table 3).



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  		Figure 6. Effect of ß-dendrotoxin ± quinine on PAF-induced weight gain in perfused rat lungs. PAF was given as a bolus injection of 5 nmol 30 minutes after the perfusion was started. ß-Dendrotoxin (25 nM) and quinine (330 µM) were given 10 minutes before injection of PAF. Closed circles = PAF (n = 45); closed squares = ß-dendrotoxin plus PAF (n = 4); closed triangles = ß-dendrotoxin/quinine plus PAF (n = 4); open circles = control (n = 12). Data represent means ± SEM. For statistics, see Table 3.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
PAF is an important mediator of pulmonary dysfunction in acute lung injury, but the mechanisms of its action are only poorly defined. Here we show that PAF-triggered edema is partly mediated by the release of PGE2 and activation of EP3-receptors. In addition, we provide the first evidence that the edematogenous actions of PGE2 depend on activation of voltage-gated potassium channels. However, in line with previous studies (4), it also became clear that PGE2 cannot account for all of the PAF-triggered edema, and that a second, simultaneously operating pathway exists that is blocked by quinine. Although it seems likely that both pathways take place in pulmonary vascular endothelial cells, it is possible that PGE2 and the second, ill-defined mechanism act in different parts of the endothelial bed, as it was shown for thapsigargin and ischemia–reperfusion, which cause edema around larger arteries and pulmonary capillaries, respectively (26).

Our conclusion that PGE2 is a mediator of PAF-induced edema formation is supported by several independent observations: (1) PGE2 production was increased in PAF-treated lungs; (2) inhibition of PGE2 synthesis by blocking cyclooxygenase attenuated edema formation to the same extent as did (3) treatment with neutralizing PGE2 antibodies; (4) EP3-receptor–deficient mice experienced attenuated pulmonary edema; and (5) finally, PGE2 was able to induce edema by itself. Nevertheless, it should be noted that the levels of PGE2 detected in lung perfusate after PAF administration (Figure 1, 75 pg/ml {cong} 0.25 nM) were at least an order of magnitude lower than the levels of PGE2 that caused pulmonary edema (Figure 3, 10 nM). The most likely explanation for this discrepancy is the instability of PGE2 and the long-known fact that lungs actively and efficiently remove PGE2 from the circulation (27, 28). This explanation is supported by the fact that the stable PGE analog misoprostol, whose activity at the EP3-receptor is comparable to that of PGE2 (29), was approximately 10 times more potent than native PGE2. However, even though short-lived, it must be the circulating PGE2 that mediates edema formation in response to PAF, because otherwise the antibody could not have been effective. We cannot completely exclude the possibility that another cyclooxygenase metabolite is recognized by the PGE2 antiserum; however, the cross-reactivity of the monoclonal antibody 2B5 toward eicosanoids other than PGE1 is low, for example: PGE1, 12%; 6-keto-PGF1{alpha}, 0.4%; PGD2, 0.04%; PGF2{alpha}, 0.25%; and thromboxane, isoprostanes, and leukotrienes all below 0.01% (30). The lack of cross-reactivity of the antiserum with thromboxane is also demonstrated by the fact that the PAF-induced pressor responses, which are largely mediated by thromboxane (10), were not affected by the PGE2 antiserum (Table 1). In addition, the stable TP and IP receptor agonists U46619 and iloprost failed to increase vascular permeability in our rat model (4).

The actions of PGE2 are mediated by G protein–coupled receptors, designated EP (for E-prostanoid). Four different EP-receptors have been identified, named EP1 to EP4, and several splice variants of the EP3-receptor are known (31). Activation of these receptors leads to well-defined alterations in intracellular calcium and cAMP concentrations: cAMP is raised by EP2 and EP4, calcium by EP1 and EP3 receptors; in addition, activation of the EP3 receptor may decrease cAMP (32). A number of functions of PGE2 have been mapped to these different EP receptor subtypes, such as analgesia and regulation of blood pressure to EP1; ovulation, fertilization, and regulation of T cell responses to EP2; mediation of febrile responses to both endogenous and exogenous pyrogens and regulation of clot formation to EP3; and decreased inflammatory bone resorption, regulation of macrophage responses, and closure of the ductus arteriosus to EP4 (32–35).

Among these receptors, EP3 and EP4 appear to be the major subtypes in lung tissue (32). In line with this, we observed that EP3-receptor–deficient mice were protected against PAF-induced pulmonary edema. The reduced edema formation in EP3-deficient mice is also in agreement with the known consequences of EP3-receptor stimulation, because a decrease in intracellular cAMP together with an elevation in cytosolic calcium was identified as an important signaling mechanisms in pulmonary edema formation (36). The importance of the EP3-receptor for PAF-induced edema formation is also supported by the ability of EP-receptor agonists to induce edema in perfused rat lungs: The EP2/3/4-receptor agonist misoprostol and the EP1/3-receptor agonist sulprostone both caused edema, whereas the EP2-receptor agonist butaprost produced only a weak weight gain. There is accumulating evidence that EP3-receptors also play an important role in edema formation in other organs. Thus, EP3-receptor–deficient mice appear to be protected from paw edema in response to arachidonic acid (37). Armstrong and coworkers suggested that the PGE2-mediated potentiation of vascular permeability to bradykinin is mediated via EP3-receptors (38). Finally, a patient with pre-eclampsia experienced pulmonary edema while receiving a perfusion with sulprostone (39).

Both PGE2- and PAF-induced edema formation were reduced by pretreatment with snake toxins ß-dendrotoxin (Figure 5) and dendrotoxin I (data not shown). The dendrotoxins belong to a family of homologous basic polypeptides isolated from two species of the green mamba Dendroaspis angusticeps and D. viridis (40, 41). The closely related toxin I and toxin K were isolated from the black mamba D. polyepsis (41). Dendrotoxins selectively inhibit voltage-dependent K+ currents (Kv) as delayed rectifier (42, 43) or slowly and noninactivating K+ currents (44, 45). Besides Kv channels, the two other major classes of potassium channels are calcium-gated K+ channels (KCa) and inward-rectifying potassium channels directly gated by intracellular factors such as G proteins, nucleotides (among them ATP), or polyamines (46). In general, potassium channels are highly regulated and protein phosphorylation is often found to modulate the sensitivity of K+ channels to their primary signals, or is itself the activating signal (46). In our experiments, blockade of KCa channels with paxilline or of KATP channels with glibenclamide failed to affect PAF-induced edema formation. On the other hand, lidocaine, a rather unselective agent that inhibits Na+ and K+ channels (47), effectively reduced pulmonary edema. Interestingly, lidocaine was previously reported to reduce lung injury induced by hyperoxia or hydrochloric acid aspiration (48, 49).

How potassium channels become activated and how this may lead to edema formation, we can only speculate. It was reported that the mRNA of one channel out of this group, Kv1.1, is degraded by elevated cAMP levels (50). Therefore, lowered cAMP levels as observed after PAF stimulation (51), PGE2 stimulation (52), and activation of the EP3A-receptor (51) might lead to elevated Kv activity. However, at higher concentrations (in the micromolar range), PGE2 can also inhibit voltage-dependent potassium currents (53, 54), suggesting that a bell-shaped dose–response curve may exist. In fact, we (Figure 3) as well as Gyires and Knoll (paw edema [55]) observed that the extent of PGE2-induced edema formation was lower at higher concentrations. In endothelial cells, in contrast to many other cells, the hyperpolarization after activation of voltage-gated potassium channels will lead to activation of voltage-gated calcium channels (56), increasing cytosolic calcium concentrations. An important role for calcium is supported by the well-known role of calcium in permeability edema (36, 57) and by the reduction in PAF-induced edema if lungs are perfused with low extracellular calcium concentrations (R. Göggel and S. Uhlig, unpublished data). These hypothetical mechanisms need to be addressed in future studies.

The present study has identified novel mechanisms of PAF-induced permeability edema. We conclude that the cyclooxygenase-sensitive part of PAF-induced pulmonary edema is mediated by PGE2 and activation of the EP3-receptor. Our data further suggest that the action of PGE2 is mediated by voltage-gated potassium channels by an as yet unknown pathway that deserves further study.


   Acknowledgments
 
The authors thank Dr. Lore Brade for providing the anti-lipid A antibody and Stefanie Schnell for excellent technical assistance.


   FOOTNOTES
 
Supported by Deutsche Forschungsgemeinschaft grant SFB 367/A9 (S. U.).

Received in original form November 9, 2001; accepted in final form May 24, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Chang SW. Endotoxin-induced lung vascular injury: role of platelet activating factor, tumor necrosis factor and neutrophils. Clin Res 1992;40:528–536.[Medline]
  2. Montrucchio G, Alloatti G, Camussi G. Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev 2000;80:1669–1699.[Abstract/Free Full Text]
  3. Chang SW, Feddersen CO, Henson PM, Voelkel NF. Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. J Clin Invest 1987;79:1498–1509.[Medline]
  4. Falk S, Göggel R, Heydasch U, Brasch F, Müller K-M, Wendel A, Uhlig S. Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation. Am J Respir Crit Care Med 1999;160:1734–1742.[Abstract/Free Full Text]
  5. Rabinovici R, Sofronski MD, Renz JF, Hillegas LM, Esser KM, Vernick J, Feuerstein G. Platelet activating factor mediates interleukin-2-induced lung injury in the rat. J Clin Invest 1992;89:1669–1673.[Medline]
  6. Carter MB, Wilson MA, Wead WB, Garrison RN. Platelet-activating factor mediates pulmonary macromolecular leak following intestinal ischemia–reperfusion. J Surg Res 1996;60:403–408.[CrossRef][Medline]
  7. Nagase T, Ishii S, Kume K, Uozumi N, Izumi T, Ouchi Y, Shimizu T. Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice. J Clin Invest 1999;104:1071–1076.[Medline]
  8. Voelkel NF, Worthen S, Reeves JT, Henson PM, Murphy RC. Nonimmunological production of leukotrienes induced by platelet-activating factor. Science 1982;218:286–288.[Abstract/Free Full Text]
  9. Hamasaki Y, Mojarad M, Saga T, Tai HH, Said SI. Platelet-activating factor raises airway and vascular resistance and induces edema in lungs perfused with platelet-free solution. Am Rev Respir Dis 1984;129:742–748.[Medline]
  10. Uhlig S, Wollin L, Wendel A. Contributions of thromboxane and leukotrienes to platelet-activating factor-induced impairment of lung function in the rat. J Appl Physiol 1994;77:262–269.[Abstract/Free Full Text]
  11. Uhlig S, von Bethmann AN. Determination of vascular compliance, interstitial compliance and capillary filtration coefficient in isolated perfused rat lungs. J Pharmacol Toxicol Methods 1997;32:119–127.[CrossRef]
  12. Clavijo LC, Carter MB, Matheson PJ, Wilson MA, Wead WB, Garrison RN. PAF increases vascular permeability without increasing pulmonary arterial pressure in the rat. J Appl Physiol 2001;90:261–268.[Abstract/Free Full Text]
  13. Wakerlin GE, Benson GV, Pearl RG. A thromboxane analog increases pulmonary capillary pressure but not permeability in the perfused rabbit lung. Anesthesiology 1991;75:475–480.[Medline]
  14. Uhlig S, Heiny O. Measuring the weight of the isolated perfused rat lung during negative pressure ventilation. J Pharmacol Toxicol Methods 1995;33:147–152.[CrossRef][Medline]
  15. Armstrong RA, Matthews JS, Jones RL, Wilson NH. Characterisation of PGE2 receptors mediating increased vascular permeability in inflammation. Adv Prostaglandin Thromboxane Leukot Res 1991;21A:375–378.[Medline]
  16. Malik AB, Perlman MB, Cooper JA, Noonan T, Bizios R. Pulmonary microvascular effects of arachidonic acid metabolites and their role in lung vascular injury. Fed Proc 1985;44:36–42.[Medline]
  17. Portanova JP, Zhang Y, Anderson GD, Hauser SD, Masferrer JL, Seibert K, Gregory SA, Isakson PC. Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J Exp Med 1996;184:883–891.[Abstract/Free Full Text]
  18. Uhlig S. The isolated perfused lung. In: Uhlig S, Taylor AE, editors. Methods in pulmonary pharmacology. Basel: Birkhäuser; 1998. p. 29–55.
  19. Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T, Hizaki H, Tuboi K, Katsuyama M, Ichikawa A, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998;395:281–284.[CrossRef][Medline]
  20. Uhlig S, Wollin L. An improved setup for the isolated perfused rat lung. J Pharmacol Toxicol Methods 1994;31:85–94.[CrossRef][Medline]
  21. Uhlig S, von Bethmann AN, Featherstone RL, Wendel A. Pharmacological characterization of endothelin receptor responses in the isolated perfused rat lung. Am J Respir Crit Care Med 1995;152:1449–1460.[Abstract]
  22. Costa DL. Interpretation of new techniques used in determination of pulmonary functions in rodents. Fund Appl Toxicol 1985;5:423–434.[CrossRef][Medline]
  23. Evans TW, Chung KF, Rogers DF, Barnes PJ. Effect of platelet-activating factor on airway vascular permeability: possible mechanisms. J Appl Physiol 1987;63:479–484.[Abstract/Free Full Text]
  24. Finner H. Some new inequalities for the RAND distribution with application to the determination of optimum significance levels of multiple range tests. J Am Stat Assoc 1990;85:191–194.[CrossRef]
  25. Brade L, Holst O, Brade H. An artificial glycoconjugate containing the bisphosphorylated glucosamine disaccharide backbone of lipid A binds lipid A monoclonal antibodies. Infect Immun 1993;61:4514–4517.[Abstract/Free Full Text]
  26. Chetham PM, Babál P, Bridges JP, Moore TM, Stevens T. Segmental regulation of pulmonary vascular permeability by store-operated Ca2+ entry. Am J Physiol 1999;276:L41–L50.[Medline]
  27. Al Ubaidi F, Bakhle YS. Metabolism of vasoactive hormones in human isolated lung. Clin Sci 1980;58:45–51.[Medline]
  28. Bakhle YS, Pankhania JJ. Inhibitors of prostaglandin dehydrogenase (Ph CL 28A and Ph CK 61A) increase output of prostaglandins from rat isolated lung. Br J Pharmacol 1987;92:189–196.[Medline]
  29. Ushikubi F, Sugimoto Y, Ichikawa A, Narumiya S. Roles of prostanoids revealed from studies using mice lacking specific prostanoid receptors. Jpn J Pharmacol 2000;83:279–285.[CrossRef][Medline]
  30. Mnich SJ, Veenhuizen AW, Monahan JB, Sheehan KC, Lynch KR, Isakson PC, Portanova JP. Characterization of a monoclonal antibody that neutralizes the activity of prostaglandin E2. J Immunol 1995;155:4437–4444.[Abstract]
  31. Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001;108:25–30.[CrossRef][Medline]
  32. Sugimoto Y, Narumiya S, Ichikawa A. Distribution and function of prostanoid receptors: studies from knockout mice. Prog Lipid Res 2000;39:289–314.[CrossRef][Medline]
  33. Stock JL, Shinjo K, Burkhardt J, Roach M, Taniguchi K, Ishikawa T, Kim HS, Flannery PJ, Coffman TM, McNeish JD, et al. The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure. J Clin Invest 2001;107:325–331.[Medline]
  34. Nataraj C, Thomas DW, Tilley SL, Nguyen MT, Mannon R, Koller BH, Coffman TM. Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse. J Clin Invest 2001;108:1229–1235.[CrossRef][Medline]
  35. Fabre JE, Nguyen M, Athirakul K, Coggins K, McNeish JD, Austin S, Parise LK, FitzGerald GA, Coffman TM, Koller BH. Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. J Clin Invest 2001;107:603–610.[Medline]
  36. Moore TM, Chetham PM, Kelly JJ, Stevens T. Signal transduction and regulation of lung endothelial cell permeability: interaction between calcium and cAMP. Am J Physiol 1998;275:L203–L222.[Medline]
  37. Tilley SL, Coffman TM, Koller BH. Mixed responses: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest 2001;108:15–23.[CrossRef][Medline]
  38. Armstrong RA, Matthews JS, Jones RL, Wilson NH. Characterisation of PGE2 receptors mediating increased vascular permeability in inflammation. Adv Prostaglandin Thromboxane Leukot Res 1991;21A:375–378.[Medline]
  39. Stock A, Jones R, Chung T, Fung HY. Pulmonary edema in association with an intravenous infusion of sulprostone. Acta Obstet Gynecol Scand 1995;74:156–158.[Medline]
  40. Hall A, Stow J, Sorensen R, Dolly JO, Owen D. Blockade by dendrotoxin homologues of voltage-dependent K+ currents in cultured sensory neurones from neonatal rats. Br J Pharmacol 1994;113:959–967.[Medline]
  41. Harvey AL, Anderson AJ. Dendrotoxins: snake toxins that block potassium channels and facilitate neurotransmitter release. Pharmacol Ther 1985;31:33–55.[CrossRef][Medline]
  42. Benoit E, Dubois JM. Toxin I from the snake Dendroaspis polylepis polylepis: a highly specific blocker of one type of potassium channel in myelinated nerve fiber. Brain Res 1986;377:374–377.[CrossRef][Medline]
  43. Brau ME, Dreyer F, Jonas P, Repp H, Vogel WA. K+ channel in Xenopus nerve fibres selectively blocked by bee and snake toxins: binding and voltage-clamp experiments. J Physiol 1990;420:365–385.[Abstract/Free Full Text]
  44. Penner R, Petersen M, Pierau FK, Dreyer F. Dendrotoxin: a selective blocker of a non-inactivating potassium current in guinea-pig dorsal root ganglion neurones. Pflugers Arch 1986;407:365–369.[CrossRef][Medline]
  45. Stansfeld C, Feltz A. Dendrotoxin-sensitive K+ channels in dorsal root ganglion cells. Neurosci Lett 1988;93:49–55.[CrossRef][Medline]
  46. Miller C. An overview of the potassium channel family: review. Genome Biol. 2000;1:REVIEWS0004.
  47. Olschewski A, Hempelmann G, Vogel W, Safronov BV. Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord. Anesthesiology 1998;88:172–179.[CrossRef][Medline]
  48. Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N, Obara H. Intravenous lidocaine attenuates acute lung injury induced by hydrochloric acid aspiration in rabbits. Anesthesiology 1998;88:1300–1309.[CrossRef][Medline]
  49. Takao Y, Mikawa K, Nishina K, Maekawa N, Obara H. Lidocaine attenuates hyperoxic lung injury in rabbits. Acta Anaesthesiol Scand 1996;40:318–325.[Medline]
  50. Allen ML, Koh DS, Tempel BL. Cyclic AMP regulates potassium channel expression in C6 glioma by destabilizing Kv1.1 mRNA. Proc Natl Acad Sci USA 1998;95:7693–7698.[Abstract/Free Full Text]
  51. Kester M, Thomas CP, Wang J, Dunn MJ. Platelet-activating factor stimulates multiple signaling pathways in cultured rat mesangial cells. J Cell Physiol 1992;153:244–255.[CrossRef][Medline]
  52. Narumiya S. Prostanoid receptors: structure, function, and distribution. Ann NY Acad Sci 1994;744:126–138.[Medline]
  53. Ren J, Karpinski E, Benishin CG. Prostaglandin E2 contracts vascular smooth muscle and inhibits potassium currents in vascular smooth muscle cells of rat tail artery. J Pharmacol Exp Ther 1995;275:710–719.[Abstract/Free Full Text]
  54. Nicol GD, Vasko MR, Evans AR. Prostaglandins suppress an outward potassium current in embryonic rat sensory neurons. J Neurophysiol 1997;77:167–176.[Abstract/Free Full Text]
  55. Gyires K, Knoll J. Inflammation and writhing syndrome inducing effect of PGE1, PGE2 and the inhibition of these actions. Pol J Pharmacol Pharm 1975;27:257–264.[Medline]
  56. Daut J. The role of potassium channels in the regulation of coronary blood flow. In: Escande D, Standen N, editors. K+ channels in cardiovascular medicine. Paris: Springer-Verlag; 1993. p. 107.
  57. Stevens T, Garcia JG, Shasby DM, Bhattacharya J, Malik AB. Mechanisms regulating endothelial cell barrier function. Am J Physiol Lung Cell Mol Physiol 2000;279:L419–L422.[Abstract/Free Full Text]



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