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Abstract |
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Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control). Three hours later, the rats were anesthetized, the lungs were isolated, and pulmonary vasoreactivity was assessed with BK (0.3, 1.0, and 3.0 µg) and HPV (3% O2). Perfusion pressure was monitored as an index of vasoconstriction. To investigate what receptor-subtype is mediating BK responses, the BK1-receptor antagonist des-Arg9-[Leu8]-BK, the BK2-receptor antagonist HOE-140, or the thromboxane A2-receptor antagonist SQ 29548 (all at 1 µM) were added to the perfusate. BK-induced vasoconstriction was significantly increased in LPS lungs (1.4–5.2 mm Hg) compared with control (0.1–1.1 mm Hg). In LPS lungs, indomethacin 10 mg/kg significantly decreased BK vasoconstriction by 78% ± 9%, whereas 5 mg/kg did not. NS-398, 4 mg/kg, significantly attenuated BK vasoconstriction at 0.3 µg (71% ± 7%) and 1.0 µg (56% ± 12%), whereas 8 mg/kg attenuated 0.3 µg BK (57% ± 14%), compared with LPS lungs. HPV was increased in LPS lungs (21.5 ± 2 mm Hg) compared with control lungs (9.8 ± 0.6 mm Hg). Indomethacin 5 mg/kg increased HPV in LPS lungs; otherwise, HPV was not altered by COX inhibition. BK-induced vasoconstriction was prevented by BK2, but not BK1 or thromboxane A2-receptor antagonism. This study suggests that nonselective COX inhibition, and possibly inhibition of the inducible isoform COX-2, may attenuate sepsis-induced, receptor-mediated vasoconstriction in rats.
Implications: This study demonstrated that, in an isolated rat lung model, nonselective inhibition of the cyclooxygenase pathway, and possibly selective inhibition of the inducible cyclooxygenase-2 isoform, may attenuate sepsis-induced endothelial dysfunction.
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Introduction |
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Sepsis causes lung inflammation with an increase of cyclooxygenase (COX) products of the arachidonic acid metabolism and endothelial injury (1,2). The COX enzyme has two isoforms. The constitutive isoform, COX-1, has important physiologic functions, and its activation includes the release of prostacyclin, which is antithrombogenic and cytoprotective (1). COX-2 is induced by a number of cells by proinflammatory stimuli and may be the relevant target for antiinflammatory effects (1). Indomethacin inhibits both COX isoforms with limited or no degree of selectivity (2). In contrast, NS-398 is highly selective for COX-2, as shown by in vitro and in vivo studies (3,4).
Bradykinin (BK) is normally an endothelium and receptor-dependent vasodilator that uses the nitric oxide (NO)/cyclic guanosine monophosphate-pathway. However, previous results from our group have demonstrated that BK and acetylcholine (ACh) cause vasoconstriction after lipopolysaccharide (LPS)-induced sepsis in rat lungs (5). The vasoconstriction may occur because endothelial dysfunction decreases NO; however, endothelial injury may also allow increased stimulation of vascular smooth muscle receptors responsible for vasoconstriction. The selective inducible NO synthase (iNOS)-inhibitor L-N6-(1-iminoethyl)-lysine attenuated receptor-mediated ACh/BK-induced vasoconstriction, but not alterations to receptor-independent hypoxic pulmonary vasoconstriction (HPV) caused by LPS. These results suggest that selective iNOS inhibition has a protective role in the pulmonary circulation during sepsis (5). Other groups have shown, in renal and mesenteric vascular models, that indomethacin decreases BK-induced vasoconstrictions in control rats (6,7). COX products also have modulatory effects on the HPV response in rats (8); however, little is known about COX inhibition and its influence on the pulmonary vasculature during sepsis.
BK receptor-subtypes (BK1 or BK2) are responsible for both vasodilation and vasoconstriction, but their role depends on the animal model and vascular bed. In endothelial denuded veins, Marsault et al. (9) showed that vasoconstriction was mediated by activation of the BK2 receptor subtype. In contrast, Pruneau et al. (10) demonstrated in rabbit carotid arteries that vasoconstriction caused by BK was mediated by BK1 receptors after endothelial injury. Thromboxane A2 (TXA2) production has been shown to mediate vasoconstriction after BK (6), indicating that products of the arachidonic acid cascade may be involved in the BK signaling pathway.
We hypothesized that inhibition of the COX-1 and/or COX-2 enzymes may attenuate endothelial dysfunction caused by LPS. We used an isolated perfused septic rat lung model to determine the effect of the nonselective COX inhibitor indomethacin and the irreversible, highly selective COX-2 inhibitor NS-398 on receptor-mediated BK-induced vasoconstriction and receptor-independent HPV. In a second group of experiments, a BK1-antagonist (des-Arg9)-[Leu8]-BK), a BK2-antagonist (HOE-140), as well as a TXA2-antagonist (SQ 29548), was used to determine the receptor subtype mediating BK-induced vasoconstriction in sepsis.
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Methods |
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Experimental Groups
This study was approved by the University of Virginia animal research committee. Rats were allowed food and water ad libitum. We studied the following groups of male rats (250–350g, Harlan Sprague-Dawley) in the first set of experiments (all drugs were given intraperitoneally): Groups 1–5 were control groups (no LPS) and were given 4 h before lung isolation either 1) saline (n = 7), 2) nonselective COX-inhibitor indomethacin (5 or 10 mg/kg) (n = 7 and 9), or 3) selective COX-2 inhibitor NS-398 (4 or 8 mg/kg) (n = 9 and 7). Groups 6–10 received LPS (15 mg/kg) 3 h before lung isolation and either 4) saline (n = 10), 5) indomethacin (5 or 10 mg/kg) (n = 10 and 9), or 6) NS-398 (4 or 8 mg/kg) (n = 12 and 9) 1 h before LPS administration. In a second set of experiments, lungs were isolated 3 h after administration of LPS followed by the addition of receptor antagonists to the perfusate. Group 11 received the BK1-receptor-antagonist des-Arg9-[Leu8]-BK (1 µM) (n = 7); Group 12, the BK2-receptor antagonist HOE 140 (1 µM) (n = 8); and Group 13, the TXA2-receptor antagonist SQ 29548 (1 µM) (n = 7).
Isolated Rat Lung Preparation
Rats were anesthetized with 
-chloralose (50 mg/kg) and urethane (650 mg/kg) intraperitoneally. A 17-gauge cannula was inserted into the trachea via a tracheostomy, and the lungs were ventilated with warmed (35°C) and humidified 21% O2 and 5% CO2, balanced N2, by using a rodent ventilator (tidal volume = 1 mL/100g, frequency = 60 breaths/min). End-expiratory pressure was set at 1 mm Hg. After sternotomy, sections of the right and left anterior chest wall were excised to expose the heart and lungs. The rat was heparinized (100 U), then partially exsanguinated by needle aspiration (6–8 mL). A 13-gauge steel cannula, connected to the perfusion system, was inserted through the pulmonic valve into the main pulmonary artery via an incision in the right ventricle. The cannula was secured by a suture tied around the pulmonary artery and aorta which prevented systemic blood flow. A 3.5-mm outside diameter cannula was inserted through the apex of the left ventricle and secured with umbilical tape around the ventricles.
Perfusate consisted of the rats’ own blood (added to the perfusate after lung isolation) diluted with physiologic salt solution to a hematocrit of 9%–12% (total perfusate volume: 35 mL). Perfusate drained from the left ventricle to a glass reservoir and was heated to 38°C by a circumferential water jacket. Perfusate was returned to the pulmonary artery at constant flow (16 mL/min) by using a peristaltic pump (Masterflex, Barrington, IL). The isolated lung preparation remained in the thoracic cavity which lay supine on a heated plate. A warmed and humidified chamber was placed over the thoracic cavity to maintain thoracic temperature at 37°C. Reservoir pH was continuously monitored (Cole-Parmer Inst., Chicago, IL) and maintained at 7.35–7.45 by addition of HCl or NaOH as required.
Pulmonary artery pressure (Pa) was continuously monitored by using a pressure transducer (Abbott, Chicago, IL). Mean pulmonary venous pressure was set at 2 mm Hg by adjusting the height of the reservoir and held constant. Normoxic (21% O2) and hypoxic (3% O2) gas mixtures were administered through individual flowmeters. The inspired O2 concentration was monitored (Fraser-Harlake, Orchard Park, NY) near the tracheal tube.
Experimental Protocol
After tracheostomy, the rats were ventilated, and the exhaled air was collected in a plastic bag for 5 min. The exhaled NO concentration in the bag was measured with a chemiluminescence detector (280 NOA; Sievers, Boulder, CO). The lungs were isolated, and the perfusion rate was set at 16 mL/min. After a stabilization period of 10 min, two hypoxic responses (HPV) were elicited. The lungs were ventilated with a hypoxic mixture (3% O2, 5% CO2, 92% N2) for 10 min and then again with a normoxic mixture (21% O2, 5% CO2, 74% N2) for an equal time allowing return to baseline Pa after each vasoconstriction. The responses to BK (0.3, 1.0, 3.0 µg) injected into the inflow of the circuit were evaluated. Each dose was administered 5 min after Pa returned to the baseline level. To investigate the receptor subtypes involved in the vasoconstriction, des-Arg9-[Leu8]-BK (1 µM, BK1-receptor antagonist), HOE 140 (1 µM, BK2-receptor antagonist), or SQ 29548 (1 µM, TXA2 receptor antagonist) were added to the perfusate. After 10 min equilibration, BK was injected.
Solutions
LPS (Salmonella typhimurium), BK, and des-Arg9-[Leu8]-BK (all from Sigma Chemicals, St. Louis, MO) were prepared by dilution in NaCl 0.9% and stored at 4°C. SQ 29548 (Cayman Chemicals, Ann Arbor, MI) was dissolved in 95% ethanol and stored at -20°C. HOE-140 was supplied by Hoechst (Hoechst Marion Roussel, Bridgewater, NJ), dissolved in NaCl 0.9%, and stored at 4°C. Indomethacin (Sigma Chemicals) was dissolved in 100% ethanol and stored at 4°C. Methanesulfonamide (NS-398; Cayman Chemicals) was dissolved in dimethyl sulfoxide and stored at -20°C. Pilot studies indicated that vehicles had no significant effect on Pa.
Changes in Pa from HPV and BK were expressed as the peak Pa - baseline Pa. The various treatments and differences within the groups were compared with one way analysis of variance followed by Student-Newman-Keuls method for pairwise multiple comparison procedures. When the data were not normally distributed, data were compared with analysis of variance on ranks. A P < 0.05 was considered significant. Data were presented as mean ± SEM.
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Results |
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Pulmonary Artery Pressure
All rats survived 3 h of LPS and underwent successful lung isolation. The baseline perfusion pressure (Pa) after lung isolation was not significantly different between the LPS and control lungs (Table 1). In control and LPS lungs, indomethacin 5 or 10 mg/kg and NS-398 4 or 8 mg/kg did not alter the baseline Pa.
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Exhaled NO
In control lungs, exhaled NO levels were low (0.9 ± 0.6 parts per billion [ppb]) and not altered by either indomethacin 5 or 10 mg/kg (0.2 ± 0.2, 0.1 ± 0.1 ppb) or NS-398 4 or 8 mg/kg (0.1 ± 0.1, 0.3 ± 0.2 ppb). LPS significantly increased exhaled NO (Figure 1). Indomethacin 10 mg/kg, but not 5 mg/kg, significantly increased the amount of exhaled NO in the LPS lungs. NS-398 had no effect on exhaled NO in LPS lungs.
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HPV
The first HPV response was not significantly different from the second in each group; therefore, the second HPV response was used for all results. Indomethacin 5 and 10 mg/kg (12.0 ± 1.0 and 12.8 ± 3.5 mm Hg, respectively) or NS-398 4 and 8 mg/kg (9.1 ± 2.1 and 10.3 ± 0.9 mm Hg, respectively) did not alter HPV response in control lungs (9.8 ± 0.6 mm Hg). LPS increased the HPV response compared with control lungs (Figure 2). In LPS lungs, indomethacin 10 mg/kg and NS-398 (4 and 8 mg/kg) did not alter HPV responses. In contrast, indomethacin 5 mg/kg significantly increased HPV responses compared with untreated LPS lungs.
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Influence of COX-Inhibitors on Vasoconstriction Induced by BK
BK-induced vasoconstriction was concentration-dependent in LPS but not control lungs (Table 1). In control lungs, indomethacin (5 or 10 mg/kg) and NS-398 (4 or 8 mg/kg) did not alter vasoconstriction secondary to three doses of BK (0.3, 1.0, 3.0 µg). BK-induced vasoconstriction was significantly increased in LPS lungs compared with control lungs at all BK doses (Figure 3). Indomethacin 10 mg/kg significantly decreased BK-induced vasoconstriction to a level not different from control levels, whereas 5 mg/kg did not significantly alter BK-induced vasoconstriction compared with untreated LPS lungs. NS-398 4 mg/kg significantly decreased vasoconstriction induced by 0.3 and 1.0 µg BK in LPS lungs, but was not different from untreated LPS lungs at the largest dose of BK (3.0 µg). The larger concentration of NS-398 (8 mg/kg) significantly attenuated the vasoconstriction caused by 0.3 µg BK.
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Effect of Receptor Antagonists
BK-induced vasoconstriction was dose-dependent in all groups with the exception of the LPS + HOE-140 group. The BK1-receptor antagonist des-Arg9-[Leu8]-BK (1 µM) and TXA2-receptor antagonist SQ 29548 (1 µM) did not alter BK-induced vasoconstriction compared with untreated LPS lungs (Figure 4). In contrast, HOE-140 (1 µM) significantly attenuated the BK-induced vasoconstriction compared with LPS alone.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We used an isolated rat lung preparation to test the hypothesis that COX-1 and/or COX-2 inhibition may attenuate sepsis-induced endothelial dysfunction. Three hours after LPS-induced sepsis, BK caused pulmonary vasoconstriction, which is suggestive of endothelial injury. This vasoconstriction is mediated by the BK2-receptor-subtype and is dose-dependently attenuated by pretreatment with the nonselective COX inhibitor indomethacin. The selective COX-2 inhibitor NS-398 partially attenuated the vasoconstriction caused BK.
Exhaled NO was significantly increased three hours after LPS exposure, indicating initiation of an inflammatory process. In a rat model of sepsis, Stewart et al. (11) demonstrated that increased exhaled NO is an early marker of lung inflammation. The source of exhaled NO is mainly from alveolar macrophages and bronchial epithelium (12), which produces more NO during inflammation. In our study, indomethacin 10, but not 5, mg/kg increased exhaled NO in LPS rats. Interaction between the COX-and NO-pathways has previously been suggested, in that indomethacin enhanced the steady state level of iNOS mRNA and nitrite production in primary rat mesangial cell cultures stimulated with interleukin-1ß (13). While our results suggest that COX may be involved in the production of NO, our study also suggests that exhaled NO is not influenced by COX-2 inhibition.
In our study, the baseline Pa was not altered after three hours of LPS as measured in the isolated lung. This is consistent with a study by Voelkel et al. (14) that showed, in an isolated rat lung model, that the Pa was not altered two hours after administration of S enteriditis endotoxin. Our group has also demonstrated that the Pa is not altered after six hours in an LPS rat model (8). In contrast, other groups have demonstrated a marked increase in Pa shortly after an IV infusion of endotoxin in vivo in sheep (15), rabbit (16), or pig models (17). It is possible that either the time period was too short to detect any increase in Pa in our model or IV administration of endotoxin produces a more rapid alteration in the Pa. In this study, neither treatment with indomethacin nor NS-398 altered the Pa, as might be expected because LPS did not alter the Pa.
LPS increased the HPV response compared with control lungs. This is consistent with previous studies which have demonstrated that LPS administered six hours before evaluation increased HPV responses in an isolated rat lung model (8). Differences between the clinically observed decrease in HPV with sepsis and our results may reflect the absence of neuronal or humoral input or the constant cardiac output present in isolated lung experiments. The etiology of the increased HPV in isolated lungs after LPS is complex. It may partly be related to decreased endothelial-derived NO, but it more likely involves alterations to the vascular smooth muscle. In our previous study (5), inhibition of iNOS and endothelial NO synthase in LPS lungs attenuated the receptor-mediated BK and ACh-induced vasoconstriction, but did not attenuate the increase in HPV. In this study, pretreatment with indomethacin in the smaller concentration (5 mg/kg) increased HPV in LPS lungs. Similarly, Frank et al. (8) showed an increase of HPV in septic rat lungs after pretreatment with larger doses of indomethacin. It is possible that different doses of indomethacin increase HPV after LPS by preferentially blocking vasodilating COX products (i.e., prostacyclin) which are elevated during sepsis (18). Because these products are not elevated in the absence of LPS, it is not surprising that pretreatment with indomethacin had no effect on control HPV responses. Pretreatment with the selective COX-2 inhibitor NS-398 did not alter HPV responses compared with LPS alone, suggesting that COX-2 is not involved in the increased HPV response associated with LPS.
BK caused dose-dependent pulmonary vasoconstriction in LPS lungs. Briner et al. (19) also concluded that BK has potential for vasoconstriction in the presence of endothelial injury. Our previous study suggested that high levels of NO produced during LPS exposure were partially responsible for endothelial injury and the subsequent vasoconstriction observed with ACh and BK. Meyrick et al. (20) reported that LPS from Escherichia coli has direct toxic effects on the endothelium. Therefore, endothelial injury may increase the vasoconstriction caused by direct receptor stimulation at the level of the vascular smooth muscle.
Indomethacin 10 mg/kg attenuated the BK-induced vasoconstriction compared with untreated LPS lungs, suggesting that COX products are partially responsible for the endothelial dysfunction caused by sepsis. The smaller dose of indomethacin (5 mg/kg) had no effect, indicating that the attenuation of endothelial dysfunction is dependent on the dose of indomethacin. Our results are consistent with other studies, showing that nonselective inhibition of COX abolished BK-induced vasoconstriction in control mesenteric and renal vasculature preparations (6). The mechanisms by which COX inhibition provides endothelial protection is unclear, but they are not related to decreased iNOS, because indomethacin increased exhaled NO. COX-2 is present in vessels as early as two hours after LPS administration in rats, and the dose of NS-398 (4 mg/kg) that we used has been shown to effectively treat brain inflammation in a rat model (21). Other studies have shown that NS-398 (0.1–10 mg/kg, given orally) has no effect on rat platelet TXB2 production, suggesting that NS-398 does not inhibit COX-1 (1). In our study, NS-398 (4 mg/kg) significantly attenuated the response to the low doses of BK (0.3 and 1.0 µg), but was not different compared with LPS alone at the large dose of BK (3.0 µg). Similarly, NS-398 (8 mg/kg) decreased the vasoconstriction to BK 0.3 µg, but not the larger doses, suggesting that COX-2 attenuation is dependent on the BK dose. Importantly, these results suggest that COX-2 inhibition in addition to COX-1 inhibition attenuate sepsis-induced endothelial dysfunction.
The role of BK receptor-subtypes in mediating vasodilation and vasoconstriction is model-dependent. BK can activate two subtypes, BK1 and BK2. BK1 receptors are mainly present in traumatized tissues and may have a significant pathophysiological role in mediating acute inflammation (22). BK2 receptors are present in the nervous system and may be partly responsible for maintenance of physiological kinin actions. However, BK2 receptors also are involved in inflammation, as the BK2-antagonist HOE-140 attenuated the increase of vascular permeability in a rat model (23,24). Our results indicate that BK2 receptors are involved in mediating BK-induced vasoconstrictions in septic lungs. In contrast, BK1 receptors do not appear to be involved in BK-induced vasoconstriction. We have previously demonstrated that BK also mediates vasodilation via the NO/cyclic guanosine monophosphate pathway if the pulmonary vasculature is preconstricted (5). However, to avoid any interference with other vasoconstrictors, we did not preconstrict the pulmonary circulation in this study and, therefore, did not evaluate the vasodilation caused by BK.
SQ 29548 was used to determine the role of TXA2 on BK-induced vasoconstriction. BK receptors are coupled to second messengers (phospholipase A2, phospholipase C), and activation of phospholipase A2 results in the release of prostanoids, including the vasoconstrictor TXA2 (25). In our model, SQ 29548 did not alter the BK vasoconstriction in LPS lungs. The concentration for SQ 29548 (1 µM) we used was shown in pilot studies to completely abolish Pa increases induced by TXA2-analog U 46619 (25–100 ng/mL). Therefore, the concentration of SQ 29548 was sufficient to block TXA2 receptors. SQ 29548 has been shown to block BK-induced vasoconstriction in rabbit afferent arterioles as well as in rat mesenteric arteries (6,7). It is possible that TXA2 plays a different role in various vascular beds.
In conclusion, BK caused vasoconstriction in an isolated lung preparation three hours after LPS. The vasoconstriction was mediated by BK2, but not BK1 receptors and does not involve TXA2. Nonselective inhibition of the COX pathway attenuates the BK-induced vasoconstriction, whereas selective inhibition of the inducible COX-2 enzyme partially attenuates the vasoconstriction.
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Acknowledgments |
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We thank Hoechst AG for donating HOE-140.
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Footnotes |
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LGF is supported by Innovative Medizinische Forschung Münster, Germany (FI 6 2 98 01).
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References |
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