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,
Departamentos de
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Bioquímica e Imunologia, e
Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, and
Centro Universitário de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil;
Departmento de Biofísica, Escola Paulista de Medicina, São Paulo, São Paulo, Brazil; and
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Molecular Biology of Peptide Hormones Group, Department of Neuroscience, Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany
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Abstract |
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Introduction |
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The results of a number of recent studies indicate that the administration of bradykinin at relatively low doses attenuates ischemia and reperfusion (I/R)3 injury, especially in the heart (14, 15, 16, 17, 18). These protective effects appear to be secondary to the potent vasodilatory effects of bradykinin on ischemic and/or reperfused vessels. However, we have recently demonstrated that, in a model of intestinal I/R in rat, the treatment with HOE 140, a specific B2R antagonist, partially ameliorated lesions associated with reperfusion injury (19). These results were justified on the basis of the well-known proinflammatory actions of bradykinin (8), which include the expression of adhesion molecules, facilitation of leukocyte infiltration, and formation of interendothelial gaps and protein extravasation in postcapillary venules (2, 8, 20, 21, 22). The activation of B2Rs is also capable of inducing the expression of B1Rs (23), suggesting that novel B1R expression and activation could participate in the cascade of events leading to tissue injury and systemic inflammation after reperfusion of an ischemic vascular territory. The objective of the present work was to investigate the role of and interaction between B1 and B2 receptors in a model of intestinal I/R injury in mice. Initial experiments confirmed a role for bradykinin B2Rs during I/R injury by using HOE 140, a well-known antagonist at B2Rs. Then, a series of experiments was conducted in mice that were deficient in B1Rs (B1R-/-) and that were treated or not with the B2R antagonist.
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Materials and Methods |
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B1R-/- mice were generated as previously described (24). B1R-/- male C57BL/6 x sv129 mice (10–12 wk) and their wild-type littermate controls were housed under standard conditions and had free access to commercial chow and water. All procedures described in this study had prior approval from the local animal ethics committee.
Ischemia and reperfusion
Mice were anesthetized with urethane (140 mg/kg, i.p.), and laparotomy was performed. The superior mesenteric artery (SMA) was isolated, and ischemia was induced by totally occluding the SMA for 60 min. For measuring percentage of surviving mice, reperfusion was re-established, and mice were monitored for the indicated time periods. For the other parameters, reperfusion was allowed to occur for 30 min when mice were sacrificed. This time of reperfusion (30 min) was chosen based on the presence of significant tissue injury without unduly high mortality rates. Sham-operated animals were used as controls. HOE 140 or vehicle (PBS) was administrated (i.v.) 10 min before reperfusion.
Evaluation of changes in vascular permeability
The extravasation of Evans blue dye into the tissue was used as an index of increased vascular permeability, as previously described (25, 26). Evans blue (20 mg/kg) was administered i.v. (1 ml/kg) via a tail vein 2 min before reperfusion of the ischemic artery. Thirty minutes after reperfusion, a segment of the duodenum (
3 cm) was cut open and allowed to dry in a petri dish for 24 h at 37°C. The dry weight of the tissue was calculated, and Evans blue was extracted using 1 ml of formamide (24 h at room temperature). The amount of Evans blue in the tissue was obtained by comparing the extracted absorbance with that of a standard Evans blue curve read at 620 nm in an ELISA plate reader. Results are presented as micrograms of Evans blue of per 100 mg of tissue. The right ventricle was flushed with 10 ml of PBS to wash the intravascular Evans blue in the lungs. The left lung was then excised and used for Evans blue extraction. The right lung was used for the determination of myeloperoxidase (MPO) as described below.
MPO concentrations
The extent of neutrophil accumulation in the intestine and right lung tissue was measured by assaying MPO activity, as previously described (27, 28). Briefly, a portion of duodenum and the flushed right lungs of animals that had undergone reperfusion injury were removed and snap frozen in liquid nitrogen. Upon thawing and processing, the tissue was assayed for MPO activity by measuring the change in OD at 450 nm using tetramethylbenzidine. Results were expressed as the neutrophil index that denotes activity of MPO related with casein-elicited murine peritoneal neutrophils processed in the same way.
Measurement of hemoglobin concentrations
The determination of hemoglobin concentrations in tissue was used as an index of tissue hemorrhage. After washing the intestines to remove excess blood, a sample of 100 mg of duodenum was removed and homogenized in Drabkin’s color reagent according to instructions of the manufacturer (Analisa, Belo Horizonte, Brazil). The suspension was centrifuged for 15 min at 3000 x g and filtered using 0.2-µm filters. The resulting solution was read using an ELISA plate reader at 520 nm and compared against a standard curve of hemoglobin.
Measurement of cytokine/chemokine concentrations in serum, intestine, and lungs
The concentration of cytokines—TNF-
, IL-1
, IL-10, and IL-18—and chemokines—keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein-1 (MCP-1)—in samples was measured in serum and tissue of animals using commercially available Abs and according to the procedures supplied by the manufacturer (R&D Systems, Minneapolis, MN). Serum was obtained from coagulated blood (15 min at 37°C, then 30 min a 4°C) and stored at -20°C until further analysis. Serum samples were analyzed at a 1/3 dilution in PBS. One hundred milligrams of duodenum or lung of sham-operated and reperfused animals were homogenized in 1 ml of PBS (0.4 M NaCl and 10 mM NaPO4) containing anti-proteases (0.1 mM PMSF, 0.1 mM benzethonium chloride, 10 mM EDTA, and 20 KI aprotinin A) and 0.05% Tween 20. The samples were then centrifuged for 10 min at 3000 x g, and the supernatant was used immediately for ELISA at a 1/3 dilution in PBS.
Expression of B1R mRNA
The methodology used was similar to that previously described by Campos et al. (29). Samples of intestine (100 mg) were collected after I/R and frozen under liquid nitrogen. The samples were then homogenized, and the total RNA was extracted using the TRIzol reagent (Life Technologies, Grand Island, NY). One microgram of total RNA was reverse transcribed using oligo(dT) as primer (25 µg/ml), and 200 U of reverse transcriptase (Life Technologies), in 20 µl of PCR buffer containing the following: 0.5 mM dNTP, 10 mM DTT, 2.5 mM MgCl2, 50 mM KCl, and 20 mM Tris-HCl (pH 8.4). The samples were incubated for 50 min at 42°C, heated for 15 min at 70°C, and cooled in ice. After treatment with 2 U of RNase H (20 min, 37°C), cDNA amplification of a specific sequence of mouse B1R and -actin was performed by PCR using the following primers: sense, 5'-AACCGTTTCAACTGGCCC-3', and antisense, 5'-GACATAAATCAGTGGGTTC-3' for B1R; and sense, 5'-CGAGGCCCAGAGCAAGAGAG-3', and antisense, 5'-CCACTGCCGCATCCTCTTCCT-3', for mouse -actin. -actin cDNA was used for standardization of the amount of RNA. Five microliters of reverse-transcribed aliquots was mixed in a 20 mM Tris-HCl buffer (pH 8.4) containing the following: 1.5 mM MgCl2, 300 µM dNTP, 2 µg/ml each primer, and 50 U/ml Taq polymerase (Life Technologies), in a final volume of 100 µl. The cycling protocol used was the following: 4 min at 94°C; 36 cycles of 35 s at 94°C, 45 s at 60°C, and 45 s at 72°C; and finally, 7 min at 72°C. Aliquots of 25 µl were analyzed on a 20% TBE (Tris/borate/EDTA) polyacrylamide gel and stained by ethidium bromide. The size of products is 646 bp for B1R and 536 bp for -actin.
Drugs and reagents
The following drugs were obtained from Sigma-Aldrich (St. Louis, MO): urethane, Evans blue, hexadecyltrimethylammonium bromide, and 3,3,5,5-tetramethyl-benzidine. HOE 140 was a gift from Dr. K. Wirth (Hoechst, Frankfurt, Germany). HOE 140 was dissolved in PBS just before use and used at 1 mg/kg, a dose previously shown to effectively block B2Rs (19).
Statistical analysis
Results are shown as the mean ± SEM. Percent inhibition was calculated by subtracting the background levels of Evans blue extravasation or MPO (obtained in sham-operated animals) from control and treated animals. Differences were evaluated by using ANOVA followed by Student-Newman-Keuls posthoc analysis. Results with a p < 0.05 were considered significant. For survival curves, differences between groups at different time points were compared using Fisher’s exact test and considered significant when p < 0.05.
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Results |
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The first series of experiments was performed with the aim of confirming the role of B2Rs in a model of intestinal I/R in mice. In this model, in addition to the severe local (intestine) and remote (lung) tissue injury, as assessed by the increase in vascular permeability, neutrophil influx, hemorrhage, and release of cytokines, there is much systemic inflammation, as seen by systemic concentrations of cytokines and significant lethality (28). Treatment with HOE 140 (1 mg/kg) significantly prevented the increase of vascular permeability and neutrophil recruitment in the intestine and lungs of reperfused animals (Fig. 1, a–d). Similarly, the B2R antagonist markedly prevented intestinal hemorrhage (Fig. 1e). Furthermore, postischemic treatment with HOE 140 partially prevented the reperfusion-induced increases in TNF- concentrations in the intestine, lungs, and serum (Fig. 2). These results are in marked agreement with our previous study in rats demonstrating that HOE 140 was also capable of diminishing the inflammatory injury and delaying lethality following intestinal I/R (19). In addition, we also assessed in this study the effects of HOE 140 treatment on the production of IL-1 family cytokines (IL-1 and IL-18) and chemokines (KC and MCP-1). After reperfusion injury, there was a significant production of IL-1, IL-18, KC, and MCP-1 in the intestine and lungs of mice (Table I). HOE 140 prevented the production of IL-18, KC, and MCP-1 concentrations but induced a further increase in the release of IL-1 release (Table I). HOE 140 treatment also greatly potentiated the release of IL-10 in the intestines and lungs after intestinal I/R injury (Fig. 3). The inhibition of tissue and systemic TNF- production was mirrored by a significant delay of lethality in HOE 140-treated mice (Fig. 4). It is of note that all animals eventually died within 2 h after reperfusion (Fig. 4).
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As B1Rs may be expressed in response to several inflammatory stimuli, including B2R activation (8, 13), we evaluated whether this receptor was induced in our model. As seen in Fig. 5 (compare lanes 1 and 2 to lanes 3 and 4), there was a significant expression of B1R mRNA in the intestine and lungs 30 min after reperfusion of the ischemic mesenteric artery. To evaluate the functional role of these B1Rs in our model, reperfusion injury was performed in B1R-/- mice. Akin to the treatment with the B2R antagonist, there was a complete prevention of tissue injury, as assessed by the increase in vascular permeability, neutrophil recruitment, and hemorrhage, in reperfused B1R-/- mice (Fig. 1). In the latter mice, the reperfusion-induced increases in TNF- production in tissue and serum were also greatly suppressed (Fig. 2). There was also a significant suppression of the production of IL-18, KC, and MCP-1 in reperfused B1R-/- mice when compared with their wild-type controls (Table I). In general, the inhibitory phenotype observed in B1R-/- mice was greater than or, at least, similar to that seen in mice treated with HOE 140 (see Fig. 2 and Table I). Similarly to the situation observed in HOE 140-treated mice, the concentrations of both IL-10 (Fig. 3) and IL-1 (Table I) were significantly enhanced in B1R-/- mice when compared with reperfused wild-type mice. In addition to the observed suppression of tissue and systemic inflammation, there was a significant delay in reperfusion-induced lethality in B1R-/- (Fig. 6). Delay in lethality was accompanied by a partial prevention of lethality, because 40% of animals were alive until 240 min of reperfusion (Fig. 6).
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The next series of experiments were conducted to evaluate whether B2R activation was a relevant stimulus for B1R up-regulation and whether concomitant inhibition of both receptors would enhance the protective effects observed with either treatment alone. The former was indeed the case because inhibition of B2Rs with HOE 140 treatment greatly prevented the up-regulation of B1 mRNA in the intestine and lungs of reperfused mice (Fig. 5, compare lanes 3 and 4 to lanes 5 and 6).
To evaluate the concomitant inhibition of both receptors, B1R-/- mice received a systemic injection of HOE 140 before the reperfusion. As seen in Fig. 1, the pretreatment of B1R-/- mice with HOE 140 failed to prevent the local (intestine) and remote (lungs) tissue injury observed in reperfused untreated wild-type mice. It is of note that concomitant inhibition of both B1 and B2 receptors actually prevented the suppressive effects observed when either receptor was blocked alone. A similar situation is observed when the concentration of inflammatory cytokines (TNF- and IL-18) and chemokines (KC and MCP-1) is measured, i.e., lack of inhibition when both the antagonist and the B1R-/- phenotype are present (Fig. 2, Table I). Furthermore, in B1R-/- mice treated with HOE 140, there was no enhancement of the concentrations of IL-10 or IL-1, as seen when either receptor is blocked alone (Fig. 3, Table I). Consistent with the results above, treatment of B1R-/- mice with HOE 140 failed to affect significantly the reperfusion-associated lethality observed in untreated wild-type mice (Fig. 6). Indeed, the concomitant functional absence of both receptors induced a lethality that was significantly greater than when either receptor was blocked/absent alone (Figs. 4 and 6).
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Discussion |
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. In addition, we show that HOE 140 prevented the reperfusion-induced elevation of chemokines (KC and MCP-1) and IL-18 in mice. The inhibitory effects were observed both in the intestine and lungs of reperfused animals. Moreover, treatment with the B2R antagonist augmented the reperfusion-induced release of IL-10 and partially prevented lethality in both species. Thus, it is clear that B2R activation plays an important role in the cascade of events leading to local (intestine), remote (lungs), and systemic injury following intestinal I/R. These results are consistent with other studies demonstrating an important role of bradykinin in acute inflammatory responses (1, 2, 3, 4, 5, 6). The mechanisms by which B2R activation facilitates inflammatory injury appear to be multiple. Thus, activation of B2Rs may directly induce leukocyte migration and degranulation, and bradykinin may also act on leukocytes and/or endothelial cells to release proinflammatory mediators, such as cytokines and platelet-activating factor (8, 30, 31). Moreover, bradykinin acting on B2Rs may activate sensory nerves to release neuropeptides and potentiate the inflammatory response further (32, 33). However, the protection afforded by blockade of B2Rs was only partial.
Several studies have now shown that B2R activation or mediators released (e.g., TNF-) during the reperfusion process may enhance B1R expression during inflammatory responses (34, 35, 36). Thus, we investigated whether B1R mRNA was being expressed and played a functional role in cooperation with B2Rs in mediating injury in our system. Initial experiments showed marked B1R mRNA expression in the lungs and intestine following I/R of the SMA in mice (see Fig. 5). This is in line with other studies demonstrating the expression of functional kinin B1Rs in the endothelium after I/R (37, 38). In support of an important functional role for the B1Rs being expressed, experiments in B1R-/- mice showed that local and remote inflammatory injury was markedly suppressed in receptor-deficient mice when compared with their wild-type counterparts. Thus, there was no increase in vascular permeability, neutrophil accumulation, and hemorrhage in the intestine and lungs of reperfused B1R-/- mice. Moreover, the reperfusion-associated tissue increase of TNF-, IL-18, MCP-1, and KC was suppressed in B1R-/- mice when compared with wild-type mice. Additionally, serum concentrations of TNF- were partially suppressed, and this was associated with a significant delay in reperfusion-associated lethality in B1R-/- mice. Not only was lethality delayed, but there was also a degree of protection because 40% of animals were alive after 2 h of reperfusion. These results strongly suggest that B1R activation plays an important functional role during intestinal I/R tissue injury and demonstrate that B1R activation plays a relevant role for reperfusion-associated inflammation and lethality.
The mechanisms underlying the role for B1R activation in our system are not known at present. However, bradykinin acting via B1Rs may induce NF-
B activation in various cell types (39, 40) and, consequently, induce the release of proinflammatory cytokines. As we have previously demonstrated the essential role of TNF- for I/R injury (28, 41), the protective effect afforded by the absence of B1Rs may be due to a decrease of TNF- production. Furthermore, B1R activation has been shown to play an important role for the migration of leukocytes in several systems of acute inflammation (13, 20). Because the influx of neutrophils is a major driving force for TNF- production following intestinal I/R injury (42), it is possible that interference with the influx of neutrophils underlies the inhibitory effects observed in B1R-/- mice. Finally, there was a significant enhancement in the reperfusion-induced production of both IL-1 and IL-10 in B1R-/- or HOE 140-treated mice. We have previously shown that IL-10 was a major protective endogenous cytokine during I/R injury in rats, and that IL-1 was a major force driving IL-10 production (43). Thus, although the reasons underlying the enhanced production of both IL-1 and IL-10 in B1R-/- mice are not known, the demonstrated increase of these cytokines may also play a role in the protective effect afforded by the B1R-/- phenotype.
Because either treatment with the B2R antagonist or the B1R-/- phenotype afforded marked protection against tissue injury and significant, albeit not complete, protection against lethality, we examined whether concomitant B1 and B2 receptor absence would afford greater protection. To our surprise, the suppression of tissue inflammation observed in B1R-/- mice was almost completely reversed by the treatment with the B2R antagonist. Indeed, in B1R-/- mice that received HOE 140, the inflammatory tissue injury, as assessed by increase in vascular permeability, neutrophil recruitment, hemoglobin content, or tissue concentration of cytokines, was overall very similar to that observed in untreated wild-type mice and greater than that in animals that were only treated with HOE 140 or only B1R-/-. Even the increase of IL-1 or IL-10 was absent in B1R-/- mice that received HOE 140 treatment. The enhanced tissue inflammation was reflected in greater lethality. As such, B1R-/- mice given the B2R antagonist died significantly more than B1R-/- mice given vehicle. Thus, either B2R blockade or the B1R-/- phenotype has a similar inhibitory effect on tissue inflammation, but the B1R-/- phenotype afforded greater protection against lethality. Treatment of B1R-/- mice with the B2R antagonist reversed all the protection seen in the transgenic mice. One possible explanation for these apparent contradictory results could be that the activation of B2Rs was having two major effects in the system—an effect on tissue cells inducing the expression B1Rs and a protective effect. As for the former effect, there is evidence to suggest that B2R activation takes place at the beginning of the inflammatory process, and that via autoregulatory mechanisms, the desensitization of B2Rs occurs, followed by the up-regulations of B1Rs (23, 44). In our experiments, blockade of B2Rs with HOE 140 prevented the up-regulation of B1Rs in the intestine and lungs of reperfused animals. Thus, in this model of I/R injury in the mouse, B2R activation is a major driving force for B1R expression. The results of a number of recent studies indicate that administration of bradykinin at comparatively low doses attenuates I/R injury (14, 15, 16). These protective effects could be playing a role in our system and appear to be secondary to the potent vasodilatory effects of bradykinin on B2Rs of ischemic and/or reperfused vessels.
In summary, our results confirm an important role for B2R activation during I/R injury. Moreover, it is shown in this study that the activation of B2Rs has two important functions during intestinal I/R injury. First, B2Rs are a major driving force for B1R activation and consequent induction of inflammatory injury and lethality. In contrast, activation of B2Rs may facilitate tissue perfusion via its vasodilatory effects, thus preventing exacerbated injury. In wild-type mice, the proinflammatory B1R-dependent effects of B2R activation prevail, and blockade of the latter receptor prevents tissue injury and lethality. However, the protective effects of B2Rs are unmasked in B1R-/- mice. In the latter animals, blockade of B2Rs is accompanied by worse tissue injury and enhanced lethality. Thus, although the activation of B2Rs is necessary for the up-regulation of B1 and consequent acute proinflammatory effects, B2 activation also leads to vasodilatation and protection against reperfusion injury. Together, the present data highlight the interaction between B1 and B2 receptors in a relevant pathophysiological in vivo model and suggest that blockade of B1Rs could be a more effective strategy than B2R or B1R/B2R blockade for the treatment of the inflammatory injuries that follow the reperfusion of an ischemic vascular bed.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mauro M. Teixeira, Departamento de Bioquímica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brazil. E-mail address: mmtex{at}icb.ufmg.br
3 Abbreviations used in this paper: I/R, ischemia and reperfusion; SMA, superior mesenteric artery; MPO, myeloperoxidase; KC, keratinocyte-derived chemokine; MCP-1, monocyte chemoattractant protein-1.
Received for publication September 16, 2003. Accepted for publication November 26, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in vivo in the mouse. J. Immunol. 156:269.[Abstract]
shift the repertoire of receptor subtypes from B2 to B1 in human lung fibroblasts. Mol. Pharmacol. 56:325.-induced up-regulation of kinin B1 receptors in rats. Br. J. Pharmacol. 135:1107.[Medline]
: modulation by dexamethasone. Mol. Pharmacol. 57:1123.B pathways. Br. J. Pharmacol. 127:1851.[Medline]
and B1 agonist occurs through independent and synergistic intracellular signaling mechanisms in human lung fibroblasts. J. Pharmacol. Exp. Ther. 298:77. on local and remote injuries following ischaemia and reperfusion injury. Br. J. Pharmacol. 134:985.[Medline]
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