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* Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada;
Department of Experimental Pharmacology, University of Naples, Naples, Italy; and
Division of Gastroenterology and Hepatology, University of Perugia, Perugia, Italy
1Correspondence: Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1, Canada. E-mail: wallacej{at}ucalgary.ca
ABSTRACT
Hydrogen sulfide (H2S) is increasingly recognized as an important signaling molecule in the cardiovascular and nervous systems. Recently, H2S donors were reported to induce neutrophil apoptosis and to suppress expression of some leukocyte and endothelial adhesion molecules. Using rats, we examined the possibility that H2S is an endogenous regulator of key inflammatory events at the leukocyte-endothelial interface. Via intravital microscopy, we observed that H2S donors (NaHS and Na2S) inhibited aspirin-induced leukocyte adherence in mesenteric venules (ED50 of 5.0 µmol/kg for Na2S), likely via activation of ATP-sensitive K+ (KATP) channels. Inhibition of endogenous H2S synthesis elicited leukocyte adherence. Leukocyte infiltration in an air pouch model was also suppressed by H2S donors (NaHS, Lawesson’s reagent, and N-acetylcysteine; ED50 of 42.7, 1.3, and 29.9 µmol/kg, respectively) and exacerbated by inhibition of endogenous H2S synthesis. Carrageenan-induced paw edema was suppressed by H2S donors (NaHS and Na2S; ED50s of 35 and 28 µmol/kg, respectively) to the same extent as by diclofenac and enhanced by an inhibitor of H2S synthesis. Suppression of edema formation by H2S donors was mimicked by a KATP channel agonist and reversed by an antagonist of this channel. These results suggest that endogenous H2S is an important mediator of acute inflammation, acting at the leukocyte-endothelium interface. These findings have important implications for anti-inflammatory drug development.—Zanardo, R. C. O., Brancaleone, V., Distrutti, E., Fiorucci, S., Cirino, G., Wallace, J. L. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation.
Key Words: CNS • H2S donor • leukocyte adhesion
GASES SUCH AS NO and carbon monoxide play important roles in various tissues in both health and disease. Recently a third gaseous mediator, hydrogen sulfide (H2S), has become recognized as an important endogenous vasodilator and neuromodulator (1
, 2)
. H2S is synthesized from L-cysteine primarily via two enzymes: cystathionine-
-lyase (CSE) and cystathionine-ß-synthetase (CBS). In some tissues, CSE and CBS are both required for H2S synthesis, whereas in others only one of these enzymes is necessary (1)
. CSE appears to be the predominant enzymatic source of H2S in the vasculature and heart (1)
, but in the central nervous system (CNS) CBS predominates (1
, 3)
. The ability of H2S to relax vascular smooth muscle most likely occurs through activation of ATP-sensitive K+ (KATP) channels (1)
.
Several recent reports provide evidence suggesting a role for H2S in inflammation. H2S can scavenge peroxynitrite (4)
and can interfere with the ability of neutrophils, through hypochlorous acid, to kill microbes and other cells (5)
. H2S can also induce neutrophil apoptosis, thereby contributing to resolution of inflammatory reactions (6)
. We recently demonstrated that H2S can exert analgesic effects in a visceral pain model (7)
. Nonsteroidal anti-inflammatory drugs (NSAIDs) suppress endogenous H2S synthesis by reducing expression of CSE (8)
. This may contribute to the production of damage in the stomach induced by NSAIDs, since administration of exogenous H2S reduced the ability of these agents to cause gastric injury. Particularly relevant to a potential role in inflammation, the H2S donor suppressed NSAID-induced granulocyte infiltration, expression of endothelial and leukocyte adhesion molecules, and expression of tumor necrosis factor 
(8)
. Leukocyte adherence to the vascular endothelium induced by aspirin was also suppressed by an H2S donor.
Recent data also suggest that H2S may contribute to inflammatory processes. For example, significant increases in H2S production and up-regulation of CSE expression were observed in studies of rodent models of acute pancreatitis (9)
and endotoxemia (10)
, whereas irreversible inhibition of CSE activity with DL-propargylglycine reduced the severity of pancreatitis and endotoxic shock. This inhibitor was also found to suppress edema formation and granulocyte infiltration in a rat model of hindpaw inflammation (9)
.
Given these apparently conflicting observations, we performed a detailed study of the effects of a number of different H2S donors in several in vivo models of inflammation, using multiple distinct phlogistic agents. We also examined the effects on several inflammatory parameters of inhibition of endogenous H2S synthesis and of blockade or activation of KATP channels (the putative target of the vascular actions of H2S). In particular, we examined the role of H2S in modulating leukocyte adhesion to the vascular endothelium, leukocyte infiltration, and edema formation. Our studies implicate H2S as an important endogenous inhibitor of these key elements of acute inflammatory reactions.
MATERIALS AND METHODS
Animals
Male Wistar rats weighing 175–200 g were obtained from Charles River Breeding Farms (Montreal, Canada, and Monza, Italy). For 18 h prior to an experiment, the rats were deprived of food, but not water. All experimental procedures described below were approved by the institutional animal care committees and were performed in accordance with the guidelines of the National Council on Animal Care.
Intravital microscopy
Examination of leukocyte-endothelial interactions in vivo was performed as described in detail (11)
. Postcapillary mesenteric venules with a length of at least 150 µm and diameters ranging from 25 to 40 µm were selected for the study. A video camera mounted on the microscope (Panasonic digital 5000) projected the image onto a monitor, and the images were recorded for playback analysis using a videocassette recorder. Images of the mesenteric microcirculation were recorded over 5 min periods starting immediately before (baseline) and after aspirin administration or initiation of fMLP superfusion, and at 15 min intervals thereafter for 60 min. Aspirin was administered intragastrically at a dose of 50 mg/kg, whereas fMLP (10 µM) was dissolved in the buffer that superfused the mesenteric venules. In controls, vehicle (1% CMC) was given intragastrically instead of aspirin and vessels were superfused with buffer not containing fMLP. Leukocyte adhesion was blindly quantified as the number of leukocytes that adhered to the vessel wall for at least 30 s per 100 µm venule length. Rolling leukocytes were defined as white blood cells moving at a velocity less than that of the erythrocytes in the same stream. The rolling leukocyte velocity was determined by the time required for a leukocyte to traverse a given distance along the length of a venule.
To assess the effects of H2S on aspirin- and fMLP-induced leukocyte adherence, rats were pretreated intragastrically with Na2S (1–100 µmol/kg), NaHS (100 µmol/kg), or Lawesson’s reagent (0.1 to 3 µmol/kg) 30 min before aspirin or fMLP administration. Control rats received vehicle at the same time. In another group of experiments, glibenclamide was given 1 h prior to Na2S or vehicle. In other experiments, rats were given a reversible inhibitor of CSE (ß-cyano-alanine, 50 mg/kg i.p.) 1 h prior to aspirin. This dose of ß-cyano-alanine (BCA) has been shown to significantly inhibit CSE activity in the rat (12)
.
Carrageenan air pouch model
An air pouch was induced as described previously (13
, 14)
. Briefly, 20 µl of air was injected subcutaneously on the back of the rat on the first day. Two days later, another 10 µl of air was injected at the same site. On the fifth day after the first injection, another 10 µl of air was injected into the pouch. Twenty-four hours later, carrageenan (2 ml of a 1% w/v solution in sterile saline) or the vehicle was injected into the air pouch. All of the injections were performed after the rats had been anesthetized with 5% (v/v) halothane. Six hours after the carrageenan injection, rats were anesthetized with sodium pentobarbital (60 mg/kg; i.p.) and 1 µl of heparinized saline was injected into the pouch. The pouch was then carefully opened by a small incision. The exudate was collected, the volume determined gravimetrically, and an aliquot was used to quantify leukocyte concentration using a Sysmex KX-21N hematology analyzer. Another aliquot was applied to a glass slide and stained with Wright’s stain to determine the relative numbers of different leukocyte subtypes.
The effects of H2S on leukocyte infiltration into the pouch were assessed by treating rats (i.p.) 30 min before carrageenan injection with vehicle (0.9% saline) or one of the following H2S donors: NaHS (1–100 µmol/kg), Lawesson’s reagent (0.1–3 µmol/kg), or N-acetylcysteine (0.5–50 µmol/kg). In other experiments rats were treated with BCA (50 mg/kg) 30 min before administration of N-acetylcysteine (50 µmol/kg). These experiments permitted us to evaluate whether or not N-acetylcysteine might affect leukocyte infiltration of the air pouch independent of metabolism via CSE. Additional experiments were performed in which rats received glibenclamide (10 mg/kg i.p.) or vehicle (dimethyl sulfoxide, 0.1 ml, i.p.) 30 min before an H2S donor to determine whether the effects of the donors were mediated via KATP channels.
Several drugs were tested in the air pouch model as positive controls, as we had found them to significantly reduce carrageenan-induced leukocyte infiltration. These included an NSAID (diclofenac, 10 mg/kg i.p.), a NOS inhibitor (L-NAME; NG-nitro-L-arginine methyl ester; 25 mg/kg i.p.), and dexamethasone (1 mg/kg i.p.). Diclofenac and L-NAME were administered 30 min prior to carrageenan, and dexamethasone was administered 2 h before carrageenan. As dexamethasone produced what was deemed to be a "maximal" reduction of leukocyte infiltration in this model, we calculated ED50 values for each of the H2S donors relative to the response induced by dexamethasone.
Paw edema
Carrageenan (100 µl of a 1% w/v solution, prepared in sterile saline) was injected into a hind footpad of rats under halothane anesthesia. Paw volume was measured prior to any treatment, immediately before carrageenan administration, and at intervals of 1 h for 5 h thereafter using a Ugo Basile Model 7140 plethysmometer (Comerio, Italy). The person performing these measurements was unaware of the treatments the rats had received. Groups of at least 5 rats each were treated intraperitoneally 30 min before carrageenan administration with an H2S donor (NaHS at 25–150 µmol/kg or Na2S at 100 µmol/kg), an NSAID as positive control (diclofenac, 10 mg/kg), or a KATP channel agonist (pinacidil, 10 mg/kg). Other rats received BCA (50 mg/kg i.p.) 30 min before carrageenan administration. Additional experiments were performed in which groups of 5 rats each received glibenclamide (10 mg/kg) or vehicle (dimethyl sulfoxide) i.p. 30 min before administration of one of the H2S donors.
Expression of CSE and CBS mRNA
Samples of rat portal vein and mesenteric venules were used to measure CSE and CBS mRNA expression by RT-polymerase chain reaction (RT-PCR), as described previously (8)
. Expression of ß-actin was determined as a control.
MATERIALS
Unless otherwise stated, all drugs were suspended in 1% carboxymethylcellulose. Aspirin, diclofenac sodium, N-formyl-Met-Leu-Phe, glibenclamide, PAG, BCA, 
-carrageenan, NaHS, Na2S, pinacidil, N-acetylcysteine, and Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) were obtained from Sigma Chemical Co. (St. Louis, MO, USA).
RESULTS
H2S donors decrease ASA-induced leukocyte adhesion through the activation of KATP channels
Oral administration of aspirin (50 mg/kg) induced a significant time-dependent increase in leukocyte adherence compared with rats that received vehicle (Fig. 1
). Pretreatment of rats with Na2S dose-dependently decreased aspirin-induced leukocyte adherence to the mesenteric microcirculation (ED50 of 5.0 µmol/kg). The reduction of leukocyte adherence by Na2S likely occurred through activation of KATP channels, since pretreatment with an antagonist of those channels, glibenclamide, reversed the effects of the H2S donor. Glibenclamide given to rats prior to vehicle or ASA did not alter basal leukocyte adherence or that induced by aspirin (data not shown). NaHS (100 µmol/kg) also inhibited aspirin-induced leukocyte adherence. As for Na2S, the inhibition of leukocyte adherence by NaHS could be inhibited by glibenclamide (data not shown).
|
H2S donors inhibit fMLP-induced leukocyte adherence
Pretreatment with Na2S or NaHS (each at 100 µmol/kg) abolished fMLP-induced leukocyte adherence to the mesenteric microcirculation (Fig. 2
). Lawesson’s reagent also inhibited leukocyte adhesion when administered at a dose of 1 µmol/kg. At a dose of 0.3 umol/kg, Lawesson’s reagent did not affect fMLP-induced leukocyte adherence (data not shown).
|
Inhibition of CSE activity promotes leukocyte adhesion
Mesenteric venules in the rat express both CSE and CBS (mRNA), whereas the portal vein exhibits a greater expression of CBS than of CSE (Fig. 3
, upper panel). Administration of BCA at a dose shown to suppress CSE activity in the rat (13)
resulted in a marked increase in leukocyte adherence that continued to increase throughout the 60 min experiment (Fig. 3
, middle panel). BCA also elicited a sharp decline in leukocyte velocity (Fig. 3
, lower panel).
|
H2S donors inhibit leukocyte infiltration through the activation of KATP channels
Administration of carrageenan into a rat air pouch results in infiltration of substantial numbers of neutrophils (Fig. 4
). Most of the leukocytes were neutrophils (87.0±1.1%) and lymphocytes (12.3±0.8%). Pretreatment with H2S donors (NaHS, N-acetylcysteine, Lawesson’s reagent) dose-dependently reduced the numbers of leukocytes infiltrating into the air pouch in response to carrageenan (ED50 values of 42.7, 29.9, and 1.3 µmol/kg, respectively, defining the response to dexamethasone as maximal). With the highest dose of each H2S donor tested, the reduction in leukocyte infiltration was comparable to that achieved by an NSAID (diclofenac), a NOS inhibitor (L-NAME), and a corticosteroid (dexamethasone).
|
The ability of N-acetylcysteine to reduce carrageenan-induced leukocyte infiltration was dependent on CSE activity. As shown in Fig. 5
(top panel), prior treatment with BCA, an inhibitor of CSE, reversed the effects of N-acetylcysteine. Moreover, the reduction of leukocyte infiltration by N-acetylcysteine could be reversed by glibenclamide, a KATP channel antagonist.
|
Inhibition of H2S synthesis promotes leukocyte infiltration
Administration of BCA resulted in a significant increase in "basal" leukocyte numbers in the air pouch (i.e., without carrageenan administration) (Fig. 5
, lower panel). Pretreatment with BCA also significantly enhanced leukocyte infiltration into the air pouch in response to carrageenan. Thus, endogenous H2S synthesis, via CSE, acts to down-regulate leukocyte infiltration.
H2S modulates edema formation via effects on KATP channels
Injection of carrageenan into the hind footpads of rats resulted in a rapid and marked increase in paw volume as a consequence of edema formation (Fig. 6
, upper panel). The increase in paw volume could be significantly reduced by pretreatment with diclofenac (an NSAID). Pretreatment with NaHS or Na2S similarly decreased carrageenan-induced paw edema (ED50s of 35 and 28 µmol/kg, respectively), as did pinacidil, a KATP channel agonist. In contrast, suppression of endogenous H2S synthesis, through administration of BCA, resulted in a significantly greater paw swelling response to carrageenan. The reduction paw edema by either of the H2S donors (NaHS or Na2S) could be reversed by pretreatment with glibenclamide (Fig. 7
, lower panel).
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DISCUSSION
Studies over the past 5 years have provided convincing evidence that H2S is an important modulator of vascular tone and acts as a neuromodulator (1
, 2)
. The results of the present study suggest that H2S also plays important roles in the context of inflammation. H2S is generated at sites of inflammation and can influence the ability of neutrophils to cause tissue injury (4)
; it was recently shown to reduce visceral pain perception (7)
. In the present study, we have demonstrated that several H2S donors can suppress leukocyte adherence to the vascular endothelium and can reduce leukocyte infiltration and edema formation. These effects of H2S were seen irrespective of the inflammatory stimulus used (carrageenan, aspirin, fMLP). Suppression of endogenous H2S synthesis, through blockade of CSE, resulted in enhanced leukocyte adhesion, leukocyte infiltration, and edema formation. These actions appeared to be mediated via KATP channels, as they were reversed by pretreatment with glibenclamide and mimicked by pinacidil. Our findings therefore suggest an important role for endogenous H2S as a modulator of some of the key components of acute inflammatory responses, particularly those occurring at the leukocyte-endothelial interface (Fig. 7)
.
As for other gaseous mediators (carbon monoxide, NO), H2S was recognized for its toxicity long before its importance in physiological processes was described. H2S is synthesized, primarily from L-cysteine, through actions of the enzymes CSE and CBS. In rats, blood and plasma levels of H2S are in the 10–100 µM range (15)
. In the present study, we used three different H2S donors at doses that would approximate concentrations of H2S that fall within this physiological range. Differences in the potency of Lawesson’s reagent vs. Na2S and NaHS in suppressing leukocyte adherence/infiltration are consistent with observed differences in their ability to elicit H2S-mediated vascular smooth muscle relaxation (unpublished observation). Moreover, the observation that suppression of endogenous H2S synthesis with ß-cyanoalanine led to increased leukocyte adherence and infiltration is consistent with a role for this mediator as a tonic inhibitor of leukocyte adherence/extravasation. Our observation that leukocyte rolling velocity decreased sharply after administration of the CSE inhibitor is consistent with previous observations that P-selectin expression can be regulated by H2S (8)
. As leukocyte expression/affinity of LFA-1 has also been shown to be suppressed by H2S (8)
, it is possible that the actions of H2S with respect to leukocyte-endothelial adherence are exerted on both cell types (Fig. 7)
.
We recently reported that NSAIDs suppress H2S synthesis by reducing expression of CSE (8)
. The accompanying reduction of H2S synthesis may contribute to the increase in leukocyte adherence that is seen after NSAID administration (16
, 17)
, which has been shown to contribute significantly to the gastric injury induced by this class of drugs (18
19
20)
. Indeed, coadministration of an H2S donor with an NSAID resulted in inhibition of NSAID-induced leukocyte adherence and reduction of the severity of gastric damage (8)
. Pertinent to the present study, administration of an H2S donor prevented many of the other "proinflammatory" effects of NSAIDs, including the elevation of ICAM-1 and LFA-1 expression and the increase in mucosal TNF expression (8)
.
Of the four H2S donors used in this study, only N-acetylcysteine requires metabolism in order for H2S to be released. N-acetylcysteine is a precursor of L-cysteine (21)
, which is the substrate for H2S generation via CSE and/or CBS. The observation that the anti-inflammatory actions of N-acetylcysteine were reversed by an inhibitor of CSE (ß-cyanoalanine) is consistent with the effects being mediated by H2S.
NO is another gaseous mediator that exerts many effects in common with H2S in the cardiovascular and nervous systems. Moreover, there is evidence of cross-talk between H2S and NO on many levels. For example, H2S promotes the release of NO from vascular endothelium (22)
, whereas an NO donor was shown to increase the conversion of L-cysteine to H2S, at least in part by increasing the expression of CSE, one of the key enzymes for H2S synthesis (23)
Hemoglobin (Hb) has been referred to as a common "sink" for H2S, NO, and carbon monoxide. Thus, saturation of Hb binding to one of these gaseous mediators could lead to enhanced plasma levels and to biological effects from the others (1
, 24)
. The extent to which NO may contribute to some of the observed actions of H2S in the present study has not yet been examined.
As was the case for studies of NO for many years, evaluation of the contributions of H2S to various processes is hampered by a paucity of precise pharmacological and genetic tools. Irreversible inhibitors of CSE and CBS have been reported to interfere with other enzymes (25
, 26)
. As with any pharmacological agent, we cannot exclude the possibility that the reversible inhibitor of CSE, ß-cyanoalanine, could exert nonspecific effects. For these reasons we chose to study four different H2S donors in order to increase the veracity of our conclusions. Genetic deletion of CSE and CBS are lethal, ruling out the use of these "knockouts." CBS heterozygotes are viable, expressing half as much CBS as wild-type (WT). When fed a diet high in homocysteine, CBS± mice have been shown to exhibit increased leukocyte adherence, increased P-selectin expression, and increased vascular permeability (in the brain) (27)
, all consistent with a role for H2S in mediating acute inflammation. However, use of these mice for direct studies of inflammation is of questionable value, as they have drastically altered vascular responsiveness to cholinergics and bradykinin (28)
.
Although our findings point to a role for H2S as an endogenous modulator of inflammation, there are reports suggesting that this mediator may contribute to inflammatory processes. In addition to reports that irreversible inhibition of CSE can attenuate the severity of experimental pancreatitis (9)
and endotoxemia (10)
, administration of DL-propargylglycine has been shown to dose-dependently reduce carrageenan-induced paw edema (29)
. The different outcomes of the latter study and the present one may be related to differences in selectivity of the inhibitors used or to the fact that one involved an irreversible inhibitor of CSE and the other a reversible inhibitor. With a very high level of suppression of H2S synthesis, a significant decrease in blood flow would be anticipated, which would result in reduced edema formation. A similar scenario has been described with respect to another vasodilator, NO. Although NO exerts many anti-inflammatory effects (30)
, suppression of NO synthesis has been shown to reduce paw edema via reduced blood flow to the tissue (31)
.
A consistent finding in the various models used in the present study was that the anti-inflammatory effects of H2S appeared to be mediated via activation of KATP channels. It is also the case that the analgesic effects of H2S donors are mediated through these channels (7)
. It is possible, therefore, that KATP channels represent a novel target for anti-inflammatory and analgesic agents.
In summary, the results of the present study have demonstrated a role for endogenous H2S as a modulator of key inflammatory events occurring at the interface of leukocytes and the vascular endothelium. H2S functions as a tonic regulator of leukocyte adherence to the endothelium and of endothelial permeability. The anti-inflammatory effects of H2S appear to be mediated via activation of KATP channels. These results, and recent reports that H2S donors can reduce pain perception and down-regulate adhesion molecule and proinflammatory cytokine expression, therefore identify H2S, the key enzymes responsible for H2S synthesis, and KATP channels as potential targets for novel anti-inflammatory therapies.
ACKNOWLEDGMENTS
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR). Dr. Wallace is an Alberta Heritage Foundation for Medical Research Senior Scientist and holds a Canada Research Chair in Inflammation Research. Dr. Zanardo is supported by a Fellowship from the Canadian Association of Gastroenterology, AstraZeneca Canada and the CIHR. The authors are grateful to Michael Dicay and Webb McKnight for their assistance in performing these studies.
Received for publication April 7, 2006. Accepted for publication May 8, 2006.
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P < 0.05 vs. the corresponding group receiving aspirin alone. Each group consisted of at least 5 rats. The results are plotted as mean ± SE.
