Hydrogen sulphide synthesis in the rat and mouse gastrointestinal tract

AimsHydrogen sulphide (H₂S) exerts several anti-inflammatory effects, accelerates the healing of experimental gastric ulcers, and can stimulate intestinal secretion. Little is known about H₂S synthesis in the gastrointestinal tract. The aim of this study was to characterize H₂S synthesis throughout the gastrointestinal tract.MethodsH₂S synthesis in various gastrointestinal tissues of rats and mice was determined. The effects and selectivity of inhibitors of two key enzymes for H₂S synthesis, cystathionine-γ-lyase and cystathionine-β-synthase, were examined. Cystathionine-γ-lyase and cystathionine-β-synthase expression was evaluated by Western blotting and immunohistochemistry. Cystathionine-γ-lyase and cystathionine-β-synthase expression in biopsies of human colon was also examined.ResultsH₂S synthesis was variable throughout the gastrointestinal tract in parallel with variations in cystathionine-γ-lyase and cystathionine-β-synthase expression. The efficacy of cystathionine-β-synthase and cystathionine-γ-lyase inhibitors to reduce H₂S synthesis in these tissues was also variable. Cystathionine-β-synthase is the predominant source of H₂S synthesis in the colon of rodents. Cystathionine-γ-lyase and cystathionine-β-synthase were also expressed in healthy human colon biopsies.ConclusionsThe capacity for H₂S synthesis varies throughout the rodent gastrointestinal tract, as does the distribution and contribution of the two key enzymes. Investigation of additional enzymatic sources of H₂S and the development of more selective inhibitors are suggested.     

Effects of olopatadine hydrochloride on the release of thromboxane B2 and histamine from nasal mucosa after antigen–antibody reaction in guinea pigs

BackgroundVarious mediators, such as thromboxane (TX) A₂, peptide leukotrienes (P-LT) and histamine, are involved in allergic nasal obstruction. The aim of the present study was to investigate the mechanism whereby olopatadine hydrochloride, a novel anti-allergic drug, ameliorated the allergic nasal obstruction.MethodsThe levels of TXB₂, P-LT and histamine in nasal lavage fluid (NLF) were measured after intranasal antigen challenge in sensitized guinea pigs.ResultsHistamine and TXB₂ levels in the NLF increased eight- and threefold, respectively, 10 min after antigen challenge, whereas the P-LT level was under the detection limit. Oral administration of olopatadine at 0.1, 1 and 3 mg/kg significantly inhibited the increases in TXB₂ and histamine levels. At 3 mg/kg, olopatadine also ameliorated the nasal obstruction caused 10 min after antigen challenge, as determined by acoustic rhinometry.ConclusionsThese results suggest that the amelioration by olopatadine of the allergic nasal obstruction involves the inhibition of the release of TXA₂ and histamine.     

Inhibition of NADPH oxidase 4-related signaling by sodium hydrosulfide attenuates myocardial fibrotic response

Background

Myocardial fibrosis plays a pivotal role in the development of heart failure. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter with potent cardioprotective properties; however, whether H₂S is involved in fibrotic process remains unknown. This study aimed to explore the role of H₂S in the process of cardiac fibrosis and the underlying mechanisms.

Methods

Myocardial infarction (MI) was established in rats by ligation of coronary artery. Activation of rat neonatal cardiac fibroblasts was induced by angiotensin II (Ang II). Fibrotic responses in ischemic myocardium and in Ang II-stimulated cardiac fibroblasts were examined. The effects of sodium hydrosulfide (NaHS, an exogenous H₂S donor) on NADPH oxidase 4 (Nox4), reactive oxygen species (ROS) production, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, heme oxygenase-1 (HO-1), and cystathionine γ-lyase (CSE) were tested to elucidate the protective mechanisms of H₂S on fibrotic response.

Results

NaHS treatment inhibited Ang II-induced expression of α-smooth muscle actin, connective tissue growth factor (CTGF), and type I collagen and upregulated expression of HO-1 in cardiac fibroblasts. Ang II-induced Nox4 expression in cardiac fibroblasts was quenched by NaHS and this was associated with a decreased ROS production and reduced ERK1/2 phosphorylation and CTGF expression. In vivo studies using MI model indicated that NaHS administration attenuated Nox4 expression and fibrotic response. Moreover, NaHS therapy also prevented cardiac inflammatory response accompanied by increases in HO-1 and CSE expression.

Conclusions

The beneficial effect of H₂S, at least in part, was associated with a decrease of Nox4-ROS-ERK1/2 signaling axis and an increase in HO-1 expression.     

Hydrogen sulfide-induced inhibition of L-type Ca2+ channels and insulin secretion in mouse pancreatic beta cells

Aims/hypothesis

L-type voltage-dependent Ca²⁺ channels (VDCCs) in pancreatic beta cells play a critical role in regulating insulin secretion. The gasotransmitter H₂S is mostly generated from l-cysteine in pancreatic beta cells by cystathionine γ-lyase (CSE) and has been reported to inhibit insulin release by opening ATP-sensitive K⁺ channels. However, whether and how H₂S affects VDCCs in beta cells is unknown.

Methods

The whole-cell patch-clamp technique was used to record VDCCs in beta cells from Cse (also known as Cth)-knockout (KO) and wild-type (WT) mice. Insulin secretion from pancreatic islets and endogenous H₂S production in pancreas were measured.

Results

The H₂S donor NaHS reversibly decreased L-type VDCC current density in a concentration-dependent fashion in WT pancreatic beta cells, and the current density was further inhibited by nifedipine. Furthermore, NaHS inhibited the channel recovery from depolarisation-induced inactivation, but did not shift the current–voltage (I–V) relationship. ACS67, another H₂S donor, also inhibited L-type VDCCs in beta cells. Inhibiting CSE activity with dl-propargylglycine increased the basal L-channel activity of beta cells from WT mice, but not that of beta cells from Cse-KO mice. Beta cells from Cse-KO mice displayed higher L-type VDCC density than those from WT mice. Insulin secretion from pancreatic islets was elevated in Cse-KO mice compared with WT mice. NaHS dose-dependently inhibited glucose-stimulated insulin secretion, which was further inhibited by nifedipine. Bay K-8644 increased glucose-stimulated insulin secretion, but this was counteracted by NaHS and nifedipine.

Conclusions/interpretation

Exogenous and endogenous H₂S inhibit L-type VDCC activity and pancreatic insulin secretion, constituting a novel mechanism for the regulation of insulin secretion by the CSE/H₂S system.     

Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis

Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H₂S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H₂S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H₂S also decreases plasma homocysteine levels in experimental animal models. In the human body, H₂S production is predominantly catalyzed by cystathionine-β-synthase (CBS) and cystathionine γ-lyase (CSE). CSE is the primary H₂S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H₂S deficiency and that H₂S supplementation by exogenous H₂S donors (such as NaHS and GYY4137) attenuates, and H₂S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523–2534) demonstrates that decreased endogenous H₂S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE^−/− mice, pinpointing that endogenously produced H₂S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H₂S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases.     

Characteristics of lower airway inflammatory changes in the minimal persistent inflammation of allergic rhinitis in mice

Objective: This study aims to establish an experimental mouse model of minimal persistent inflammation (MPI), observe the features of inflammation and hyper-responsiveness of the upper/lower airways, and explore the relationship between inflammation and hyper-responsiveness in the upper/lower airways. Methods: Sixty-four female BALB/c mice were randomly divided into four groups: allergic rhinitis (AR) group as positive control, MPI group, negative control group and blank control group. Mice were given high and low-concentrated ovalbumin solution after basic and intensive sensitization to establish AR model and MPI model. Nasal mucosa and lung tissues were stained to observe eosinophil infiltration, goblet cell hyperplasia, and expression of intercellular adhesion molecule 1 (ICAM-1). Airway hyper-responsiveness was assessed. Levels of specific immunoglobulin E (sIgE), interleukin (IL)-4 and IL-5 in peripheral blood, nasal lavage fluid (NLF), and bronchoalveolar lavage fluid (BALF) were detected by Enzyme-linked immunosorbent assay. Results: The eosinophil infiltration and expression of ICAM-1 on nasal mucosa and in lung tissues in the AR and MPI groups were significantly elevated compared to control groups. Goblet cells count increased only in the nasal mucosa and not in lung tissues. Eosinophil and neutrophil count of NLF and BALF in the AR and MPI groups increased significantly compared to control groups. Level of IL-4 did not increase significantly, but sIgE and IL-5 did. Conclusions: Mice in the MPI status exhibits lower airway inflammation and hyper-responsiveness with increase in eosinophil count, goblet cells, ICAM-1, IL-4, and IL-5. These results provide further evidence for the importance of MPI of AR in lower airway diseases.     

Nitric Oxide and Hydrogen Sulfide Interact When Modulating Gastric Physiological Functions in Rodents

Aim

The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H₂S) donors and possible interactions between these two systems in modulating gastric function.

Methods

Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1 h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson’s reagent (H₂S donor), PAG + SNP, l-NAME, l-NAME + NaHS, or l-NAME + Lawesson’s reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated.

Results

SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson’s reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and l-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and l-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and l-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or l-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus.

Conclusion

NO and H₂S interact in gastric physiological functions, and this “cross-talk” is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.

     

Absence of Nasal Blockage in a Japanese Cedar Pollen-Induced Allergic Rhinitis Model Mouse

BackgroundJapanese cedar pollen-induced allergic rhinitis in a guinea pig model clearly induced not only sneezing but also biphasic nasal blockage. To date, there have only been a few reports on models of murine allergic rhinitis which clearly show nasal blockage. Therefore, in order to try and develop such a model, we administered multiple dosages of intranasal pollen or purified antigen protein Cry j 1.MethodsB10.S mice were sensitized by intranasal instillations of either pollen extract or Cry j 1 twice a day for 7 days, which was adsorbed on Al(OH)₃. Subsequently, once a week, the mice were given multiple intranasal instillation challenges of either the pollen suspension or Cry j 1 and the frequency of sneezing was observed after respective challenges were made. Specific airway resistance (sRaw) was measured as an indicator for nasal blockage. Cry j 1-specific IgE levels were measured using an enzyme-linked immunosorbent assay.ResultsThe serum Cry j 1-specific IgE level showed clear elevation only in the group sensitized by Cry j 1 + Al(OH)₃ and then challenged by Cry j 1. No elevations were seen in the groups sensitized by pollen extract + Al (OH)₃ followed by a pollen suspension challenge. There was an immediate increase in sneezing after challenges in all of the sensitized-challenged groups. Nevertheless, no increases in sRaw in any of the groups were detected at any of the time points during the 8 hours following the challenges.ConclusionsCry j 1 may be more effective than crude antigens for efficient sensitization/challenge in mice. No increase in sRaw occurred, even in mice that possessed high amounts of Cry j 1-specific IgE and that exhibited sneezing.     

Hydrogen sulfide-induced enhancement of gastric fundus smooth muscle tone is mediated by voltagedependent potassium and calcium channels in mice

AIM:To investigate the effect of hydrogen sulfide(H2S)on smooth muscle motility in the gastric fundus.METHODS:The expression of cystathionineβ-synthase(CBS)and cystathionineγ-lyase(CSE)in cultured smooth muscle cells from the gastric fundus was examined by the immunocytochemistry technique.The tension of the gastric fundus smooth muscle was recorded by an isometric force transducer under the condition of isometric contraction with each end of the smooth muscle strip tied with a silk thread.Intracellular recording was used to identify whether hydrogen sulfide affects the resting membrane potential of the gastric fundus in vitro.Cells were freshly separated from the gastric fundus of mice using a variety of enzyme digestion methods and whole-cell patch-clamp technique was used to find the effects of hydrogen sulfide on voltage-dependent potassium channel and calcium channel.Calcium imaging with fura-3AM loading was used to investigate the mechanism by which hydrogen sulfide regulates gastric fundus motility in cultured smooth muscle cells.RESULTS:We found that both CBS and CSE were expressed in the cul tured smooth muscle cel ls from the gastric fundus and that H2S increased the smooth muscle tension of the gastric fundus in mice at low concentrations.In addition,nicardipine and aminooxyacetic acid(AOAA),a CBS inhibitor,reduced the tension,whereas Nω-nitro-L-arginine methyl ester,a nonspecific nitric oxide synthase,increased the tension.The AOAA-induced relaxation was significantly recovered by H2S,and the Na HS-induced increase in tonic contraction was blocked by 5 mmol/L4-aminopyridine and 1μmol/L nicardipine.Na HS significantly depolarized the membrane potential and inhibited the voltage-dependent potassium currents.Moreover,Na HS increased L-type Ca2+currents and caused an elevation in intracellular calcium([Ca2+]i).CONCLUSION:These findings suggest that H2S may be an excitatory modulator in the gastric fundus in mice.The excitatory effect is mediated by voltagedependent potassium and L-type calcium channels.     

Reduction of leukocyte-derived H2S linked to abnormal glycolipid metabolism in hypertensive subjects

We deduced that leukocyte-derived H₂S would also play a pivotal role regarding nutrition homeostasis in hypertensive subjects. Plasma was obtained from patients with hypertension (n = 151) as well as control (n = 41). Leukocyte-derived H₂S speed was determined, and biochemical indices of glucose and lipid metabolism were measured. Western blot analyses of CSE were also performed. Inflammation factors were measured. Leukocyte-derived H₂S is produced at a significantly lower rate in overweight or obese patients (p < 0.05). There is a significant negative correlation between H₂S and the levels of HOMA-RI and insulin in overweight patients and has a positive relationship with HDL-C only in overweight hypertensive patients (p < 0.05). Patients with high insulin levels showed down-regulation of CSE (p < 0.05). The levels of IL-10 decreased in both the obese and the overweight which showed significant relationship with all metabolism parameters such as HDL-C(r = 0.176, p = 0.031), insulin (r = ?0.181, p = 0.027), HOMA-IR (r = ?0.166, p = 0.045), and H₂S speed (r = 0.995, p = 0.001). Linear regression analysis showed that insulin levels will increase (β = ?1.685, p = 0.041) with the slower speed of H₂S. Leukocyte-derived H₂S production varied according to the nutritional status of hypertensive subjects, and the H₂S/IL-10 signaling pathway may be the junction point among hypertension, disturbance of nutritional status, and inflammation.     

Exogenous hydrogen sulfide (H2S) protects against regional myocardial ischemia–reperfusion injury

Hydrogen sulfide (H₂S) is a gaseous mediator, produced by the metabolic pathways that regulate tissue concentrations of sulfur–containing amino acids. Recent studies indicate that endogenous or exogenous H₂S exerts physiological effects in the cardiovascular system of vertebrates, possibly through modulation of K_ATP channel opening. The present study was undertaken to examine the hypothesis that H₂S is cytoprotective against myocardial ischemia–reperfusion injury and that this protective action is mediated by K_ATP opening. Rat isolated hearts were Langendorff–perfused and underwent 30 min left main coronary artery occlusion and 120 min reperfusion. The resulting injury was assessed as infarct size, determined by tetrazolium staining. Treatment of hearts with the H₂S–donor, NaHS, commencing 10 min prior to the onset of coronary occlusion and maintained until 10 min reperfusion, resulted in a concentration–dependent limitation of infarct size (control, 41.0 ± 2.6% of risk zone; NaHS 0.1 μM, 33.9 ± 2.1%, [0.05 > P < 0.1]; NaHS 1 μM, 20.2 ± 2.1% [P < 0.01]). Pretreatment with the K_ATP channel blockers glibenclamide 10 μM or sodium 5–hydroxydecanoate (5HD) 100 μM led to abrogation of the infarct–limiting effect of NaHS 1 μM (glibenclamide + NaHS 42.5 ± 3.6%; 5HD + NaHS 44.7 ± 2.2%). No statistically significant effects of NaHS treatment on coronary flow, heart rate or left ventricular developed pressure were observed in this experimental preparation. These data provide the first evidence that exogenous H₂S protects against irreversible ischemia–reperfusion injury in myocardium and support the involvement of K_ATP opening in the mechanism of action. Further work is required to elucidate the potential role of endogenous H₂S as a cytoprotective mediator against myocardial ischemia–reperfusion injury, the mechanisms regulating its generation, and the nature of its interaction with protein targets such as the K_ATP channel.     

H2S mitigates severe acute pancreatitis through the PI3K/AKT-NF-κB pathway in vivo

AIM: To study the effect of hydrogen sulfide (H₂S) on severe acute pancreatitis (SAP) in a rat model.METHODS: Sprague-Dawley (SD) rats were administered an intraperitoneal injection of saline containing 20% L-Arg (250 mg/100 g) hourly for over 2 h to induce SAP. The rats were treated with DL-propargylglycine (PAG, 50 mg/kg) or different dosages of NaHS (5 mg/kg, 10 mg/kg, 20 mg/kg or 100 mg/kg). PAG or NaHS was administered 1 h before induction of pancreatitis. Rats were sacrificed 24 h after the last L-Arg injection. Blood and pancreas tissues were collected.RESULTS: The H₂S and cystathionine-γ-lyase mRNA levels in SAP rats were significantly lower than those in the control group, and treatment with PAG further reduced the H₂S level. Nevertheless, H₂S was significantly increased after NaHS administration compared with the SAP group, and the degree of upregulation was associated with the NaHS dosage. NaHS reduced the levels of plasma amylase, interleukin-6 and myeloperoxidase in pancreatic tissue. NaHS suppressed the degradation of IκBα and the activity of nuclear factor-κB, as well as the phosphorylation of PI₃K/AKT.CONCLUSION: H₂S plays an anti-inflammatory role in SAP in vivo.     

H2S mediates O2 sensing in the carotid body

Gaseous messengers, nitric oxide and carbon monoxide, have been implicated in O₂ sensing by the carotid body, a sensory organ that monitors arterial blood O₂ levels and stimulates breathing in response to hypoxia. We now show that hydrogen sulfide (H₂S) is a physiologic gasotransmitter of the carotid body, enhancing its sensory response to hypoxia. Glomus cells, the site of O₂ sensing in the carotid body, express cystathionine γ-lyase (CSE), an H₂S-generating enzyme, with hypoxia increasing H₂S generation in a stimulus-dependent manner. Mice with genetic deletion of CSE display severely impaired carotid body response and ventilatory stimulation to hypoxia, as well as a loss of hypoxia-evoked H₂S generation. Pharmacologic inhibition of CSE elicits a similar phenotype in mice and rats. Hypoxia-evoked H₂S generation in the carotid body seems to require interaction of CSE with hemeoxygenase-2, which generates carbon monoxide. CSE is also expressed in neonatal adrenal medullary chromaffin cells of rats and mice whose hypoxia-evoked catecholamine secretion is greatly attenuated by CSE inhibitors and in CSE knockout mice.     

Hydrogen sulfide ameliorates aging-associated changes in the kidney

Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H₂S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H₂S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H₂S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18–19 month-old male C57BL/6 mice to receive 30 μmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1β, and IL-6, components of the senescence-associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H₂S deficiency. Administration of H₂S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis.     

The protective role of hydrogen sulfide in myocardial ischemia-reperfusion-induced injury in diabetic rats

Background

Hydrogen sulfide (H₂S) displays anti-inflammatory and cytoprotective activities to attenuate myocardial ischemia-reperfusion (MIR)-induced injury, but its role in MIR in diabetics is not known. This study was undertaken to investigate whether H₂S plays a protective role in MIR in diabetic rats.

Methods

Diabetes was induced by streptozocin in Wistar rats, which were subjected to myocardial ischemia by blocking the left circumflex artery for 30 min, followed by 2 h reperfusion. dl-propargylglycine (PAG) and sodium hydrosulfide (NaHS) were administered to the rats to investigate their effects on severity of MIR-induced injury.

Results

Diabetic rats had smaller myocardial infarct sizes and higher serum levels of H₂S (both P < 0.05) than non-diabetics when they underwent MIR. MIR significantly increased the serum level of H₂S (49.5 ± 7.1 μM), H₂S-synthesizing activity (7.4 ± 1.6 nmol/mg) and the myocardial infarct size (44.0 ± 7.2%), compared with sham-operated diabetic rats (21.7 ± 2.1 μM, 0.15 ± 0.4 nmol/mg and 1.2 ± 0.4%, respectively). Administration of NaHS increased the H₂S level (65.8 ± 6.9 μM) and had little effect on H₂S production activity (6.5 ± 2.2 nmol/mg), while PAG reduced both the H₂S level (29.2 ± 5.0 μM) and H₂S-synthesizing activity (2.2 ± 1.8 nmol/mg). NaHS significantly reduced the myocardial infarct size (31.2 ± 4.7%), inhibited the production of lipid peroxidation, MPO activity, and cell apoptosis, and downregulated expression of caspase-3, Fas, FasL, and TNF-α, which had been elevated by MIR, while PAG further increased the myocardial infarct size (58.3 ± 5.9%), and displayed opposite effects.

Conclusions

The study indicates that H₂S may play a protective role in MIR-induced myocardial injury in diabetics by its anti-apoptotic, anti-oxidative and anti-inflammatory activities.     

Sodium hydrosulfide alleviates pulmonary artery collagen remodeling in rats with high pulmonary blood flow

This study aimed to explore the effect of sodium hydrosulfide (NaHS) on pulmonary artery collagen remodeling in rats with high pulmonary blood flow. Thirty-two Sprague-Dawley rats were randomly divided into a sham group, shunt group, sham + NaHS (an H₂S donor) group, and shunt + NaHS group. After 11 weeks of shunting, mean pulmonary artery pressure (MPAP), relative median area (RMA) of pulmonary arteries, H₂S concentration in lung tissues, plasma endothelin-1 (ET-1) levels, and ET-1 mRNA in lung tissues were investigated. Collagen I and collagen III were evaluated by immunohistochemistry. Hydroxyproline assay and Sirius-red staining were performed. Matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and connective tissue growth factor (CTGF) were evaluated by immunohistochemistry. After 11 weeks of shunting, rats showed a significant pulmonary hypertension and pulmonary artery collagen remodeling in association with a decrease in lung tissue H₂S content. After NaHS treatment for 11 weeks, lung tissue H₂S content was increased, whereas MPAP was attenuated and RMA was reduced. Meanwhile, pulmonary artery collagen I and collagen III protein expressions of intra-acinar pulmonary arteries were inhibited, but MMP-13/TIMP-1 ratio was augmented with a decreased plasma ET-1 content and lung tissue ET-1mRNA and CTGF expressions. The downregulation of H₂S is involved in the development of pulmonary artery collagen remodeling induced by high pulmonary blood flow.     

Cystathionine gamma-lyase-deficient smooth muscle cells exhibit redox imbalance and apoptosis under hypoxic stress conditions

BACKGROUND:

Hydrogen sulphide (H₂S) has recently emerged as a novel and important gasotransmitter in the cardiovascular system, where it is generated mainly by cystathionine gamma-lyase (CSE). Abnormal metabolism and functions of the CSE/H₂S pathway have been linked to various cardiovascular diseases including atherosclerosis and hypertension. An important role for H₂S in regulating the balance between cellular growth and death has been demonstrated whereby inhibition of the endogenous CSE/H₂S pathway results in greater apoptosis of vascular smooth muscle cells (SMCs). H₂S is increasingly recognized as a critical regulator of vascular integrity, but its role in SMCs during hypoxia has not been explored in a model of CSE deficiency.

METHODS:

Cell viability, apoptosis, redox status and mitochondrial activity in hypoxia-exposed (12 h at 1% O₂) SMCs derived from the mesenteric artery of CSE-knockout (CSE-KO) mice were analyzed. These were compared with those from CSE-wild-type (CSE-WT) mice.

RESULTS:

CSE-KO cells exhibited redox imbalance and aberrant mitochondrial activity versus CSE-WT cells, indicating an essential regulatory role for the endogenous CSE/H₂S pathway on SMC function. CSE-KO cells were also more susceptible to hypoxia-induced cell death, indicating a critical contribution of endogenous CSE/H₂S pathway to the protective hypoxia stress response.

CONCLUSION:

These findings support the concept that H₂S is a crucial regulator of vascular homeostasis, the deficiency of which is associated with various pathologies, and provide further evidence that H₂S is a potent vasculoprotectant.     

Therapeutic Evaluation of Outpatient Submucosal Inferior Turbinate Surgery for Patients with Severe Allergic Rhinitis

BackgroundSurgical treatment for inferior turbinate (IT) is selected to treat severe allergic rhinitis (AR) that is unresponsive to conservative treatment. This study aimed to determine the clinical effects of outpatient sub- mucosal IT surgery (OSITS) on patients with severe AR.MethodsBetween January 2008 and August 2012, 95 patients with severe AR who underwent OSITS at the Department of Otolaryngology, Hyogo College of Medicine, were retrospectively analyzed. There were 53 men and 42 women. Their mean age was 27 years (11–75 years). OSITS was bilaterally performed using a bipolar radiofrequency electrocautery under local anesthesia. Symptoms, QOL, and physical findings were evaluated using scores from both pre- and postoperative periods (average: 12.4 months), according to Practical Guideline for the Management of AR in Japan 2009.ResultsIn perennial AR, all mean scores of nasal symptoms, QOL, and physical findings significantly improved after OSITS (p < 0.05, n = 83). Nasal obstruction, sleep problems, and IT congestion were the most strongly affected. Eye symptoms were not influenced by OSITS. OSITS also showed significant effects on nasal obstruction and IT congestion in seasonal AR (p < 0.05, n = 12), but not sneezing, nasal discharge, and QOL. In terms of the efficacy, OSITS was beneficial in 90% of perennial AR cases and 75% of seasonal AR cases. Epistaxis (1%), vestibulitis (1%), and IT atrophy (4%) were observed after OSITS.ConclusionsThese data indicate that OSITS using radiofrequency electrocautery could be a beneficial therapeutic option in patients with severe AR.