Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation

Roviezzo, Fiorentina; Bertolino, A.; Sorrentino, Rosalinda; Terlizzi, Michela; Matteis, Maria; Calderone, Vincenzo; Mattera, Valentina; Martelli, Alma; Spaziano, Giuseppe; Pinto, Aldo; D’Agostino, Bruno; Cirino, Giuseppe

doi:10.1016/j.phrs.2015.07.032

Cited by 42 publications

(38 citation statements)

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“…Although the role of mast cells in experimental asthma models is still controversial, recently several researchers have demonstrated the role of innate immune cells in asthma development and in this context, mast cells seem to play an important role, especially in the process of sensitization to allergen (Deckers et al, 2013). Indeed, mast cell infiltration in the smooth muscle is correlated with responsiveness to cholinergic stimuli as, we have already demonstrated in our experimental setting (Roviezzo et al, 2015). In particular, mast cells, armed with specific IgE and residing in the mucosa, serve as airway sentinels, sensing and responding to inhaled antigens.…”

Section: Discussionsupporting

confidence: 76%

“…In particular, we used as experimental approach a systemic exposure of mice to OVA that induces an significant increase in plasmatic IgE level. This effect is coupled to a significant increase in bronchial hyperreactivity and pulmonary inflammation associated to pulmonary mast cell recruitment (Roviezzo et al, 2015). Measurements of bronchial reactivity in vitro evidenced a significant increase in carbachol-induced contractions, that was reversed by Salvinorin A.…”

Section: Discussionmentioning

confidence: 99%

“…Animals were injected with 0.4 ml s.c. of a suspension containing 100 μg of OVA absorbed to 3.3 mg of aluminium hydroxide gel on days 1 and 8 (OVA-sensitized mice) ( Figure 1A ) (Das et al, 1997; Roviezzo et al, 2007, 2015; Sullo et al, 2013). Salvinorin A (10 mg/kg; Rossi et al, 2016) or vehicle (dimethyl sulfoxide 4%, 0.5 ml) were administered i.p.…”

Section: Methodsmentioning

confidence: 99%

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Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

et al. 2017

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Salvinorin A, a neoclerodane diterpene isolated from Salvia divinorum, exerts a number of pharmacological actions which are not solely limited to the central nervous system. Recently it has been demonstrated that Salvinorin A inhibits acute inflammatory response affecting leukotriene (LT) production. Since LTs are potent lipid mediators implicated in allergic diseases, we evaluated the effect of Salvinorin A on allergic inflammation and on airways following sensitization in the mouse. Mice were sensitized with s.c. injection of ovalbumin (OVA) on days 1 and 8. Sensitized mice received on days 9 and 12 on the shaved dorsal surface air administration to induce the development of the air-pouches. On day 15 animals were challenged by injection of OVA into the air-pouch. Salvinorin A, administered (10 mg/kg) before each allergen exposure, significantly reduced OVA-induced LT increase in the air pouch. This effect was coupled to a reduction in cell recruitment and Th2 cytokine production. In another set of experiments, mice were sensitized with OVA and both bronchial reactivity and pulmonary inflammation were assessed. Salvinorin A abrogated bronchial hyperreactivity and interleukin (IL)-13 production, without effect on pulmonary inflammation. Indeed cell infiltration and peribronchial edema were still present following diterpenoid treatment. Similarly, pulmonary IL-4 and plasmatic IgE levels were not modulated. Conversely, Salvinorin A significantly reduced LTC4 production in the lung of sensitized mice. Finally mast cell activity was evaluated by means of toluidine blue staining. Data obtained evidenced that Salvinorin A significantly inhibited mast cell degranulation in the lung. Our study demonstrates that Salvinorin A inhibits airway hyperreactivity induced by sensitization by inhibition of LT production and mast cell degranulation. In conclusion Salvinorin A could represent a promising candidate for drug development in allergic diseases such as asthma.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

et al. 2017

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“…Noteworthy, H 2 S was reported to inhibit antigen-induced degranulation of rat basophile leukemic RBL-2H3 cells (a well known mast-cell like model) and murine bone marrow-derived mast cells, suggesting an inhibitory role of this gasotransmitter in mast cell-mediated inflammatory responses [18,19]. Therefore, a possible H 2 S-mediated inhibition of the degranulation of resident heart mast cells may be a further (and poorly investigated) mechanism contributing, at least in part, to the overall cardioprotective activity.…”

Section: Introductionmentioning

confidence: 99%

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

Testai

Marino

Piano

et al. 2016

Pharmacological Research

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a b s t r a c tThe endogenous gasotransmitter hydrogen sulphide (H 2 S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H 2 S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H 2 S-donors, i.e. pro-drugs able to generate exogenous H 2 S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H 2 S-donor 4-carboxy phenylisothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R.In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoK ATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H 2 S-producing enzymes to be present in myocardial tissue: cystathionine ␥-lyase (CSE), cystathionine ␤-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE.In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells.In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of K ATP channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix.Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/Rinduced tissue injury.In conclusion, H 2 S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.

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“…In a rat model of isoproterenol‐induced cardiac failure, in which local mast cell number and renin levels increase, administration of NaHS reduced both mast cell density and renin (Liu et al , ). Also, exogenous H 2 S inhibited allergen‐induced airway hyper‐reactivity, which was attributed to a reduction of mast cell degranulation, observed in vitro in rat basophilic leukaemia (RBL‐2H3) cells (Roviezzo et al , ). Yet, little is known about a possible role of endogenous H 2 S and H 2 S‐releasing compounds in mast cell pathophysiology.…”

Section: Introductionmentioning

confidence: 95%

The novel H₂S donor 4‐carboxy‐phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium

Marino

Martelli

Citi

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEHydrogen sulfide (H 2 S) modulates many pathophysiological processes, including inflammation and allergic reactions, in which mast cells act as major effector cells. IgE receptor (FcεRI) cross linking leads to an increase in intracellular calcium ([Ca +2 ] i ), a critical step in mast cell degranulation. The aim of this study was to investigate the role of H 2 S in [Ca +2 ] i -dependent mast cell activation. EXPERIMENTAL APPROACHWe investigated the effects of H 2 S, either endogenously produced or released by the slow H 2 S donor 4-carboxy-phenyl isothiocyanate (PhNCS-COOH), on antigenic-and non-antigenic degranulation of native murine mast cells, and human and rat (RBL-2H3) mast cell lines. We measured the release of specific mast cell degranulation markers (β-hexosaminidase and renin), as well as changes in [Ca +2 ] i and phosphorylation of proteins downstream of FcεRI activation. KEY RESULTSEndogenously produced H 2 S inhibited antigen-induced degranulation in RBL-2H3. Similarly, H 2 S released by PhNCS-COOH (10-300 μM) reduced, in a concentration-dependent manner, antigenic and non-antigenic degranulation and renin release in all mast cell types. Notably, PhNCS-COOH also prevented in a concentration-dependent mode the increase in [Ca +2 ] i elicited by Ca +2 ionophore, thapsigargin and FcεRI activation. Moreover, PhNCS-COOH attenuated the phosphorylation of Syk, cPLA-2 and PLCγ1 in antigen-stimulated RBL-2H3 cells. CONCLUSION AND IMPLICATIONSCollectively, our results demonstrate that, by attenuating the phosphorylation of proteins downstream of FcεRI cross-linking on mast cells, H 2 S diminishes [Ca +2 ] i availability and thus mast cell degranulation and renin release. These findings suggest that PhNCS-COOH could be a strategic therapeutic tool in mast cell-mediated allergic conditions. AbbreviationsAng I, angiotensin I; BMMC, bone marrow-derived murine mast cells; [Ca 2+ ] i , intracellular Ca 2+ level; CBS, cystathionine β-synthase; cPLA2, cytosolic phospholipase A2; CSE, cystathionine γ-lyase; DNP, dinitrophenylated-human serum albumin; D-Pen, D-penicillamine; FcεRI, high affinity IgE receptor; HMC-1, human mastocytoma cell line; MEF, mouse embryo fibroblast; PhNCS-COOH, 4-carboxy-phenyl-isothiocyanate; PLCγ1, phospholipase Cγ1; RBL-2H3, rat basophilic leukaemia cell line; β-HEX, β-hexosaminidase

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Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation

Cited by 42 publications

References 27 publications

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

The novel H₂S donor 4‐carboxy‐phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium

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Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation

Cited by 42 publications

References 27 publications

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

Salvinorin A Inhibits Airway Hyperreactivity Induced by Ovalbumin Sensitization

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

The novel H2S donor 4‐carboxy‐phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium

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The novel H₂S donor 4‐carboxy‐phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium