CURE TERMALI E VIE AEREE: RAZIONALE ED EVIDENZE SCIENTIFICHE NEL TERZO MILLENNIO. Carlo Sturani Direttore Scientifico Terme di Sirmione

CURE TERMALI E VIE AEREE:

RAZIONALE ED EVIDENZE SCIENTIFICHE NEL TERZO MILLENNIO

Carlo Sturani

Direttore Scientifico Terme di Sirmione

Cure termali con acque sulfuree

•

T0 ?

•

T1 Ippocrate

•

T2 Galeno, Celso, Plinio

•

T3 1713 Ramazzini…..



La tradizione dalla medicina narrativa agli studi

osservazionali clinici

Terme e Grandi Alberghi Sirmione SpA

Bernardino Ramazzini

nella sua opera

“de morbis artificum diatriba”

la cui prima edizione risale al 1700, riconferma l’importanza,

già nota agli antichi,

delle cure termali con acque sulfuree

per diverse, numerose, patologie.

Cure termali

•

T4 1960-2000 La specializzazione medica in idrologia e le altre specialità mediche dai trial clinici alle metanalisi

•

I LEA ed il ruolo di medicina ufficiale nell’ambito della Prevenzione, della Cura e della Riabilitazione

•

T5 1990-2020

La ricerca scientifica ed il ruolo dell’H2S

AGENDA

I risultati della ricerca scientifica

sugli effetti delle acque termali sulfuree

nel terzo millennio

Centro di Ricerca Terme di Sirmione/FORST

•

Hydrogen sulfide prevents apoptosis of human PMN via inhibition of p38 and caspase 3.

Rinaldi L, Gobbi G, Pambianco M, Micheloni C, Mirandola P, Vitale M.

Lab Invest. 2006;86:391-7.

•

Exogenous hydrogen sulfide induces functional inhibition and cell death of cytotoxic lymphocytes subsets.

Mirandola P, Gobbi G, Sponzilli I, Pambianco M, Malinverno C,Cacchioli A, De Panfilis G, Vitale M . J Cell Physiol 2007; 213(3):826-33.

Centro di Ricerca Terme di Sirmione/FORST

-Rinaldi L. et al, Laboratory Investigation 2006, 86: 391-97;

-Mirandola P. et al, J. Cellular Physiology 2007, 213:826-33.

hanno dimostrato gli effetti cellulari dell’idrogeno solforato su globuli bianchi e linfociti del sangue periferico,

proposti come la base per l’effetto favorente la risoluzione dei processi infiammatori e l’ inibizione della loro cronicizzazione.

Centro di Ricerca Terme di Sirmione/FORST

• Sulphurous thermal water increases the release of the anti-inflammatory cytokine IL-10 and modulates antioxidant enzyme activity

Prandelli C, Parola C, Buizza L, Marziano M, Salvi V, Zacchi V, Memo D.

Int J Immunopathol Pharmacol. 2013 26(3):633-46

Sulphurous thermal water increases the release of the anti-

inflammatory cytokine IL-10 and modulates antioxidant enzyme activity

•

these results represent the first evidence suggesting that Sulphurous Thermal Water may prove useful in

•

chronic inflammatory and age-related illness

•

due to combined anti-inflammatory

and anti-oxidant properties.

• L’idroterapia termale nel trattamento

delle broncopneumopatie croniche.

• Risultati del progetto NAIADE .

Melillo G., Nappi G, Valenti M.

• Rassegna di Patologia dell’Apparato Respiratorio

• 2002; 17:37-42.

L’idroterapia termale nel trattamento delle broncopneumopatie croniche

Risultati del progetto NAIADE (Ministero salute-Federterme)

5038 pazienti

con patologia respiratoria cronica

Prima

del primo ciclo

Dopo il primo ciclo

Prima del

secondo ciclo

Dopo

il secondo ciclo

p

% pazienti ospedalizzati

10,6 4,5 7,8 1,3 <0,03

%giorni persi lavoro

16,1 10,5 10,3 5,4 <0,05

%consumo abituale antibiotici

45,9 38,9 <0,05

%consumo abituale

broncodilatatori

20,7 13,2 <0,05

%consumo abituale mucoattivi

51,8 29,4 <0,05

Sintomi respiratori

<0,05

Effect of inhalation of thermal water on airway inflammation in COPD.

Pellegrini M, Faggian D, Saetta M, Maestrelli P

Respir Med. 2005 Jun;99(6):748-54

Inhalation of sulphurous thermal water induced

•

a significant decrease in percentages of sputum neutrophils (P < 0.01)

•

and a parallel increase in macrophages (P <0.01).

Ther Adv Respir Dis.

2010 Dec;4(6):333-40.

• Effects of sulphurous water on human

neutrophil elastase release.

• Antioxidant effect of

sulphurous thermal water on human

neutrophil bursts:

chemiluminescence evaluation.

Respiration.

2008;75(2):193-201

Reducing agents decrease the oxidative burst and improve clinical outcomes in COPD: a randomised controlled trial on the effects of suphurous thermal water.

Scientific World Journal. 2013: Article ID 927835; http://dx.doi.org./10.1155/2013/927835.

Inhalation of suphurous thermal water resulted in

• a significant reduction of O2−production in exhaled breath condensate of COPD patients and in clinical outcome (CAT)

•

at the end of the inhalatory treatment

• and at follow-up compared to baseline.

Thermal Water Applications in the Treatment of Upper Respiratory Tract Diseases:

A Systematic Review and Meta-Analysis

Institute of Medical Statistics, Informatics and Epidemiology , University Hospital of Koln, Germany

J Allergy. 2014: Article ID 943824, doi: 10.1155/2014/943824.

• 8 evaluable outcome parameters

• from 13 prospective clinical studies

• were identified for 840 patients.

Thermal water applications in the treatment of upper respiratory tract diseases: a systematic review and meta-analysis.

J Allergy. 2014:Article ID 943824, 17 pages; doi: 10.1155/2014/943824.

•

Mucociliary clearance time improves significantly (𝑃 < 0.001) for the pooled thermal water sulphurous subgroup

•

after 2 weeks (−6.69/minutes) and after 90 days (−8.33/minutes),

•

not for isotonic sodium chloride solution (ISCS).

Thermal water applications in the treatment of upper respiratory tract diseases: a systematic review and meta-analysis.

J Allergy. 2014:Article ID 943824, 17 pages; doi: 10.1155/2014/943824.

•

Adverse events of minor character were rare for sulphurous treatment (19/370)

Conclusion.

•

Thermal water applications with sulphur recommended as

•

additional nonpharmacological treatment in upper

airway diseases.

Sulphurous water inhalations in the prophylaxis of recurrent upper respiratory tract infections.

Salami A, Dellepiane M, Crippa B, et al.

Int. J Pediatr Otorhinolaryngol 2008;72:1717-22

•

La crenoterapia con acqua termale sulfurea ha ridotto

•

frequenza, durata e severità degli episodi patologici,

•

mostrando attività immunomodulante nei bambini con

infezioni ricorrenti del tratto respiratorio superiore.

Acqua di Sirmione® per la poliposi naso-sinusale

Sinergie tra terapia chirurgica e termale nella poliposi naso-sinusale.

Tomenzoli D, Berlucchi M, Nicolai P, Antonelli AR. Otorinolaringol 2000;50 (Suppl. 1 ,N. 4): 40-42.

nasale ha determinato

•

un miglioramento generale della sintomatologia

•

e dell’obiettività endoscopica

Impact of sulphurous water Politzer inhalation on audiometric parameters in children with Otitis Media with effusion.

Mirandola P, Gobbi G, Carubbi C.

Clin Experimental Othorinolaryngology 2013; 6: 7-11.

• La valutazione dell’outcome è stata eseguita con es.audiometrico.

• I risultati hanno evidenziato che l’udito del bambino è migliorato in modo significativo al termine del singolo ciclo (ridotta perdita di dB a 500,1000,2000 Hz; p<0,05).

All’inizio del ciclo successivo è tornato ad evidenziarsi il deficit che, a partire dal termine del secondo ciclo di cure, è migliorato

progressivamente

fino a sparire virtualmente dopo 5 cicli.

A comparative randomized study on the efficacy of a systemic steroid therapy vs. a thermal therapy in Otitis media with effusion in children.

Califano L, Salafia F, Mazzone S, D’Ambrosio G, Malafronte L, Vassallo A.

Minerva Pediatr 2016; 68: 241-9

• Le variazioni del timpanogramma sono state utilizzate come outcome primario dello studio.

• Il passaggio del timpanogramma da un tipo B a un tipo C o A e da un tipo C a un tipo A viene considerato un outcome positivo.

La terapia termale ha dimostrato migliori risultati a tutti i tempi d’indagine, con differenze statisticamente significative.

Insufflazione endotimpanica tecnica nata presso le Terme di Sirmione più di 30 anni fa

Terme di Sirmione

Scuola di Specializzazione in ORL Univ Milano, Brescia, Padova, Verona, Ferrara

Terme e Grandi Alberghi Sirmione SpA

Salute: il Centro Ipoacusia Rinogena: > 3000 BAMBINI/ANNO

Terme Virgilio

2 ambulatori medici, 9 specialistici

6 postazioni per le insufflazioni endotimpaniche

1 cabina audiometrica

Il Centro si avvale anche del Reparto cure inalatorie, con 144 postazioni

Terme Catullo

3 ambulatori specialistici 1 cabina di audiometria e impedenzometria

3 postazioni per l’insufflazione endotimpanica

Il Centro si avvale anche del Reparto cure inalatorie, con 104 postazioni

Carbon Monoxide CO

Nitric Oxide NO

Hydrogen Sulphide H

S

Physiological gaseous mediators

H

S AS AN ENDOGENOUS MEDIATOR

(slide by courtesy of H. Kimura)

HYDROGEN SULFIDE IS A SIGNALING MOLECULE

AND A

CYTOPROTECTANT.

Kimura H, Shibuya N, Kimura Y.

Antioxid Redox Signal.

2012 1;17(1):45-57.

Hydrogen sulfide is a signaling molecule and a cytoprotectant. Kimura H, Shibuya N, Kimura Y.

Antioxid Redox Signal. 2012 l 1;17(1):45-57.

• Accumulating evidence shows that H2S may function as a

signaling molecule in processes such as neuromodulation in the brain and smooth muscle relaxation in the vascular

system.

• It also has a cytoprotective effect, since it can protect neurons and cardiac muscle from oxidative stress and ischemia-

reperfusion injury, respectively.

• H2S also modulates inflammation, insulin release, and angiogenesis

Hydrogen Sulphide

Vascular System Inflammation

Molecular and Cellular Biology

2013; 33(6): 1104–1113 2013

Am J Physiol Cell Physiol. 2017; 312:C537-49

Am J Physiol Cell Physiol. 2017; 312:C537-49

Functional and molecular insights of hydrogen sulfide signaling and protein sulfhydration

J Mol Biol. 2017; 429(4): 543–561.

Molecular and Cellular Biology

2013; 33(6): 1104–1113 2013

Molecular and Cellular Biology

2013; 33(6): 1104–1113 2013

The role of hydrogen sulfide in aging and age-related

pathologies.

.

Microvascular Endothelial Dysfunction in Obesity Is Driven by Macrophage-Dependent Hydrogen Sulfide Depletion

Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:889–89

Idrogeno solforato (H₂S)

il più importante gas trasmettitore nel nostro organismo

• Per la regolazione del ciclo cellulare, dei processi di citoprotezione e di rigenerazione tessutale

• Per contrastare

-lo stress ossidativo e post traumatico -le patologie cronico degenerative

-i processi d’invecchiamento -le infezioni (virus e batteri) -il dolore cronico

Water Science & Technology: Water Supply | 18.4 | 2018

doi: 10.2166/

UPDATE 2020 respiro e longevità

Acqua termale sulfurea salsobromoiodica

Carlo Sturani

Direttore Scientifico Terme di Sirmione

CSE

International Journal of COPD 2018:13 3165–3172

Autophagy, selective autophagy, and necroptosis in COPD

Cellular Mechanisms of Proteostasis

Cigarette smoke-induced autophagy impairment

accelerates lung aging, COPD-emphysema exacerbations and pathogenesis

Am J Physiol Cell Physiol. 2018 Jan 1; 314(1): C73–C87^.

• Tobacco/cigarette smoke (CS) exposure and aging can induce proteostasis and autophagy impairment, serving as a central mechanism to induce inflammatory-oxidative stress.

• Chronic-CS-exposure-mediated steep decline in

proteostasis/autophagy accelerates inflammatory-oxidative stress, apoptosis, and senescence, serving as a mechanism for accelerated lung aging and emphysema progression.

Front. Pharmacol.

8:675. doi: 10.3389/fphar.2017.00675

Front. Pharmacol.

8:675. doi: 10.3389/fphar.2017.00675

Front. Pharmacol.

8:675. doi: 10.3389/fphar.2017.00675

H₂S inhibited lung tissue damage

by attenuating CS induced ERS in rat lung

and exogenous H₂S attenuated nicotine induced ERS- mediated apoptosis in bronchial epithelial cells.

Am J Pathol. 2013 Apr;182(4):1188-95.

HYDROGEN SULPHIDE INHALATION AMELIORATES ALLERGEN INDUCED AIRWAY HYPERREACTIVITY BY MODULATING MAST CELL ACTIVATION. Pharmachological Research 2015; 100:85-92

H2S

•

Prevented mast cell activity as IL-13 upregulation

•

Abrogated ovalbumin-induced bronchial

hyperreactivity as well as the increase in lung resistance

•

Inhibited ovalbumin induced proliferation of

primary fibroblasts

HYDROGEN SULPHIDE INHALATION AMELIORATES ALLERGEN

INDUCED AIRWAY HYPERREACTIVITY BY MODULATING MAST CELL ACTIVATION.

Roviezzo et Al . Pharmachological Research 2015; 100:85-92

In conclusion,

inhaled hydrogen sulfide

•

Improves lung function

• Inhibits allergen induced bronchial hyperreactivity by modulating mastcells

• and in turn fibroblast activation

The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide

Perry et al. Respiratory Research (2018) 19:85

• For the first time, we demonstrate that

•

both endogenous and exogenous H2S

•

inhibits human ASM cell proliferation

•

and cytokine release induced by FCS,

•

and that this effect was dependent on the patient.

Role of endogenous H2S in nerve evoked relaxation of pig terminal bronchioles.

Pulmonary Pharmacology & Therapeutics 2016; 41:1-10

• Results suggest that relaxation induced by Electrical Field Stimulation in terminal bronchioles involves the H2S/CSE pathway.

• H2s response is produced via NO independent mechanisms involving k channels and intracellular Ca 2+ desensitivation- dependent pathways.

• Based on our current results exogenous H2S might be useful as bronchodilator agent for the treatment of lung diseases with persistent airflow limitation such as asthma and COPD.

Hydrogen Sulfide Signaling in Neonatal Airways

Mayo Clinic. Am J Respir Crit Care Med 2020;201:A1247 ATS 2020

• Supplemental O2 (hyperoxia) is necessary for preterm infants in the neonatal ICU but is associated with development of

bronchial airway hyperreactivity (AHR) and asthma.

• Our goal is to understand early mechanisms that link altered contractility/relaxation and remodeling with prematurity and/or

hyperoxia.

• Our data provide novel information regarding the potential

• for H₂S to act as a bronchodilator in developing airways in the context of oxygen exposure.

FASEB September 2020, 34: 12991-13004

•

Hydrogen sulfide, oxygen, and calcium regulation in developing human airway smooth muscle

•

Colleen M. Bartman ET Al .

•

Department of Anesthesiology, Mayo Clinic,

Rochester, MN, USA

Sirtuin 1

• Mammals have 7 sirtuins (SIRT1-7)

• SIRT1 is the best-characterized sirtuin and largely located in the lungs, which plays a pivotal role in many

pathophysiological processes, including

cellular senescence,

inflammation,

oxidative stress,

and mitochondria dysfunction

Molecular and Cellular Biology 2013; 33(6): 1104–1113 2013

Hydrogen sulfide attenuates mitochondrial dysfunction-induced cellular senescence and apoptosis in alveolar epithelial cells by upregulating sirtuin 1.

Guan R. et Al. Aging (Albany NY). 2019. 23;11(24):11844-11864.

• H2S attenuated cigarette smoke extract - induced oxidative stress,

• mitochondrial dysfunction,

• cellular senescence

• and apoptosis in A549 cells.

• This was associated with SIRT1 upregulation.

These findings provide novel mechanisms underlying the protection of H₂S against cigarette smoke-induced COPD

Hydrogen sulfide attenuates cigarette smoke-induced

airway remodeling by upregulating SIRT1 signaling pathway Redox Biology 28 (2020) 101356

• Exogenous H2S decreases coronary artery wall thickness in the spontaneously hypertensive rat by inhibiting reactive oxygen species (ROS).

• H2S reduces oxidative stress in myocardial hypertrophy via a SIRT3-dependent manner

• H2S inhibits TGF-β1-induced EMT in renal tubular epithelial cells via Wnt/catenin pathway.

• H2S also ameliorates chronic restrain stress- induced cognitive impairment in hippocampus by upregulating SIRT1.

Hydrogen sulfide attenuates cigarette smoke-induced airway remodeling by upregulating SIRT1 signaling pathway

Redox Biology 28 (2020) 101356

• Here, we investigated the effects and mechanisms of hydrogen sulfide (H₂S) on pulmonary EMT in vitro and in vivo.

• We found that H₂S donor NaHS inhibited

• -cigarette smoke (CS)-induced airway remodeling,

• -EMT and collagen deposition in mouse lungs.

In human bronchial epithelial 16HBE cells, NaHS treatment also reduced CS extract (CSE)-induced EMT, collagen deposition and oxidative stress.

Hydrogen sulfide attenuates cigarette smoke-induced airway remodeling by upregulating SIRT1 signaling pathway

Redox Biology 28 (2020) 101356

Smettere di fumare riduce l'infiammazione ma solo dopo diversi anni

•

Questo studio dimostra che smettere di fumare è utile anche dopo i 50 anni,

•

ma che è possibile abbattere il rischio in chi ha una PCR elevata agendo sugli altri fattori che possono ridurla, come alcuni farmaci anti-infiammatori, una dieta più sana, e una regolare attività fisica.

• Lo studio è stato condotto su oltre 3.000 fumatori in collaborazione con l'Istituto di Ricerche Farmacologiche Mario Negri di Milano

• ed è il più ampio studio prospettico disponibile finora .

.

Acta Physiologica 2018. 225:2 e13177.

Exercise training

• ameliorates bleomycin-induced

epithelial mesenchymal transition (EMT) and lung fibrosis

• through restoration of H

S synthesis.

H2S attenuates Particulate Matter-Induced Emphysema and Airway Inflammation Through Nrf2-Dependent Manner.

Front. Pharmacol. 2020. 11:29. doi: 10.3389

•

The Nrf2 related antioxidant system was impaired in tobacco smoke-induced COPD mice model and PM-induced COPD model,

•

also activation of Nrf2 attenuated COPD and

emphysema caused by cigarette smoke exposure

(Sussan 2009; Han 2011; Zhang 2018).

H2S attenuates Particulate Matter-Induced Emphysema and Airway Inflammation Through Nrf2-Dependent Manner.

Front. Pharmacol. 2020. 11:29. doi: 10.3389

H2S Prevented

•

Particulate Matter2.5-Induced Reactive Oxygen

Species Generation,

•

NLRP3 Inflammasome Formation,

•

and Apoptosis in A549 Cells



but Not in Nrf2 Silenced A549 Cells

Hydrogen Sulfide Attenuates Particulate Matter–Induced Human Lung Endothelial Barrier Disruption via Combined Reactive

Oxygen Species Scavenging and Akt Activation.

Am J Respir Cell Mol Biol 2012; 47:491–496.

Furthermore, H2S reduced

•

vascular protein leakage,

•

leukocyte infiltration,

•

and proinflammatory cytokine release in BAL fluids.

•

These data suggest a potentially protective role for

H2S in PM-induced inflammatory lung injury and

vascular hyperpermeability.

The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation.

Cai WJ, Wang MJ, Moore PK. Cardiovasc Res 2007;76:29–40.

Aging 2018 Jul 19;10(7):1666-1681.

• Mitochondria-targeted hydrogen sulfide attenuates endothelial

senescence by selective induction of splicing factors HNRNPD and SRSF2.

• Latorre E¹, Torregrossa R¹, Wood ME², Whiteman M¹, Harries LW¹.

Protective effect of exogenous hydrogen sulfide on pulmonary

artery endothelial cells by suppressing endoplasmic reticulum stress in a rat model of COPD

Ding H.-B., Liu K.-X., Huang J.-F., Wu D.-W., Chen J.-Y., Chen Q.-S.

Biomedicine and Pharmacotherapy, 2018; : 734-741.

The key findings of the current study highlight

•

ERS in COPD rats,

•

as well as reduced apoptosis in pulmonary artery

endothelial cells (in connection with exogenous

H2S by suppressing ERS.

Oxidative Medicine and Cellular Longevity

2017, Article ID 3715037, doi.org/10.1155/2017/371503

• Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through

PI3K/Akt Signaling

 Limits Ventilator-Induced Lung Injury

Front. Public Health, 2019

https://doi.org/10.3389/fpubh.2019.00128

Role of Hydrogen Sulfide in Chronic Diseases

• DNA and Cell Biology. 2020 vol 39, No. 2

• Reviews 2020

• https://doi.org/10.1089/dna.2019.50 67

2020

• Il Prof. Papi (Univ Ferrara) , Chairman del Simposio ha concluso:

• "questo simposio ha evidenziato come il mantenimento dell'omeostasi ossidanti-antiossidanti sia fondamentale

per preservare la funzione polmonare

prevenire la progressione di patologie croniche e il ruolo che potrebbe svolgere nel trattamento delle IPF

come anche di forme di fibrosi successive all'infezione da COVID-19".

Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Corona virus

SHOCK. 2020 , doi: 10.1097/SHK.0000000000001562

• Survivors had significantly higher H2S levels on day 1 and 7 after admission. A cut-off point of 150.44 μM could discriminate survivors

• Mortality was significantly greater among patients with a

decrease of H2S levels from day 1 to day 7 greater or equal to 36% (p: 0.0005).

• Serum H2S on day 1 was negatively correlated with IL- 6 and CRP and positively correlated with the absolute lymphocyte count in peripheral blood.

• It is concluded that H2S is a potential marker for severity and final outcome of pneumonia by the SARS-CoV2

Respiratory viral infections and subversion of cellular antioxidant defenses.

Komaravelli N., Casola A. Journal Pharmacogenomics Pharmacoproteomics 2014

5. https://doi.org/10.4172/2153-0645.1000141

• Many pulmonary viral infections increase ROS levels and impair antioxidant enzymes, including those associated with the Nrf2–

ARE pathway, with consequent reduction of antioxidant response.

• This leads to the suggestion that agents able to activate the Nrf2 system and induce sustained antioxidant activity may represent a useful strategy to counteract the viral infection by respiratory viruses.

Am J Respir Cell Mol Biol Vol 55, Iss 5, pp 684–696, Nov 2016

Hydrogen Sulfide: A Novel Player in Airway Development,

Pathophysiology of Respiratory Diseases, and Antiviral Defenses.

Am J Respir Cell Mol Biol. 2017 Oct;57(4):403-410.

• In the respiratory tract, endogenous H₂S has been shown to participate in the regulation of important functions such as airway tone, pulmonary circulation, cell proliferation or apoptosis, fibrosis, oxidative stress, and inflammation.

• In the past few years, changes in the generation of H₂S have been linked to the pathogenesis of a variety of

acute and chronic inflammatory lung diseases, including asthma and COPD

Hydrogen Sulfide: A Novel Player in Airway Development,

Pathophysiology of Respiratory Diseases, and Antiviral Defenses.

Am J Respir Cell Mol Biol. 2017;57(4):403-410.

•

Recently, our laboratory made the critical discovery that cellular H

S exerts broad-spectrum antiviral activity both in vitro and in vivo, in addition to independent antiinflammatory activity.

•

These findings have important implications for the development of novel therapeutic strategies for viral respiratory infections, as well as other

inflammatory lung diseases.

Am J Respir Cell Mol Biol Vol 57, Iss 4, pp 403–410, 2017 Copyright © 2017 by the American Thoracic Society

The Virome, a Convoluted System Molding Human Immune

Defenses and Possibly Affecting the Development of Asthma and Respiratory Diseases in Childhood.

Front.Microbiol. 2018 Apr 10;9:686

• Role of hydrogen sulfide in paramyxovirus infections.

J Virol. 2015 May;89(10):5557-68.

• Role of human metapneumovirus and respiratory syncytial virus in asthma exacerbations

Clin Sci (Lond). 2017 Jun 30;131(14):1713-1721

• Virome and Inflammasomes, a Finely Tuned Balance with Important Consequences for the Host Health.

Viruses 2018, 10, 249; doi:10.3390/v10050249

Using a mouse model of RSV infection, intranasal delivery of TAGDD-1 to infected mice significantly

• reduced viral replication and lung inflammation,

• markedly improving clinical disease parameters

• and pulmonary dysfunction, compared to vehicle treated controls.

Anti-inflammatory effects of H2S

during acute bacterial infection: a review

Benedetti et al. J Transl Med (2017) 15:100 . DOI 10.1186/s12967-017-1206-8

.

IUBMB Life 70:5, 393-410.

Online publication date: 30-Mar-2018.

Hydrogen sulfide in physiology and pathogenesis of bacteria

and viruses

Anti‐inflammatory and antiviral roles of hydrogen sulfide:

Rationale for considering H2S donors in COVID‐19 therapy.

British Journal of Pharmacology, 11 August 2020, DOI: (10.1111/bph.15230)

Role of H2S in lung inflammation.

H2S shows many beneficial effects in lung inflammation disease.

Citi V et al. Br J Pharmacol. 2020;1–11.

(a)H2S is able to break mucin disulfide bonds, making the mucus less viscous and easier to be expelled by the

respiratory ciliary apparatus,

facilitating the elimination of potentially harmful viruses or extraneous particles.

Role of H2S in lung inflammation.

H2S shows many beneficial effects in lung inflammation disease.

Citi V et al. Br J Pharmacol. 2020;1–11.

(b)H2S blocks activation of the NF‐κB pathway through the sulfhydration and inhibition of IKκβ enzyme, preventing the

translocation of NF‐κB into the nucleus,

thus preventing generation of the cytokine storm.

Role of H2S in lung inflammation.

H2S shows many beneficial effects in lung inflammation disease.

Citi V et al. Br J Pharmacol. 2020;1–11.

(c) H2S promotes the activation of Nrf2 (nuclear factor erythroid 2- related factor 2) enhancing the expression of antioxidant molecules

and enzymes.

Moreover, H2S is endowed with direct antioxidant activity, thus protecting the tissues from the oxidative stress.

Role of H2S in lung inflammation.

H2S shows many beneficial effects in lung inflammation disease.

Citi V et al. Br J Pharmacol. 2020;1–11.

(d) H2S activates KATP channels (ATPsensitive potassium

channels) expressed on the cell membrane of bronchial smooth muscle cells, promoting bronchodilation,

H2S blocks the Na+/K+ ATPase pump, triggering

electrolyte absorption and enhancing mucociliary clearance

Anti‐inflammatory and antiviral roles of hydrogen sulfide:

Rationale for considering H2S donors in COVID‐19 therapy.

British Journal of Pharmacology, 11 August 2020, DOI: (10.1111/bph.15230)

ANTI-INFLAMMATORY AND ANTIVIRAL ROLES OF HYDROGEN SULFIDE: RATIONALE FOR

CONSIDERING H2S DONORS IN COVID-19 THERAPY.

CITI V ET AL. BR J PHARMACOL. 2020;1–11.

H2S AS A POTENTIAL DEFENCE AGAINST COVID-19?

YANG, G. AMERICAN JOURNAL OF PHYSIOLOGY. CELL

PHYSIOLOGY. 2020; 319: C244–C249

H2S as a potential defence against COVID-19?

American Journal of Physiology. Cell Physiology, 319, C244–C249.

H2S as a potential defence against COVID-19?

American Journal of Physiology. Cell Physiology, 319, C244–C249.

Morphogenesis and cytopathic effect of SARS CoV-2 infection in human airway epithelial cells

NATURE 2020. 11:3910 https://doi.org/10.1038/s41467-020-17796-z

• SARS-CoV-2 shows a similar morphogenetic process as other coronaviruses but causes plaque-like cytopathic effects in HAE cultures.

• Cell fusion, apoptosis, destruction of epithelium integrity, cilium shrinking and beaded changes are observed in the plaque regions.

•

• Taken together, our results provide important insights into SARS-CoV-2 cell tropism, replication and morphogenesis

" Per gestire i pazienti molto gravi o già in terapia intensiva colpiti da COVID-

19, è stato essenziale cercare di ridurre lo stress ossidativo nei polmoni

Prof. Joan B Soriano, 2020

• "

Water Science & Technology: Water Supply | 18.4 | 2018 doi:

10.2166/

Microbial biodiversity of thermal water

and mud in an Italian spa by metagenomics: a pilot study

Paduano S, Valeriani F, Romano-Spica V, Bargellini,A, Borella P, Marchesi I.

T 0?

Macacus Fuscata

Terme Jikogudani Japan 2019

Un camino idrotermale:

questi ambienti hanno ospitato le prime forme di vita.

Jet Propulsion Laboratory NASA 2015

I primi organismi sulla Terra si sarebbero

formati grazie

all'interazione di alcune sostanze chimiche

con l'acqua

proveniente da

camini idrotermali

geotermici

Looking for LUCA,

the Last Universal Common Ancestor

•Around 4 billion years ago there lived a microbe called LUCA

•There is evidence that it could have lived a somewhat ‘alien’ lifestyle, hidden away deep

underground in iron-sulfur rich hydrothermal vents.

•Anaerobic and autotrophic, it didn’t breath air and made its own food from the dark, metal-rich environment around it.

•Most remarkable of all, this little microbe was the beginning of a long lineage that encapsulates all life on Earth.

Hydrogen Sulfide Attenuates Particulate Matter–Induced Human Lung Endothelial Barrier Disruption via Combined Reactive

Oxygen Species Scavenging and Akt Activation.

Am J Respir Cell Mol Biol 2012; 47:491–496.

H2S

• Significantly scavenged PM-induced EC ROS

• and inhibited the oxidative activation of p38 mitogen- activated protein kinase.

• Concurrent with these events activated Akt, which helps maintain endothelial integrity.

• Both of these pathways contribute to the protective effect ofH2S againstPM-induced endothelial barrier dysfunction

Exp Biol Med . 2020 Feb;245(3):190-200.

• The results showed that H2S effectively improved pulmonary function and reduced histopathological changes, lung edema, and permeability.

• Airway remodeling, oxidative stress, and inflammation were also reduced by hydrogen sulfide treatment

• These findings suggest that H₂S may have therapeutic potential for the prevention and treatment of COPD.

Suppression and Reversal of Cigarette Smoke-Induced Inflammasome Activation/Activity and Lung Injury

by Novel Mitochondria-Targeted Sulfide Delivery Molecules Am J Respir Crit Care Med 2020;201:A2543

• mtH2SD significantly suppressed CS-induced alveolar destruction, fibrosis and improved lung gas exchange.

• In mice with experimental COPD (at 8 weeks), reversed CS-induced lung neutrophil, eosinophil and macrophage infiltration, loss of lung function, and partially reversed airway resistance.

• CONCLUSIONS:

• Targeting H2S to mitochondria may be a novel therapeutic approach to prevent and/or reverse mitochondria-driven inflammation and lung injury in COPD and related diseases.

Hydrogen sulfide inhibits cigarette smoke-induced inflammation and injury in alveolar epithelial cells by suppressing PHD2/HIF-1α/MAPK signaling pathway

Intern.Immunopharmacology 2019. doi.org/10.1016

• H₂S improved pulmonary function and relieved emphysema in CS-exposed mice.

• H₂S downregulated inflammatory cytokines TNF-α, IL-6 and IL- 1β in vivo and in vitro.

• H₂S donor inhibited alveolar epithelial cell injury and apoptosis in vivo and in vitro.

• H₂S donor NaHS suppressed CS-activated PHD2/HIF-1α signaling.

• H₂S donor NaHS inhibited CS-induced activation of ERK, JNK and p38 MAPK signaling pathway.

Imbalance of Endogenous Hydrogen Sulfide and Homocysteine in Chronic Obstructive Pulmonary Disease Combined with

Cardiovascular Disease.

Front Pharmacol. 2017 . 12;8:624

The imbalance of H

S/Hcy may be involved in the pathogenesis of COPD

combined with CVD

and provide novel targets for therapy .

Protective Role of Nuclear Factor Erythroid 2-Related Factor 2 against RSv and Human Metapneumovirus Infections

Front immunol. 2018 Apr 23;9:854.

• RSV and hMPV -infected Nrf2 KO mice lost more body weight and had increased airway obstruction at time points characterized by a

remarkable increase in inflammatory cytokines and airway neutrophilia.

• Airway levels of antioxidant enzymes AOEs and enzymes that regulate synthesis of the endogenous hydrogen sulfide (H₂S) pathway, which we showed to play an important antiviral function, were decreased

• in RSV and hMPV -infected Nrf2 KO compared to WT.

Considering the emergence of data suggesting a degree of cross- talk between H2S and epigenetic modifiers such as miRNAs

• Am Emerging role of hydrogen sulfide-microRNA crosstalk

in cardiovascular diseases. Hackfort BT, Mishra PK.

J Physiol Heart Circ Physiol. 2016; 310:802–12

• Cross-talk of MicroRNA and hydrogen sulfide: A novel

therapeutic approach for bone diseases.

Zhai Y, Tyagi SC, Tyagi N. Biomed Pharmacother. 2017; 92:1073–84.

• Airway smooth muscle inflammation is regulated by

microRNA-145 in COPD.

O'Leary L, Sevinç K, Papazoglou IM, Tildy B, Chung KF FEBS Lett. 2016;590(9):1324–34.

Am J Respir Cell Mol Biol Vol 55, Iss 1, pp 72–81, Jul 2016 Copyright © 2016 by the American Thoracic Society

H2S administration

prevented and partially reversed ozone-induced features of lung inflammation and emphysema

via regulation of the NLRP3–caspase-1,

p38 mitogen-activated proteinkinase (MAP),

And Akt pathways.

Hydrogen Sulfide Attenuates Hydrogen Peroxide-Induced Injury in Human Lung Epithelial A549 Cells

Int. J. Mol. Sci.

• Cell death induced by H2O2 treatment could be

significantly attenuated by the pre-treatment of H2S,

• Resulting in a decrease in the Bax/Bcl-2 ratio

• and the inhibition of caspase-3 activity in human lung epithelial cell line A549 cells.

• Additionally, the results showed that H2S decreased reactive oxygen species (ROS),

• as well as neutralized the damaging effects of H2O2 in mitochondria energy-producing and cell metabolism.