Meveol Publications
in Cystic Fibrosis cases
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SANDRE-BALLESTER C.1, FICHANT E.2, STORDEUR Ph.2, BORDEAU Ph.1, DELAHAUT, Ph.2, PERRAUDIN JP.3
1 ALAXIA, 3-11 rue de la Perlerie F-69120 Vaulx-En-Velin, 2 CER, 8 rue du Point du jour B-69000 Marloie, 3 TARADON Laboratory, 2 avenue Léon Champagne B-1480 Tubize
BACKGROUND :
The CFTR gene is responsible for the production of a protein regulating outflow of water and salts (like chloride Cl- but also rhodanide SCN-) from cells that cover internal and external surfaces of the body, the so-called epithelial cells. Inactivation of CFTR is likely to cause multiple defects in the airway that together alter local innate immunity (Childers M, 2007). As shown in recent publications, hypothiocyanite (OSCN-) antimicrobial molecule (Moskwa P, 2007 and Conner GE) and lactoferrin (Rogan MP, 2004) are deficient in Cystic Fibrosis condition.
RESULTS:
OSCN- molecule is well known by ALAXIA scientists who demonstrated with appointed experts during MEVEOL® development its antimicrobial efficacy on various strains including MRSA, Burkholderia cepacia, and mucoïd Pseudomonas aeruginosa.
MEVEOL® tackles a wide range of micro-organisms including biofilm due to its composition associating naturally linked compounds. Hypothiocyanite and lactoferrin, main bio molecules, are normally present in human body and especially in human airways suggesting low risk of bacterial resistance.
The effects of MEVEOL® have been evaluated both In Vitro (Fig 1) and In Vivo (Fig 2).
In Vitro
Efficacy vs Burkholderia cepacia (Strain ATCC BAA-245 : tobramycin and colistin resistant)
(Same kind of results on MRSA, mucoïd Pseudomonas aeruginosa, not shown here)
In Vivo
Demonstration of efficacy on mice, previously infected with mucoïd Pseudomonas aeruginosa strain
isolated from CF Patients.
CONCLUSION :
MEVEOL® (inhalation use) is of potential significant benefit for the treatment of lung micro-organisms proliferation in Cystic Fibrosis condition thanks to its combined antimicrobial and local mechanism of action. It can be inhaled also in combination with other treatments.
MEVEOL® MAIN BENEFITS
Due to its composition associating OSCN-/Lactoferrin
Acts on super bugs including biofilm and mucoïd protection forms,
Acts on MRSA
No antibioresistance risk
Compensates compounds missing in CF lung
Low risk of side effects due to compounds naturally present in non CF cases
Easy to breathe, less visits to Hospital for antibiotics IV cure
• Childers M, et al. A new model of cystic fibrosis pathology: lack of transport of glutathine anosiss thiocyanate conjugates. Med Hypotheses. 2007;68(1):101-12.
[ SCN- doesn’t cross CFTR
• Moskwa P et al. A novel host defense system of airways is defective in cystic fibrosis. Am J Respir Crit Care Med. 2007;175(2):174-83
[ OSCN- natural antimicrobial compound miss in CF
• Conner GE, et al. The lactoperoxidase system links anion transport to host defense in cystic fibrosis. FEBS Lett. 2007;581(2):271-8
[ Lactoperoxidase innate host defense can’t work in CF
• Rogan MP, et al. Loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis. J. Infec. Dis. 2004; 190:1245-53
[ Lactoferrin activity is decreased in CF
Project initiated and supported by Cystic Fibrosis non profit organization Mucoviscidose Innovation and with the collaboration of Vaincre la Mucoviscidose.
29 June 2009 ANNEX 1 : CFTR, ALSO a SCN- CHANNEL A model for an antibacterial mechanism based on the Duox/Lactoperoxidase system is based on the observations that normal, uninflamed airways continuously release H2O2 into the Airway Surface Liquid where Lactoperoxidase generates antibacterial OSCN- from H2O2 and SCN-. Thus, in the airways, Duox of the surface epithelium releases H2O2 into the airway surface liquid and lactoperoxidase, secreted mainly by submucosal glands (but also by surface goblet cells), produces bactericidal OSCN-. SCN- transport was stimulated by CFTR activation or blocked by CFTR inhibition and thus is greatly diminished in CF airways. At the same time, bacterial killing by airways in presence of Lactoperoxidase was shown to be directly related to the availability of SCN-. These investigations gave strong support for the role of the Duox/Lactoperoxidase system as a defense mechanism of the airways that requires normal CFTR function. Thus, this mechanism links CFTR function immediately to innate defense (Fischer H, 2009). Fischer H. Mechanism and function of DUOX in epithelia of the lung. Antioxid Redox Signal. 2009;11(10):1-13. [ CFTR, ALSO a SCN- CHANNEL [ CFTR, Aussi un canal rhodanide ( SCN-)
The lactoperoxidase system links anion transport to host defense in cystic fibrosis
- Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M. FEBS Lett. 2007 Jan 23;581(2):271-8. Epub 2006 Dec 19.
Chronic respiratory infections in cystic fibrosis result from CFTR channel mutations but how these impair antibacterial defense is less clear. Airway host defense depends on lactoperoxidase (LPO) that requires thiocyanate
(SCN-) to function and epithelia use CFTR to concentrate SCN- at the apical surface. To test whether CFTR mutations result in impaired LPO-mediated host defense, CF epithelial SCN- transport was measured. CF epithelia had significantly lower transport rates and did not accumulate SCN- in the apical compartment. The lower CF [SCN-] did not support LPO antibacterial activity. Modeling of airway LPO activity suggested that reduced transport impairs LPO-mediated defense and cannot be compensated by LPO or H2O2 upregulation.
Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M. The lactoperoxidase system links anion transport to host defense in cystic fibrosis. FEBS Lett. 2007 Jan 23;581(2):271-8. Epub 2006 Dec 19.
Source Pub Med : http://www.ncbi.nlm.nih.gov/pubmed/17204267
A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates.
- Childers M, Eckel G, Himmel A, Caldwell J. Med Hypotheses. 2007;68(1):101-12. Epub 2006 Aug 24.
Many of the symptoms of cystic fibrosis are not explained by the current disease mechanisms. Therefore, the authors conducted an extensive literature review and present a new model of cystic fibrosis pathology, which is the culmination of this research. Understanding that the cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for glutathione
(GSH) transport, the authors hypothesize that mutations of the CFTR, which create abnormal GSH transport, will lead to aberrations of GSH levels in both the intracellular as well as the extracellular milieu. These alterations in normal cellular GSH levels affect the redox state of the cell, thereby affecting the intracellular stress protein, metallothionein.
The authors describe how this disruption of the redox state caused by excess cellular GSH, will naturally prevent the delivery of zinc as a cofactor for various enzymatic processes, and how these disruptions in normal redox may cause alterations in both humoral and cell-mediated immunity. Moreover, the symptom of thick sticky mucus in these patients might be explained through the understanding that oversulfation of mucus is a direct result of elevated cellular GSH and cysteine. The issues of hyperinflammation, altered pH and the imbalance of fatty acids that are typical in cystic fibrosis are addressed-all of which may also be linked to disruptions in GSH homeostasis.
Additionally, this new model of cystic fibrosis pathology, clarifies the relationship between the CFTR and the multi-drug resistance proteins, and the lack of cell-mediated immunity by predicting that the substrate of these proteins is a glutathione adduct of thiocyanate. Finally, a new therapeutic strategy by using isothiocyanates to rectify the GSH imbalance and restore the immune system is suggested for the treatment of cystic fibrosis patients.
- Childers M, Eckel G, Himmel A, Caldwell J. A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates. Med Hypotheses. 2007;68(1):101-12. Epub 2006 Aug 24.
Article complet :
http://www.sharktank.org/research/A%20New%20Model%20of%20CF%20Pathology.pdf
sur le site http://www.sharktank.org
A novel host defense system of airways is defective in cystic fibrosis.
- Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB Jr, Nauseef WM, Dupuy C, Bánfi B. Am J Respir Crit Care Med. 2007 Jan 15;175(2):174-83. Epub 2006 Nov 2.
The respiratory tract is constantly exposed to airborne microorganisms.
Nevertheless, normal airways remain sterile without recruiting phagocytes.
This innate immune activity has been attributed to mucociliary clearance and antimicrobial polypeptides of airway surface liquid. Defective airway immunity characterizes cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator, a chloride channel. The pathophysiology of defective immunity in CF remains to be elucidated.
OBJECTIVE: We investigated the ability of non-CF and CF airway epithelia to kill bacteria through the generation of reactive oxygen species (ROS).
METHODS: ROS production and ROS-mediated bactericidal activity were determined on the apical surfaces of human and rat airway epithelia and on cow tracheal explants. MEASUREMENTS AND MAIN RESULTS: Dual oxidase enzyme of airway epithelial cells generated sufficient H(2)O(2) to support production of bactericidal hypothiocyanite (OSCN(-)) in the presence of airway surface liquid components lactoperoxidase and thiocyanate (SCN(-)). This OSCN(-) formation eliminated Staphylococcus aureus and Pseudomonas aeruginosa on airway mucosal surfaces, whereas it was nontoxic to the host. In contrast to normal epithelia, CF epithelia failed to secrete SCN(-), thereby rendering the oxidative antimicrobial system inactive. CONCLUSIONS: These data indicate a novel innate defense mechanism of airways that kills bacteria via ROS and suggest a new cellular and molecular basis for defective airway immunity in CF.
- Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB Jr, Nauseef WM, Dupuy C, Bánfi B. A novel host defense system of airways is defective in cystic fibrosis. Am J Respir Crit Care Med. 2007 Jan 15;175(2):174-83. Epub 2006 Nov 2.
