Active Resolution of inflammation in airway diseases - New theme

Research focus:

The inflammatory response is a protective mechanism, but chronic inflammation results in tissue damage. Thus, inflammation is normally self-regulated by an active resolution phase which involves specialized pro-resolving mediators (SPMs) such as lipoxins, resolvins, protectins and maresin. SPMs limit the infiltration of neutrophils and stimulate their clearance; they improve phagocytosis and the elimination of bacteria. SPMs are also involved in adaptive immunity with the regulation of T and B lymphocytes. Thus, abnormalities in SPMs biosynthesis or function could play a major role in chronic inflammatory diseases and excessive inflammatory conditions associated with cystic fibrosis, chronic obstructive pulmonary disease, surfactant metabolism abnormalities, viral and bacterial infections, air pollution and some cancers.

 

In cystic fibrosis (CF), dehydration of the airways surface which promotes chronic bacterial colonization, persistent inflammation, progressive lung destruction and respiratory failure is classically explained by abnormalities of electrolyte transport due to CFTR gene mutation. However, CF airway inflammation is excessive and ineffective against pathogens, it can occur early in the development of the disease. The systematic new-born screening revealed that young patients can develop an airway inflammatory disease without prior infection. The pulmonary function of CF patients correlates with the rate of SPMs measured in their sputum or blood and several groups, including ours, have revealed SPM biosynthesis abnormalities in CF, even in absence of bacterial infection. We have shown that lipoxin A4 and resolvin D1 control inflammation, ion transport, bacterial colonization, and repair of the airway epithelium from patients with CF. Thus, the imbalance between the production of pro- and anti-inflammatory lipid mediators could play a fundamental role in the pathogenicity of CF airway disease.

 

The cellular and molecular mechanisms of action of SPMs in the airways as well as the processes involved in abnormalities of their biosynthesis are not elucidated. Our activity based on the collaboration between scientists and clinicians is currently focused on 3 main axes:

 

• Impact of SPMS on the airway epithelial functions which are impaired in CF

• Cellular and molecular mechanisms involved in the abnormal SPMs biosynthesis in CF

• SPMs biosynthesis in other airway inflammatory diseases

 

Main results:

Resolvin D1 regulates epithelial ion transport, cytokine production and macrophage activity in models (in vitro and in vivo) of CF airways (Ringholz et al, 2018).

Lipoxin A4 delays the colonization of CF bronchial epithelial cells by Pseudomonas aeruginosa (Higgins et al, 2016).

Lipoxin A4 restores airway surface liquid layer height in CF airway epithelial cells by stimulating a calcium-activated chloride secretion and inhibiting sodium absorption (Verriere et al, 2012, Higgins et al, 2014, Al-Alawi et al, 2014).

Lipoxin A4 protects CF airway epithelial structure by stimulating wound healing and tight junction formation (Grumbach et al, 2009, Buchanan et al 2013, Higgins et al, 2014).

The 15-lipoxygenase 2 and lipoxin A4 / leukotriene B4 ratio are reduced in bronco-alveolar lavage fluid of children with CF (Ringholz et al, 2014).

The 15-lipoxygenase expression is reduced in nasal polyps from CF patients compared to non-CF subjects (Jeanson et al, 2014).

Lipoxin A4 level increases while interleukin-8 decreased in CF sputum after antibiotic therapy and correlated with an improved lung function (Chiron, 2008).

 

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Selected publications

Philippe R, Urbach V. Specialized Pro-Resolving Lipid Mediators in Cystic Fibrosis.

Int J Mol Sci. 2018 Sep 21;19(10). pii: E2865. doi: 10.3390/ijms19102865. Review.

Ringholz FC, Higgins G, Hatton A, Sassi A, Moukachar A, Fustero-Torre C, Hollenhorst M, Sermet-Gaudelus I, Harvey BJ, McNally P, Urbach V. Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways.

J Cyst Fibros. 2018 Sep;17(5):607-615. doi: 10.1016/j.jcf.2017.11.017.

Sermet-Gaudelus I, Brouard J, Audrézet MP, Couderc Kohen L, Weiss L, Wizla N, Vrielynck S, LLerena K, Le Bourgeois M, Deneuville E, Remus N, Nguyen-Khoa T, Raynal C, Roussey M, Girodon E. Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening.

Arch Pediatr. 2017 Dec;24(12):e1-e14. doi: 10.1016/j.arcped.2017.07.015.

Mesbahi M, Shteinberg M, Wilschanski M, Hatton A, Nguyen-Khoa T, Friedman H, Cohen M, Escabasse V, Le Bourgeois M, Lucidi V, Sermet-Gaudelus I, Bassinet L, Livnat G. Changes of CFTR functional measurements and clinical improvements in cystic fibrosis patients with non p.Gly551Asp gating mutations treated with ivacaftor.

J Cyst Fibros. 2017 Jan;16(1):45-48. doi: 10.1016/j.jcf.2016.08.006.

Higgins G, Fustero Torre C, Tyrrell J, McNally P, Harvey BJ, Urbach V. Lipoxin A4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa.

Am J Physiol Lung Cell Mol Physiol. 2016 Jun 1;310(11):L1053-61. doi: 10.1152/ajplung.00368.2015.

Higgins G, Ringholz F, Buchanan P, McNally P, Urbach V. Physiological impact of abnormal lipoxin A₄ production on cystic fibrosis airway epithelium andtherapeutic potential.

Biomed Res Int. 2015;2015:781087. doi:10.1155/2015/781087

Grimaldi C, Brémont F, Berlioz-Baudoin M, Brouard J, Corvol H, Couderc L, Lezmi G, Pin I, Petit I, Reix P, Remus N, Schweitzer C, Thumerelle C, Dubus JC. Sweat test practice in pediatric pulmonology after introduction of cystic fibrosis newborn screening.

Eur J Pediatr. 2015 Dec;174(12):1613-20. doi: 10.1007/s00431-015-2579-4.

Bonfils P, Escabasse V, Coste A, Gilain L, Louvrier C, Serrano E, de Bonnecaze G, Mortuaire G, Chevalier D, Laccourreye O, Mainardi JL. Efficacy of tobramycin aerosol in nasal polyposis.

Eur Ann Otorhinolaryngol Head Neck Dis. 2015 Jun;132(3):119-23. doi: 10.1016/j.anorl.2015.03.008.

Bitam S, Pranke I, Hollenhorst M, Servel N, Moquereau C, Tondelier D, Hatton A, Urbach V, Sermet-Gaudelus I, Hinzpeter A, Edelman A. An unexpected effect of TNF-α on F508del-CFTR maturation and function. Version 2.

F1000Res. 2015 Jul 10 [revised 2015 Jan 1];4:218. doi: 10.12688/f1000research.6683.2.

Ringholz FC, Buchanan PJ, Clarke DT, Millar RG, McDermott M, Linnane B, Harvey BJ, McNally P, Urbach V. Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis.

Eur Respir J. 2014 Aug;44(2):394-404. doi: 10.1183/09031936.00106013.

Higgins G, Buchanan P, Perriere M, Al-Alawi M, Costello RW, Verriere V, McNally P, Harvey BJ, Urbach V. Activation of P2RY11 and ATP release by lipoxin A4 restores the airway surface liquid layer and epithelial repair in cystic fibrosis.

Am J Respir Cell Mol Biol. 2014 Aug;51(2):178-90. doi: 10.1165/rcmb.2012-0424OC.

Al-Alawi M, Buchanan P, Verriere V, Higgins G, McCabe O, Costello RW, McNally P, Urbach V, Harvey BJ. Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium.

Physiol Rep. 2014 Aug 7;2(8). pii: e12093. doi: 10.14814/phy2.12093. Print 2014 Aug 1.

Jeanson L, Guerrera IC, Papon JF, Chhuon C, Zadigue P, Prulière-Escabasse V, Amselem S, Escudier E, Coste A, Edelman A. Proteomic analysis of nasal epithelial cells from cystic fibrosis patients.

PLoS One. 2014 Sep 30;9(9):e108671. doi:10.1371/journal.pone.0108671.