Active Resolution of inflammation in airway diseases - New theme
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
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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Mathieu Panel, ex-PhD student of Bijan Ghaleh-Marzban’s team, recently received the Prix des Sciences du Médicament from the French National Academy of Pharmacy for his thesis work under the supervision of Didier Morin entitled “Study of the effect of new cyclophilin D ligands on the mitochondrial permeability transition pore and their protective effect”. […]Read more