Group leader: Thomas Trian
Group members: Fabien Beaufils, Rihab Ben Sighaier, Patrick Berger, , Elisa Celle, Pauline Esteves, Mickaël Fayon, Pierre-Olivier Girodet, Olga Ousova, Angie Vicré
Asthma is a very common respiratory disease characterized by bronchial remodelling, hyper responsiveness and inflammation. This disease presents different levels of severity up to severe asthma, which represents less than 5% of all asthma patients but 50% of the disease costs. Two of the most important characteristics of severe asthma are the presence of an increased bronchial smooth muscle (BSM) mass and the occurrence of frequent exacerbations mainly induced by respiratory viral infections such as rhinoviruses. These two characteristics are strongly related in both severe asthmatic adults and preschool wheezing children.
Underlying mechanisms of BSM remodelling and cellular interplay communication during viral infection are still not well understood. Also, despite the emergence of new therapy, including biotherapy, remission is still not completely achieved for every patient. There is a need to develop therapeutics targeting BSM remodelling, which is one of the main challenges for our research group.
Recent achievements
- In asthmatics adults, we demonstrated that BSM remodelling is associated to mitochondrial metabolism alteration which led to an increased consumption of fatty acids (1). Moreover, we also demonstrated that asthmatic BSM can interfere with bronchial epithelial cells in order to increase rhinovirus infection through cytokines and microvesicles releases (2, 3).
- In severe preschool wheezing children, we identified two endotypes based on bronchial remodelling (4, 5). These endotypes are characterized by different disease trajectories from preschool to school age whereas they were initially indistinguishable. Interestingly, endotype with high BSM remodelling were at increased risk of exacerbations and present more airway functional obstruction with less asthma remission at school age. Moreover, at cellular level, we showed that BSM remodelling involved an alteration in mitochondrial biogenesis (6).
Current project
The objectives of the current project are:
- To assess the effects of targeting fatty acid consumption in adult asthmatic BSM cells on remodelling using home-made developed therapeutics (PI: Pauline Esteves)
2. To compare epithelial metabolism and its role in rhinovirus infection in asthmatic and non-asthmatic children (PI: Pauline Esteves)
3. To identify predictive biomarkers and pathophysiological mechanisms of high BSM remodelling endotype in severe preschool wheezers (PI: Fabien Beaufils)
4. To investigate whether intrinsic age-controlled properties of the bronchial epithelium under resting physiological conditions determine adenovirus and rhinovirus infection (PI: Thomas Trian)
5. To unravel the complex interactions between respiratory infections, immune responses, and asthma development in children, with a particular focus on epigenetic regulation (PI. Thomas Trian)
Main references
- Esteves P, Blanc L, Celle A, Dupin I, Maurat E, Amoedo N, Cardouat G, Ousova O, Gales L, Bellvert F, Begueret H, Thumerel M, Dupuy JW, Desbenoit N, Marthan R, Girodet PO, Rossignol R, Berger P, Trian T. Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling. Eur Respir J. 2021, 58(5): 2004252. (* co-last author)
- Esteves P, Allard B, Celle A, Dupin I, Maurat E, Ousova O, Thumerel M, Dupuy JW, Leste-Lasserre T, Marthan R, Girodet PO, Trian T, Berger P. Asthmatic bronchial smooth muscle increases rhinovirus replication within the bronchial epithelium. Cell Report 2022, 38(13): 110571. (* co-last author)
- Celle E, Chahin A, Beaufils F, Cardouat G, Eyraud E, Bouchet C, Campagnac M, Ousova O, Begueret H, Thumerel M, Dubois R, Dupuy JW, Leste-Lasserre T, Lacomme S, Lager-Lachaud N, Bellvert F, Marthan R, Girodet PO, Berger P, Trian T, Esteves P. Bronchial smooth muscle extracellular vesicles interfere with bronchial epithelium metabolism and function in asthma. ISciences 2025, in press.
- Fayon M, Beaufils F, Esteves P, Campagnac M, Maurat E, Michelet M, Siao-Him-Fa V, Lavrand F, Simon G, Begueret H, Berger P. Bronchial remodeling-based latent class analysis predicts exacerbations in severe preschool wheezers. Am J Respir Crit Care Med 2023, 207(4): 416-26. (* co-first author)
- Beaufils F, Fayon M, Esteves P, Michelet M, Siao-Him-Fa V, Lavrand F, Begueret H, Berger P. Bronchial remodeling identifies new endotypes in severe preschool wheezers. Am J Respir Crit Care Med 2024, 210(7): 941-44.
- Beaufils F, Esteves P, Siao-Him Fa V, Trian T, Debelleix S, Maurat E, Marthan R, Fayon M, Berger P. Mitochondria are involved in bronchial smooth muscle remodeling in severe recurrent preschool wheezers. J Allergy Clin Immunol. 2021, 148(2): 645-51. (* co-last author)
