Asthma is a very frequent airway disease that affects 6 to 20% of the population of western European countries. In the European Community Respiratory Health Survey II, the majority of asthmatic patients remains uncontrolled. Whereas asthma mortality has decreased within the last 30 years, uncontrolled asthma has still major consequences on morbidity, quality of life, and economic burden. According to the last ATS/ERS task force, severe asthma represents 5-10% of all asthmatic patients and generate a large proportion of resource expenditure.
Asthma physiopathology is characterized by bronchial hyperresponsiveness, inflammation and remodeling, the latter being initially considered as the result of an incomplete repair process. However, the early onset of this remodeling process, even prior to the eosinophilic inflammation, suggests that remodeling may be the cause and not the consequence of chronic inflammation. Clinically, bronchial smooth muscle (BSM) remodeling has a poor prognostic value in asthma, since higher BSM mass is statistically associated with lower lung function and higher exacerbation rate.
Bronchial remodeling in Asthma
Group leader Thomas Trian
Asthma exacerbations represent a major unmet need in severe asthma management that require new therapeutic strategy. Viral infection of the bronchial epithelium is implicated in 80% of asthma exacerbations in children and adolescents and in 60% in adults. In each case, the human rhinovirus is the dominant viral pathogen and represents 60% of all virus-induced exacerbations.
Mechanisms of asthma bronchilal remodeling are partially unknown but it has been well documented that asthmatic BSM is, intrinsically, different from non-asthmatic BSM. Asthmatic BSM hyperplasia have been shown both in vitro and in vivo. In 2007, we showed that asthmatic BSM cells have an increased mitochondrial mass in vitro and ex vivo. Moreover, we clearly demonstrated that this increased mitochondrial biogenesis was the cause and not the consequence of the increased proliferation observed in severe asthmatic BSM cells. Furthermore, we found that a default in calcium homeostasis was responsible for this increased mitochondrial biogenesis and could be reversed using the calcium blocker gallopamil. These findings clearly demonstrated the presence of a mitochondrial dysfunction in asthmatic BSM cells, which could, in turn, increase BSM cell proliferation.
We then performed a clinical trial assessing the effect of adding gallopamil to the treatment of severe asthmatic patients in a proof of concept double blind clinical trial. Interestingly, we found a significant decrease in BSM thickness after 12 months of treatment by gallopamil, as compared to placebo. Moreover, during the 3-months follow up, patients from the gallopamil group presented a significant decrease of the exacerbation rate as compared to those in the placebo group. This suggests that BSM acts as a key modulator of asthma exacerbations.
The ambition of our project is to highlight new therapeutic targets against both BSM remodeling and exacerbations in asthma.
The current objectives of the group are the following:
1) To evaluate the role of mitochondrial dysfunction in asthmatic BSM remodeling (supported by the “Fondation pour la recherche médicale”).
2) To identify the role of asthmatic BSM in rhinovirus induced exacerbation (supported by the “Agence nationale pour la recherche”).
Celle A, et al. Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients. J Allergy Clin Immunol 2022, 150(1): 104-113.
Esteves P, et al. Asthmatic bronchial smooth muscle increases rhinovirus replication within the bronchial epithelium. Cell Report 2022, 38(13): 110571.
Beaufils F, et al. Mitochondria are involved in bronchial smooth muscle remodeling in severe recurrent preschool wheezers. J Allergy Clin Immunol 2021, 148(2) : 645-651.
Esteves P, et al. Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling. Eur Respir J. 2021, 58(5) : 2004252.
Trian T et al. Selective dysfunction of p53 for mitochondrial biogenesis induces cellular proliferation in bronchial smooth muscle from asthmatic patients. J Allergy Clin Immunol. 2015. PMID: 26688517.
Trian T et al. House Dust Mites Induce Proliferation of Severe Asthmatic Smooth Muscle Cells via an Epithelium-dependent Pathway. Am J Respir Crit Care Med. 2015. PMID: 25569771
Girodet PO et al. Bronchial Smooth Muscle Remodeling in Non-severe Asthma. Am J Respir Crit Care Med. 2016. PMID: 26540234.
Girodet PO et al. Calcium Channel Blocker Reduces Airway Remodeling in Severe Asthma: a Proof-of-concept Study. Am J Respir Crit Care Med. 2015. PMID: 25633090
Trian T et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med. 2007. PMID: 18056286.