Understanding the pathogenesis of steroid-resistant exacerbation of allergic airways disease

Asthma is a chronic inflammatory disease of the airways characterized by airway obstruction, mucus production and airway hyperresponsiveness (AHR). The worsening of those symptoms, also known as asthma exacerbations, are triggered by allergens, respiratory infection, pollution and smoking. The exacerbation of the disease may lead to hospitalization, negatively affects the quality of patient's life. Exacerbations are often difficult to control by mainstay corticosteroid and bronchodilator therapy. Hence, it is important to understand the mechanisms predisposing to steroid resistance during asthma exacerbation to develop new effective therapies for those patients. Using well-established animal models of asthma, and functional studies by depleting cells, inhibiting cytokines and chemokines, and using genetically modified mice, to identify cell populations by flow cytometry, as well as using RNA sequencing, we were able to investigate some mechanisms regulating steroid-resistant exacerbation of asthma. This thesis consists of three publications. The first investigates the role of CXCL3 and CXCL5, chemokines that have been shown to play a role in asthma, in regulating neutrophilic and inflammatory responses in Rhinovirus-induced asthma exacerbation. The seasonal variation of respiratory viral infections is not only largely responsible for exacerbation of asthma but also exposes the lung to secondary opportunistic bacterial infection, which further complicates the management of the disease. Indeed, increased levels of LPS derived from bacteria are commonly linked to exacerbations and the severity of disease. Subsequently, in my second publication, to investigate how bacteria may induce disease, we developed a new mouse model of LPS-induced (mimicking infection) exacerbation of asthma. We then investigated the mechanisms underlying steroid-resistant asthma, exploring the role of IL-13 and alveolar macrophages in this model. The final publication identified molecules and cells involved in the mechanism of LPS-induced exacerbation using state-of-art single-cell RNA sequencing. This latter investigation identifies potential molecular pathways and genes that may be involved in promoting steroid-resistant asthma. Collectively, my findings advance our knowledge of understanding the mechanisms involved in the pathogenesis of asthma exacerbation induced by viruses and bacteria.