Mechanisms and treatments for severe, steroid‐resistant allergic airway disease and asthma

Abstract

Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.

Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment

“…In acute exacerbations of asthma, resistance to treatment with glucocorticoids is a significant clinical problem [41], which is at least in part related to inflammatory activation of macrophages that are unresponsive to glucocorticoids [11,42]. Current research on alternative approaches to controlling inflammation includes a focus on mechanisms underlying resolution of inflammation and the lipid-derived mediators associated with this [20].…”

Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

“…NF‐κB is also regulated by PHD (primarily PHD1), which reveals a common molecular pathway connecting hypoxia‐dependent regulation of HIF‐1 and NF‐κB . However, it remains unclear when CS‐induced HIF‐1α activation/overexpression and related pathology become important in the human disease course, which needs further investigation in experimental mouse models that recapitulate human disease features, and confirmed in prospective human studies …”

“…COPD patients with bacterial respiratory tract colonization experience increased daily respiratory symptoms (breathlessness, cough and sputum), accelerated decline in lung function, increased airway and systemic inflammation and reduced quality of life . These bacteria, especially NTHi, are also implicated as chronic colonizers in the pathogenesis of severe asthma, as well as corticosteroid resistant in mouse models of asthma . Low pathogenic strains of S. pneumoniae and their components and vaccines may be protective in mild‐to‐moderate asthma through the induction of regulatory T cells …”

“…The role of HIF‐1α‐induced PAFR expression as a driver of bacterial infection has not been widely studied in the lungs . Advances in developing representative murine models of human COPD have occurred in the past decade that is enabling us to elucidate the mechanisms involved in HIF‐1α‐induced, PAFR‐mediated bacterial infections in AECOPD …”

The potential of siRNA based drug delivery in respiratory disorders: Recent advances and progress

“…Current asthma therapies focus on reduction of symptoms and limit exacerbations during the course of the disease. However, the proportion of asthmatics with the uncontrolled disease remain significantly high and utilizes the majority of healthcare expenses globally (Hansbro et al, ; Peters, Ferguson, Deniz, & Reisner, ). Despite the increasing classification/categorization of asthmatics into various endotypes/phenotypes (based on a number of molecular biomarkers, clinical presentation and responsiveness to common therapies; Fajt & Wenzel, ), the key pathological feature of asthma is involvement of multiple inflammatory mediators that are often regulated by “key” genes/proteins, which are also referred as master transcription regulators (Sel, Henke, Dietrich, Herz, & Renz, ).…”