Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention

The chronic inflammatory response within the airways of asthmatics is associated with structural changes termed airway remodeling. This remodeling process is a key feature of severe asthma. The 5-10% of patients with a severe form of the disease account for the higher morbidity and health costs rela...

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Bibliographic Details
Published in:Pharmacology & therapeutics (Oxford) 2011-06, Vol.130 (3), p.325-337
Main Authors: Girodet, Pierre-Olivier, Ozier, Annaig, Bara, Imane, Tunon de Lara, Jose-Manuel, Marthan, Roger, Berger, Patrick
Format: Article
Language:English
Subjects:
Airway Remodeling - drug effects
Airway Remodeling - physiology
Animals
Anti-Asthmatic Agents - pharmacology
Anti-Asthmatic Agents - therapeutic use
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
Asthma - drug therapy
Asthma - pathology
Asthma - physiopathology
Clinical Trials as Topic - trends
Humans
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Summary:The chronic inflammatory response within the airways of asthmatics is associated with structural changes termed airway remodeling. This remodeling process is a key feature of severe asthma. The 5-10% of patients with a severe form of the disease account for the higher morbidity and health costs related to asthma. Among the histopathological characteristics of airway remodeling, recent reports indicate that the increased mass of airway smooth muscle (ASM) plays a critical role. ASM cell proliferation in severe asthma implicates a gallopamil-sensitive calcium influx and the activation of calcium-calmodulin kinase IV leading to enhanced mitochondrial biogenesis through the activation of various transcription factors (PGC-1α, NRF-1 and mt-TFA). The altered expression and function of sarco/endoplasmic reticulum Ca(2+) pump could play a role in ASM remodeling in moderate to severe asthma. Additionally, aberrant communication between an injured airway epithelium and ASM could also contribute to disease severity. Airway remodeling is insensitive to corticosteroids and anti-leukotrienes whereas the effect of monoclonal antibodies (the anti-IgE omalizumab, the anti-interleukin-5 mepolizumab or anti-tumor necrosis factor-alpha) remains to be investigated. This review focuses on potential new therapeutic strategies targeting ASM cells, especially Ca(2+) and mitochondria-dependent pathways.
ISSN:0163-7258
1879-016X
DOI:10.1016/j.pharmthera.2011.02.001