Allergy Asthma Immunol Res.  2013 Nov;5(6):343-347. 10.4168/aair.2013.5.6.343.

Mechanisms of Asthma and Implications for Its Prevention and Treatment: A Personal Journey

• Holgate ST

• KMID: 2260276
• DOI: http://doi.org/10.4168/aair.2013.5.6.343

Abstract

My research career has focused on the causes of asthma and its treatment. After establishing the key role that mast cells play in the inflammatory response in asthma, attention was turned towards understanding disease chronicity and variability across the lifecourse. Through a combination of studies on airway biopsies and primary cell cultures we have established that asthma is primarily an epithelial disease driven by increased environmental susceptibility to injury and an altered repair response as depicted by sustained activation of the epithelial mesenchymal trophic unit (EMTU) that is invoked in foetal branching morphogenesis. Varied activation of the EMTU connects the origins of asthma to its progression over time with involvement of epithelial susceptibility through impaired barrier and innate immune functions and altered mesenchymal susceptibility as exemplified by polymorphisms of the metalloprotease gene, ADAM33. Taken together these observations have led to a fundamental re-evaluation of asthma pathogenesis. Rather than placing allergic inflammation as the prime abnormality, it is proposed that the airway epithelium lies at the center of asthma pathogenesis, and that in conjunction with the underlying mesenchyme, it is the principle orchestrator of both the induction of asthma and its evolution over the lifecourse. This concept has provided 'the basis for a new preventative and therapeutic approach focused more on increasing the airways resistance to environmental insults rather than suppressing downstream inflammation once it is established.

Keyword

Asthma; management; prevention; treatment

MeSH Terms

Asthma
Biopsy
Epithelium
Humans
Inflammation
Mast Cells
Mesoderm
Morphogenesis
Primary Cell Culture

Figure

• 

  Figure Schematic representation of the epithelial mesenchymal unit in chronic asthma. The epithelial set point for displaying an injury/repair phenotype is altered as a consequence of dysregulated expression of selected morphogenic transcription factors including sdef, Fox A2, TTF-1 and STAT 6. Increased expression of TTF1 and reduced expression of FoxA2 drives increased expression of spef and STAT6 linked to a propensity to undergo mucus metaplasia and drive a Th2 immune response. These and related epithelial signals also drive growth factor release to remodel the airways that in turn is linked to a defect in innate immunity e.g. IFNβ.

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