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Thursday, September 1, 2011

State of the art: Asthma treatment effects on airway remodeling

In this month’s issue, Durrani, Viswanathan, and Busse take a look at what we know – and what we don’t know – about the effects of asthma therapy on airway mesenchymal-epithelial remodeling in asthma (J Allergy Clin Immunol 2011;128:439-448). After summarizing the current information about remodeling mechanisms, Durrani et al. discuss the effects of specific asthma drugs.

Airway remodeling is known to occur in some asthma patients, but the authors point out that it is not linked to any clinical indicators. While remodeling is considered to contribute to the pathology of asthma, the causal relationship has not been confirmed. Typically, remodeling has been considered a response to chronic inflammation and dysregulation of repair mechanisms in the lung, so it has been suggested that treatments aimed at reducing inflammation would impact remodeling. Durrani et al. note that this concept has not held out, in light of evidence that suggests remodeling occurs in parallel with inflammation, as well as clinical data that traditional therapies, such as ICSs, are not effective for all asthma patients. Of interest, they comment that there is new evidence that remodeling is a direct response to increased inflammation during asthma exacerbation, supporting the idea that remodeling and inflammation are concomitant. The authors then focus their review on what is known about effects of asthma therapies on aspects of remodeling, such as airway smooth muscle (ASM) hyperplasia, subepithelial fibrosis, and goblet cell hypertrophy.

Inhaled corticosteroids. Durrani et al. discuss several studies that have reported positive effects of ICSs on elements of airway remodeling, such as decreasing reticular membrane thickening, goblet cell hypertrophy, and vascular remodeling. They note that the same is not true of ASM hyperplasia and epithelial injury and detachment where both positive and negative effects have been observed.

Combination treatments. The authors discuss in vitro studies that have shown that ICS+LABA combination products are more effective than monotherapy with either on matrix deposition in human fibroblasts. Another study reported decreased airway wall thickness and epithelial growth factors in asthma subjects on combination product. The authors are cautiously optimistic about these findings, but note a paucity of research specifically evaluating the effects of ICSs+LABAs and LABAs alone on airway remodeling mechanisms.

Monoclonal antibody therapy. Reviewing studies on omalizumab, mepolizumab, and golimumab, Durrani et al. comment on the lack of direct evidence suggesting that mAb therapy mitigates airway remodeling, even though there are reports of mAb decreasing inflammatory cytokines, eosinophilia, and exacerbations, all of which have been associated with remodeling.

The authors briefly cover other therapies, such as leukotriene antagonists and tyrosine kinase inhibitors, before concluding that pivotal pathways in remodeling need to be identified prior to outcomes research on the clinical impact of remodeling to exacerbation and impairment in asthma.

We asked senior author William W. Busse, MD, from the University of Wisconsin, what he felt the most promising areas are for future research on airway remodeling:

Dr. Busse: As pointed out in our review, there are a number of complicating features which make it difficult to determine the best treatment for processes involved in remodeling. First, as noted, the mechanisms underlying remodeling have not been fully identified making the selection of a target intervention difficult. Second, it is likely for those patients in whom remodeling becomes a part of their disease processes, it begins early in life and is linked to other events in asthma, i.e., injury and repair. Given this information, it is likely that treatment most likely to prevent remodeling will need to begin early in life and in the development of asthma. Since two early life events that are key to asthma development include allergic sensitization and respiratory infections, these two areas are likely to be the best targets. Of these two events, allergic sensitization is emerging to be perhaps the most important and amendable to treatment and, perhaps, prevention.

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