On 2016 May 02, Riccardo Polosa commented:

We read with great interest the recent article by Grainge and coll. (1) showing that experimental airway narrowing induced by serial bronchoprovocation testing in patients with asthma may in itself be a stimulus for the development of airway remodelling. These tissue changes were independent of the broncoprovocant used in the study, development of remodelling being equivalent either after allergen or methacholine challenge. Surprisingly, however, the occurrence the characteristic late asthmatic response associated with a progressive fall in FEV1 after allergen (but not methacholine) challenge, failed to produce additional effects in term of enhanced airway remodeling changes in this study.

As for the action of hemodynamic sheer stress in endothelial pathophysiology and atherosclerotic plaque formation (2), it is likely that adaptative wall remodelling in asthma occurs only in response to a brisk mechanical stimulus (as in the severe acute bronchoconstriction of the early asthmatic response), whereas a slow, more progressive fall in FEV1 (as in the late asthmatic response of the allergen challenge) is not able to induce a sufficient stress response for tissue remodeling. Given the wide variability in individual fall in FEV1 and remodelling responses reported in the study by Grainge and coll., it cold have been relevant to investigate a possible correlation between severity of bronchoconstriction and amplitude of remodelling changes. This is important to substantiate these authors speculations.

Remodelling changes in response to bronchoconstriction are not necessarily detrimental, and may have a protective role by stabilizing airway calibre and limiting further narrowing (3). However, in presence of an inflammatory infiltrate and of an intrinsically dysfunctional epithelium – as in asthma (4,5) - mechanotransduction may promote a more harmful form of airway remodelling. To test specificity of the observed effects in asthma, a further study group to control for a non specific effect of bronchoconstriction (by high dose inhaled methacholine) in non-asthmatic individuals would have been highly informative.

Given the relative insensitivity of inhaled corticosteroids in modulating airway remodelling and its progression (6), the search for novel therapies that can specifically reverse or prevent airway remodeling has become an active area for drug development. For the time being, as appropriately pointed out by Grainge and coll., sustained (and safe) bronchodilatation should be recommended more insistently in addition to classical means of disease exacerbation prevention. Unsurprisingly, these considerations may be also valid for patients with chronic obstructive pulmonary disease (COPD).

REFERENCES

1. Grainge CL, Lau LCK, Ward JA, Dulay V, Lahiff G, Wilson S, Holgate ST, Davies DE, Howarth PH. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011; 364: 2006-15.
2. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009; 6(1): 16-26.
3. McParland BE, Macklem PT, Pare PD. Airway wall remodelling: friend or foe? J Appl Physiol 2003; 95: 426-434.
4. Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, Davies DE. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000;14: 1362-74.
5. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006 Aug 26;368(9537):780-93.
6. Royce RG, Tang ML. The effects of current therapies on airway remodelling in asthma and new possibilities for treatment and prevention. Curr Mol Pharmacol 2009; 2(2):169-81.

On 2016 May 02, Riccardo Polosa commented:

We read with great interest the recent article by Grainge and coll. (1) showing that experimental airway narrowing induced by serial bronchoprovocation testing in patients with asthma may in itself be a stimulus for the development of airway remodelling. These tissue changes were independent of the broncoprovocant used in the study, development of remodelling being equivalent either after allergen or methacholine challenge. Surprisingly, however, the occurrence the characteristic late asthmatic response associated with a progressive fall in FEV1 after allergen (but not methacholine) challenge, failed to produce additional effects in term of enhanced airway remodeling changes in this study.

As for the action of hemodynamic sheer stress in endothelial pathophysiology and atherosclerotic plaque formation (2), it is likely that adaptative wall remodelling in asthma occurs only in response to a brisk mechanical stimulus (as in the severe acute bronchoconstriction of the early asthmatic response), whereas a slow, more progressive fall in FEV1 (as in the late asthmatic response of the allergen challenge) is not able to induce a sufficient stress response for tissue remodeling. Given the wide variability in individual fall in FEV1 and remodelling responses reported in the study by Grainge and coll., it cold have been relevant to investigate a possible correlation between severity of bronchoconstriction and amplitude of remodelling changes. This is important to substantiate these authors speculations.

Remodelling changes in response to bronchoconstriction are not necessarily detrimental, and may have a protective role by stabilizing airway calibre and limiting further narrowing (3). However, in presence of an inflammatory infiltrate and of an intrinsically dysfunctional epithelium – as in asthma (4,5) - mechanotransduction may promote a more harmful form of airway remodelling. To test specificity of the observed effects in asthma, a further study group to control for a non specific effect of bronchoconstriction (by high dose inhaled methacholine) in non-asthmatic individuals would have been highly informative.

Given the relative insensitivity of inhaled corticosteroids in modulating airway remodelling and its progression (6), the search for novel therapies that can specifically reverse or prevent airway remodeling has become an active area for drug development. For the time being, as appropriately pointed out by Grainge and coll., sustained (and safe) bronchodilatation should be recommended more insistently in addition to classical means of disease exacerbation prevention. Unsurprisingly, these considerations may be also valid for patients with chronic obstructive pulmonary disease (COPD).

REFERENCES

1. Grainge CL, Lau LCK, Ward JA, Dulay V, Lahiff G, Wilson S, Holgate ST, Davies DE, Howarth PH. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011; 364: 2006-15.
2. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009; 6(1): 16-26.
3. McParland BE, Macklem PT, Pare PD. Airway wall remodelling: friend or foe? J Appl Physiol 2003; 95: 426-434.
4. Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, Davies DE. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 2000;14: 1362-74.
5. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006 Aug 26;368(9537):780-93.
6. Royce RG, Tang ML. The effects of current therapies on airway remodelling in asthma and new possibilities for treatment and prevention. Curr Mol Pharmacol 2009; 2(2):169-81.