Remodeling in asthma and COPD-recent concepts.

Remodeling in airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), is defined as structural alterations of both small and large airways due to subepithelial fibrosis, increased smooth muscle mass of airways, neovascularization, and glandular hypertrophy. Unlike the true remodeling or renovation of a structure which should result in improvement, the airway remodeling causes further functional and clinical deterioration due to thickening of bronchial walls and narrowing of the lumina.

Airway remodeling in occurring in asthma patients, which was first documented in 1922, is now a recognized entity.[1] However, it is not commonly appreciated that airway remodeling also occurs in patients with COPD, although the structural damage to the airways and the lung parenchyma is known to occur. Further, remodeling is not limited to the airways alone. It is also the pulmonary vascular remodeling that adds to the complications, especially in COPD patients.

Airway remodeling in asthma patients has been documented in all degrees of asthma severity and types of airways.[2] It is not necessarily related to the duration of the illness since it may also occur in children with early asthma when it may act as a precursor to a chronic and debilitating respiratory disease.[3] It possibly occurs as a result of ongoing inflammation and activation of different inflammatory cells. The inflammatory cells such as the mast cells, eosinophils, and CD8 + lymphocytes correlate with airway hyperresponsiveness.[4] Some important inflammatory mediators with significant remodeling action are transforming growth factor (TGF)-beta, interleukin (IL) 11, IL-17, and histamine.[56]

In asthma, airway remodeling is responsible for significant clinical effects such as greater asthma symptomatology, higher aryl hydrocarbon receptor (AHR), excessive use of rescue medication, and an accelerated decline in lung function. However, it is not clear if it results in permanent alterations in lung function.

Remodeling also occurs in patients with COPD, typically involving the peripheral airways causing thickening of walls and narrowing of bronchial lumen.[78] In the recent years, it has been shown that the larger and central airways are also involved.[9] This happens apparently due to deposition of extracellular matrix in subepithelial layer and hypertrophy of smooth muscles in the airway walls. Of various pathobiological mechanisms, the proteolytic enzymes matrix metalloproteinases (MMPs), especially MMP-9, play an important role in remodeling in patients suffering from asthma and COPD.[10] Integrins, a group of transmembrane proteins, are also likely to cause AHR and remodeling.[11]

Vascular remodeling is another common pathological consequence of inflammation in patients suffering from COPD and asthma. Pulmonary hypertension is known to occur as a complication of COPD that is responsible for chronic cor pulmonale. It has been recently recognized that airway remodeling not only results in severity of airway obstruction but also correlates with mean pulmonary artery pressure (mPAP) and pulmonary hypertension.[12]

The exact mechanism to link pulmonary hypertension with bronchial obstruction is not clear. Pulmonary vascular remodeling may also occur in chronic asthma although to a lesser extent than in COPD.

It has been observed recently that mPAP >25 mmHg used to define pulmonary hypertension is not a good indicator to suggest the development of symptoms and severity of COPD. Pulmonary artery stiffness is a more important marker for early detection of pulmonary vascular disease and right ventricular failure.[13]

Some of these findings have an important bearing on early diagnosis and treatment of remodeling as well as prevention of development of severe airway obstruction and pulmonary hypertension. Role of inhaled corticosteroids that constitute the cornerstone of treatment of asthma and acute exacerbations of COPD is not clearly understood for prevention of remodeling and chronic structural changes in the airways.[14] Same holds true regarding the role of antileukotriene.[14] There is little effect of beta-agonists and anti-immunoglobulin E (IgE) treatment on airway remodeling.

Several potential therapies have emerged which are still undergoing further tests for their place in clinical prescriptions. Prostanoids such as prostacyclins (i.e. prostaglandin E-2 and I-2), which elevate cyclic AMP, constitute an attractive target.[15] MMP-9 inhibition is another potential line of approach to therapy.[10] Anti-IL-5 molecules and Bacillus Calmette–Guérin (BCG) vaccinations are also under investigation.[14] Similarly, the integrin antagonists may find their role as a potential target for treatment.[11]

In summary, one can conclude that a lot of progress has been made in the understanding of pathological alterations and mechanisms of airway and vascular remodeling in patients suffering from asthma and COPD. A number of new and potential therapeutic targets have been also found. One can only hope that one or more of them find place in the clinical armamentarium.