Our current failure to treat some phenotypes of severe asthma is a reflection from our poor understanding of its underlying etiology. Classic interventions are directed to exacerbation management and prevention, including mainly bronchodilators and steroids to keep most patients away from flares, but in many cases they are ineffective as shown by clinical trials. Prospective placebo-controlled studies have not shown long-term beneficial effect of steroid treatment for RSV bronchiolitis and subsequent wheezing or asthma⁽²⁴³⁾. Doubling the dose of inhaled steroids in moderate to severe asthmatics was ineffective in two unrelated studies^{(280, 281)}. Moreover, in adults with persistent asthma even optimal therapy is only able to reduce the frequency of exacerbations by around 40%⁽²⁸²⁾. In school-age children, moderate doses of inhaled steroids are completely ineffective at reducing exacerbation frequency, duration and severity of wheezing episodes associated with viral infection⁽²⁸³⁾. Furthermore, 5-day course of oral steroids at the onset of exacerbations in preschool children was ineffective at reducing the duration or exacerbation severity, even in children with systemic eosinophilia⁽²⁸⁴⁾. Not to mention the detrimental effects of glucocorticoids, seen on patients who had fatal asthma, in addition to the side effects by a prolonged therapy⁽²⁸⁵⁾. The reasons of failure could be secondary to an acquired insensitivity to glucocorticoid actions, which could prevent these drugs from blocking many events that conduce to airway remodeling. A review of the potential mechanisms has been recently published⁽²⁸⁶⁾. It is beyond the objectives of this review to analyze all the current recommended asthma and COPD therapies, for which there are available guidelines^{(287, 288)}, or to underestimate the corroborated benefits of steroid treatment in the vast majority of asthmatic patients. However, recognizing that common interventions could not affect final outcomes is crucial to find better therapeutic targets. If novel therapies for airway remodeling are developed, it is possible that steroids might be sent apart from the primary treatment of asthma, and COPD progression could be effectively delayed. In this section, we explore some experimental evidence that supports such potential interventions.

Long-Acting Muscarinic Receptor Antagonists

The long-acting muscarinic antagonists (LAMAs), aclidinium, glycopyrronium and tiotropium, bind to human M₁-M₅ receptors in a concentration-dependent manner, but the highest selectivity is for M₃, followed by M₂⁽²⁸⁹⁾. Blockage of mAChRs has anti-inflammatory and anti-remodeling properties, although, most studies include only tiotropium in their protocols. For example, the anti-inflammatory activity associated with tiotropium on cigarette smoke-induced pulmonary inflammation in mice was related to a dose-dependent reduction of leukotriene-B4, IL-6, chemokines and TNF-α, and also a decreased cell numbers in BAL⁽²⁹⁰⁾. In the same way, eosinophil recruitment and AHR in a guinea-pig model of asthma were inhibited by vagal blockade-independent mechanisms⁽²⁹¹⁾. The mechanism of tiotropium was linked to inhibition of TGF-β-induced MAPK signaling and a decreased MMP expression⁽²⁹²⁾. LAMAs would further affect cell plasticity, as it was demonstrated that aclidinium can inhibit the CCh-, TGF-β-, and cigarette-induced transition from human fibroblast to myofibroblast⁽²⁹³⁾. Tiotropium also significantly inhibited ASM thickening and Th2 cytokine production by human peripheral blood mononuclear cells in a murine model⁽²⁹⁴⁾. The anti-remodeling effect also include decreased sm-MHC expression and decreased isometric relaxation of tracheal strips that were previously exposed to repeated allergen challenge⁽¹²¹⁾. From the clinical standpoint, in COPD, all three drugs produced significant FEV₁ improvement,but only glycopyrronium reduced dyspnea. In severe asthma, only tiotropium has been tested, and it has demonstrated to raise FEV₁and decline the risk of exacerbations⁽²⁸⁹⁾.

Emerging Therapies: Statins, Macrolides, Endothelin Antagonists, Calcium Channel Antagonists and PPARγ Agonists

Statins, through inhibition of 3-hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), reduce the synthesis of groups needed for protein isoprenylation, farnesylation and geranylgeranylation, influencing cell signaling. The inhibitory effect ofsimvastatinon FBS-inducedRhoAactivation is antagonized by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate. These isoprenoids are required for prenylation of the small G proteinsRhoAand Ras, and it was shown that inhibition ofASMC proliferationbysimvastatinwas due to prevention of geranylgeranylation ofRhoA, but not by farnesylation of Ras⁽²⁹⁵⁾. Moreover, lovastatin, isoprenylation inhibitors, or other pharmacological approaches for preventing localization of RhoA in the membrane localization should be considered as a preventiveantiviraltherapyfor selected groups with high risk for severe RSV disease⁽²⁹⁶⁾. However, statins are known to decreased cell survival, impacting on signaling that also contributes to bring cells under molecular stress. Autophagy, especially macroautophagy, was discussed as a potential mechanism of phenotypic modulation. Considering that some RNA viruses take advantage of the double-membrane vacuoles, potential improvement of RV replication could be an undesirable effect due to autophagic induction in response to statins⁽²⁷⁴⁾. Affecting some pathways associated with maturation can also reinforce ASMC modulation. This may explain why despite the well-stablished anti-inflammatory and pleiotropic effects of statins, clinical trials still failed to show any improvement of inflammatory and functional outcomes in patients with severe asthma⁽²⁹⁷⁾.

Macrolides are antibiotics that have been widely used in the treatment infectious diseases. Additionally, immunomodulatory and anti-inflammatory effects have been shown in relation to a suppression of goblet cell hyperplasia and cytokine secretion by regulating the activation of a MAPK/NF-κB pathway⁽²⁹⁸⁾. Experimental evidence supports anti-remodeling actions of macrolides, e.g., roxithromycin inhibited ASMC proliferation in a dose-manner dependent. This effect was dependent on the loss of the mitochondrial membrane potential, cytoplasmic accumulation of Cyt c, caspase activation and increasing of p27^Kip1expression⁽²⁹⁹⁾. The same researcher group showed that roxithromycin decreased bronchial wall thickness andASM layer in OVA-sensitized rats, and also downregulated ERK1/2 and upregulated caveolin-1 expression⁽³⁰⁰⁾.Long-term therapy may improve some functional parameters without affecting clinical outcomes, as showed by a recent metanalysis⁽³⁰¹⁾.

Endothelin-1 induces bronchoconstriction, mediates eosinophil recruitment during allergic inflammation, and contributes to airway remodeling by inducing fibroblast and ASMC differentiation and proliferation⁽³⁰²⁾. Despite of in vitro results obtained with endothelin receptor antagonists, such as sitaxsentan or bosentan, a recent small clinical trial did not demonstrate any improvement of functional tests or symptoms in poorly controlled asthma when compared to placebo⁽³⁰³⁾. On the other hand, calcium channel blockers were classically tested as bronchodilators, but after recent findings of pro-remodeling effects of altered calcium signals, long-term blockade has been proposed. Therefore, gallopamil administration reduces the mitochondrial mass and subsequent ASMC proliferation⁽³⁰⁴⁾. A recent doubled-blind randomized clinical trial showed that this calcium channel blocker decreased ASM thickness after 1 year of treatment. Although, there was no immediate clinical improvement during the treatment phase, a significant reduction in asthma exacerbations related to ASM mass reduction was seen during the follow-up⁽³⁰⁵⁾. In the same way, the PPAR-γ ligands, rosiglitazone and pioglitazone, have shown to regulate noncontractile and contractile functions of in vitro ASMCs, including decreased in proliferation and synthetic activities by increasing heme oxigenase-1 activity, and β₂-AR expression that could reduce AHR⁽³⁰⁶⁾. However, its benefits in obstructive airway diseases remains to be tested in humans.

Biologic Therapy

Current management of autoimmune diseases and cancer, is based on blocking specific molecular targets through inhibitors and monoclonal antibodies. Unquestionable evidence has been obtained with anti-IgE (omalizumab) for treatment of severe asthma associated with high IgE levels, being included in GINA guidelines. Similar medications have been considered on behalf of their efficacy in chronic inflammatory diseases. A large list, including anti-IL-5 (mepolizumab, reslizumab, enralizaumab), anti-TNF-α (etanercept), anti-IL-4 (pascolizumab, nuvance), anti-IL-4/13 (pitrakinra), anti-IL-9, anti-CD25 (daclizumab), anti-VCAM-1 and anti-TSLP, are now under clinical trials, and some recent publications have shown controversial results^{(307, 308)}. Based on animal models, blocking those pathways results in a reduced airway remodeling via decreased eosinophil, monocyte and T cell recruitment. However, decreasing inflammation was not always correlated with anti-remodeling effects. Clinical studies have not shown consistent results regarding improvement of FEV₁, symptom control, and decreased use of short-acting β₂-agonists. A common finding is that the number of exacerbations tends to decrease in the higher-steroid dose groups, without significant clinical efficacy. Whether or not these results were related to prevention of remodeling is unknown, because histopathological assessment were not included in their protocols.

A specific approach is attained with the c-kit/PDGF receptor tyrosine kinase inhibitor mastinib. RTK inhibition by imatinib mesylate decreases collagen deposition, eosinophil infiltration, and ASM thickening in a murine model⁽³⁰⁹⁾. Mastinib improved the asthma control score and number of exacerbations⁽³¹⁰⁾. However, no significant improvement in lung function was observed. More randomized clinical trials are needed to precise what biologic therapy is suitable for specific subgroups. New drugs that target specific pathways, such as: antiproteases for modulation of ECM deposition, NFκB inhibitors, PI3K inhibitors, chemokine receptor antagonists, and even old drugs with anti-inflammatory properties, like thalidomide, increase the spectrum of therapeutic interventions⁽³¹¹⁾, but no experimental and clinical research focusing on ASM remodeling have been addressed.

Bronchial Thermoplasty

Reduction of dense ASM using physical forces, like radiofrequency energy, has shown promising results. Bronchial thermoplasty is a FDA-approved bronchoscopy procedure for patients with severe asthma, which delivers high thermal energy to the airway wall to heat and reduce the amount of its cellular components. Although, airways swell on immediate heat administration, this blanching and erythema usually resolved within 1 week, and no long-term adverse effects were noted. In essence, epithelial, blood vessel and nerve injury are follow by tissue regeneration, however for unknown reasons, ASM has demonstrated almost no capacity of regeneration after this procedure, being replaced by connective tissue, instead. Increased airway distensibility, decreased bronchomotor tone both at baseline and in response to increasing doses of methacholine suggest that the AHR reduction correlated well with the degree of ASM reduction, supporting a role of ASM remodeling in humans⁽³¹²⁾.

Conclusion