Targeting the airway smooth muscle for asthma treatment

Abstract

Asthma is a complex respiratory disease whose incidence has increased worldwide in the last decade. There is currently no cure for asthma. While bronchodilator and anti-inflammatory medications are effective medicines in some asthmatic patients, it is clear that an unmet therapeutic need persists for a subpopulation of individuals with severe asthma. This chronic lung disease is characterized by airflow limitation and lung inflammation and remodeling that includes increased airway smooth muscle (ASM) mass. In addition to its contractile properties, the ASM also contributes to the inflammatory process by producing active mediators, modifying the extracellular matrix composition, and interacting with inflammatory cells. These undesirable functions make interventions aimed at reducing ASM abundance an attractive strategy for novel asthma therapies. There are at least three mechanisms that could limit the accumulation of smooth muscle -decreased cell proliferation, augmented cell apoptosis, and reduced cell migration into the smooth muscle layer. Inhibitors of the mevalonate pathway or statins hold promise for asthma because they exhibit antiinflammatory, anti-migratory, and anti-proliferative effects in pre-clinical and clinical studies, and they can target the SM. This review will discuss current knowledge of ASM biology and identify gaps in the field in order to stimulate future investigations of the cellular mechanisms controlling ASM overabundance in asthma. Targeting ASM has the potential to be an innovative venue of treatment for patients with asthma. Keywordsairway smooth muscle; asthma; contractile; cytokine; hyperplasia; hypertrophy; inflammation; mevalonate; progenitor cells; statins; TGF beta; translational The Smooth Muscle in Lung Diseases: An Overlooked Target for TherapyThe majority of the smooth muscle present in the human lung localizes within two major compartments, the vasculature and the airways. The function of the pulmonary vascular smooth muscle (VSM) in maintaining appropriate gas exchange is well established. The peristaltic activity of the ASM is known to contribute to the normal branching of the respiratory tree during lung embryogenesis (1) (2). While ASM plays a central role in regulating the airway caliber, the real function of the ASM in the adult lung remains unclear and controversial. It has Send Correspondence to:

CC and CXC Chemokines Induce Airway Smooth Muscle Proliferation and Survival

“…To date, many growth factors, proinflammatory cytokines, and contractile agonists such as histamine and endothelin-1 have been shown to promote ASMC proliferation (16). Little is known about the effect of chemokines on ASM growth and survival.…”

“…Presently, ASMCs are considered a new target in asthma therapy. The increase in ASM mass might also explain the acute symptoms related to airway hyperresponsiveness (16). Smooth muscle contraction is FIGURE 6.…”

Transforming Growth Factor–β–Induced Differentiation of Airway Smooth Muscle Cells Is Inhibited by Fibroblast Growth Factor–2

“…The deposition of collagens I and III in the subepithelial layer and within smooth muscle bundles by airway mesenchyma increases airway wall thickness and reduces airway wall distensibility (2,3). An effective anti-remodeling treatment is expected to reduce airway reactivity and symptoms in asthma (4,5).…”

Pathophysiology of bronchial smooth muscle remodelling in asthma

“…Along the same lines, since endothelin and TGF-b have been evoked in the mechanism of BSM cell hypertrophy, it may be interesting to investigate the effect of endothelin-or TGF-b-receptor antagonists in asthma as already assessed in pulmonary vascular diseases in human [161] or murine models of asthma [162]. More recently, simvastatin has been demonstrated to induce BSM cell apoptosis in vitro [163] but, results from clinical trials remain controversial in asthmatics [164]. Another strategy could focus on the migration of fibrocytes by means of chemokine receptor blockage.…”