Abstract
Asthma is a chronic airway disorder associated with aberrant inflammatory and remodeling responses. Angiogenesis and associated vascular remodeling are one of the pathological hallmarks of asthma. The mechanisms underlying angiogenesis in asthmatic airways and its clinical relevance represent a relatively nascent field in asthma when compared to other airway remodeling features. Matrix metalloproteinases (MMPs) are proteases that play an important role in both physiological and pathological conditions. In addition to facilitating extracellular matrix turnover, these proteolytic enzymes cleave bioactive molecules, thereby regulating cell signaling. MMPs have been implicated in the pathogenesis of asthma by interacting with both the airway inflammatory cells and the resident structural cells. MMPs also cover a broad range of angiogenic functions, from the degradation of the vascular basement membrane and extracellular matrix remodeling to the release of a variety of angiogenic mediators and growth factors. This review focuses on the contribution of MMPs and the regulatory role exerted by them in angiogenesis and vascular remodeling in asthma as well as addresses their potential as therapeutic targets in ameliorating angiogenesis in asthma.
Highlights
Asthma is a highly heterogeneous chronic respiratory disease characterized by inflammation, hyperresponsiveness, and remodeling of the airways
Frequent asthma exacerbations triggered mainly by allergen exposure or viral or bacterial infections are primarily caused by chronic inflammatory processes that progress to a series of structural changes to the bronchial wall, including the resident airway epithelium, basal membrane, fibroblasts, smooth muscles, and blood vessels
Proteolysis being a key regulator of angiogenesis, proteases such as matrix metalloproteases (MMPs), the closely related family of a disintegrin and metalloprotease (ADAM) domain proteins, which includes ADAM and ADAMTS, as well as cysteine and serine proteases, have been implicated in regulating the angiogenic process
Summary
Asthma is a highly heterogeneous chronic respiratory disease characterized by inflammation, hyperresponsiveness, and remodeling of the airways. The growing family of MMPs comprise of members including collagenases, gelatinases, stromelysins, membrane-type MMPs (MT-MMPs), matrilysins, and various other MMPs. Depending on the presence of a transmembrane domain, the MMPs are broadly classified into two—MT-MMPs and secreted MMPs. As part of the homeostatic mechanism, the activated MMPs are deterred by a group of endogenous inhibitors called tissue inhibitors of Journal of Immunology Research metalloproteases (TIMPs). As part of the homeostatic mechanism, the activated MMPs are deterred by a group of endogenous inhibitors called tissue inhibitors of Journal of Immunology Research metalloproteases (TIMPs) Four members of this family, namely, TIMP-1, TIMP-2, TIMP-3, and TIMP-4, have been identified till date. We summarize the therapeutic modalities currently under investigation to target MMPs and their implications in improving angiogenesis and vascular remodeling in asthma
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