Matrix Metalloproteinase-9/Gelatinase B is a Putative Therapeutic Target of Chronic Obstructive Pulmonary Disease and Multiple Sclerosis

Abstract

Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in an array of physiological and pathological processes from development, morphogenesis, reproduction, wound healing, and aging to inflammation, angiogenesis, neurological disorders, and cancer cell invasion and metastasis. The imbalance between MMP activity and the inhibitory action of tissue inhibitors of metalloproteinases (TIMPs) are implicated in multiple diseases. Secreted in the body in a latent form, upon activation MMP-9 (gelatinase B) acts on many inflammatory substrates, and thus is suspected of contributing to the progression of cardiovascular disease, rheumatoid arthritis, and the subjects of this review, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS). COPD is the fourth most common cause of death in the United States. In COPD, increased expression of MMP-9 by inflammatory cells e.g. neutrophils and macrophages is correlated with a variety of processes that cause lung damage. MMP-9 is also important in cytokine and protease modulation; it degrades the serine protease inhibitor alpha(1)-antitrypsin, which thus may lead to lung destruction. MS affects approximately 400,000 Americans and over a million people worldwide. Upregulation of MMP-9 increases the permeability of the blood brain barrier (BBB), facilitates the infiltration of leukocytes into the central nervous system, and causes myelin sheath degradation and neuronal damage. Early stage clinical trials have shown promising results when MMP-9 is inhibited in MS. These observations lead to the hypothesis that MMP-9 is a potential drug target for both COPD and MS and further development of highly potent and specific MMP-9 inhibitors is warranted.

Abrogation of MMP-9 Gene Protects Against the Development of Retinopathy in Diabetic Mice by Preventing Mitochondrial Damage

“…This implies that the inhibitors of MMP-9 have potential to impede the development of retinopathy in diabetic patients. Optimistically, these inhibitors are being used in clinical trials for other diseases, including chronic obstructive pulmonary disease and multiple sclerosis (23). …”

Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation

“…A marked increase in COX-2 expression was observed in alveolar macrophages, as well as in alveolar epithelial cells following NM exposure. MMP-9 is a matrix metalloproteinase produced by proinflammatory/cytotoxic macrophages and is important in tissue injury and remodeling (Muroski et al, 2008). We found that MMP-9 was upregulated in lung macrophages after NM exposure (Figure 5).…”

Indacaterol Inhibits Tumor Cell Invasiveness and MMP-9 Expression by Suppressing IKK/NF-κB Activation

“…TNF-α-stimulated NF-κB activation induces the expression of MMP-9, a potential drug target for treatment of COPD (Muroski et al, 2008). We therefore tested whether indacaterol, which inhibits TNF-α-stimulated NF-κB signaling, also down-regulates the expression of MMP-9.…”

“…Previous studies have shown MMP-9 to be a potential drug target for COPD (Muroski et al, 2008), since overexpression of MMP-9 is correlated with lung damage (Chetty et al, 2008), while selective inhibition of MMP-9 prevents smoke-induced increase in small airway wall thickness in a guinea pig model (Churg et al, 2007). Therefore, we investigated whether MMP-9 expression and enzymatic activity are regulated by indacaterol in human fibrosarcoma (HT1080), which express MMP-9 in abundance.…”