Therapeutic inhibition of matrix metalloproteinases for the treatment of chronic obstructive pulmonary disease (COPD).
BACKGROUND
The incidence of chronic obstructive pulmonary disease (COPD) is increasing worldwide and is ranked as the fourth most common cause of death in the United States. COPD is caused by long-term exposure to cigarette smoke, toxic gases, and particulate matter, leading to airway flow limitation and pulmonary failure. The disease is characterized by an excess of extracellular matrix deposition, increased thickness of airway walls, and destruction of alveolar septae, resulting in reduced functional lung parenchyma and reduced elastic tethering forces to maintain airway patency. Matrix metalloproteinases (MMPs) have been suggested as the major proteolytic enzymes involved in the pathogeneses of COPD because these proteins are a unique family of metalloenzymes that, once activated, can destroy connective tissue. Although several MMP inhibitors have been developed, in vivo specificity and selectivity have slowed the progress.


METHODS
This review discusses the structural features of MMPs, their pulmonary cellular sources during the course of the disease, past anti-MMP therapies, and future approaches to inhibiting these proteins for treating COPD patients. Literature searches of PubMed, BioMed, and Medline formed the basis of this analysis and our current understanding of pulmonary changes associated with COPD and the capacity of MMPs to induce a variety of these changes of current biomedical and clinical interest.
Daheshia
Massoud
M
Lovelace Respiratory Research Institute and the Department of Pharmacy and Pathology, School of Medicine, University of New Mexico, Albuquerque, NM, USA. mdaheshi@LRRI.org
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases