Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease:  genetic factors and treatment implications.
OBJECTIVE
The aim is to describe the involvement of matrix metalloprotease (MMP), A Disintegrin And Metalloproteases (ADAM), tissue inhibitors of MMP (TIMP) polymorphisms and the role of α-2 Macroglobulin (α-2M) in chronic obstructive pulmonary disease (COPD) development and progression, with a focus on interventions with synthetic MMP inhibitors alone or associated with current drugs used in COPD therapy in order to restore MMPs/TIMPs imbalance.


RESULTS
COPD is one of the major causes of death in the elderly. It is characterized by progressive development of airflow limitation manifested by decreased forced expiratory volume in one second (FEV1) and reduction in the percentage of FEV1/forced vital capacity. The major pathogenic role is played by metalloproteases (MMPs, ADAMs)/anti-metalloproteases (TIMPs, α-2M) imbalance, which is responsible for MMP overproduction not sufficiently counteracted by TIMPs or α-2M. As a consequence, the lung extracellular matrix is destroyed with obstruction of small airways and appearance of emphysema.


CONCLUSIONS
The disease is mainly caused by exposure to cigarette smoke or noxious gases and air pollutants, but also genetic factors are involved. Among them, polymorphisms of MMPs (MMP1, MMP2, MMP9, MMP12), ADAMs (ADAM33) and TIMPs (TIMP1, TIMP2) are relevant, in which the inflammation and the smoking habit play key roles especially in unfavorable allele carriers. The association between these polymorphisms and the current drugs paves the way for personalized therapy with a great impact at clinical level.
Translational Research Centre of Nutrition and Ageing, Scientific and Technological Area, Italian National Research Centres on Ageing (INRCA), Ancona, Italy. e.mocchegiani@inrca.it
Eugenio
E
Mocchegiani
Robertina
R
Giacconi
Laura
L
Costarelli
D051722:ADAM Proteins; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000276:immunology; D004646:Emphysema / Q000201:enzymology / Q000235:genetics; D005260:Female; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*; D014797:Vital Capacity; D000511:alpha-Macroglobulins
D019714:Tissue Inhibitor of Metalloproteinases; D000511:alpha-Macroglobulins; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases