Clinical outcomes of bosentan in pulmonary arterial hypertension do not correlate with levels of TIMPs.
BACKGROUND
Matrix metalloproteinases (MMP) and their inhibitors, tissue inhibitors of metalloproteinases (TIMP), are involved in tissue inflammation and fibrotic processes. Treatment with bosentan has been shown to improve the clinical outcome of patients with pulmonary arterial hypertension (PAH) with and without association with systemic sclerosis (SSc), and also to modulate the serum levels of matrix metalloproteases-9. We measured TIMP-1 and TIMP-2 in the serum of patients with SSc with and without PAH treated with long-term bosentan compared with healthy donors (HD).


METHODS
Serum samples from HD (n = 16) and patients with SSc (n = 35), including patients with SSc without PAH (n = 23) and patients with PAH (n = 12), were analyzed using enzyme-linked immunosorbent assays (ELISAs) for total TIMP-1 and TIMP-2.


RESULTS
Both mean TIMP-1 and TIMP-2 levels were significantly increased in patients with SSc compared with HD, but no differences were observed between patients with SSc with and without PAH. In the eight bosentan-treated patients, TIMP-1 and TIMP-2 levels did not change during 1 year of treatment, while bosentan increased the 6-min walking distance by 136 meters after 1 year, as well as clinical outcomes.


CONCLUSIONS
Increased levels of TIMP-1 and TIMP-2 in patients with SSc compared with HD suggest that the inhibition of proteolysis allows the accumulation of ECM proteins. As bosentan does not stimulate TIMPs, it appears to favour proteolytic imbalance and to increase the turnover of ECM proteins.
Giannelli
G
G
Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy. g.giannelli@.intmed.uniba.it
Iannone
F
F
Marinosci
F
F
Lapadula
G
G
Antonaci
S
S
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D000077300:Bosentan; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000097:blood / Q000150:complications; D013449:Sulfonamides / Q000008:administration & dosage*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000097:blood; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D013449:Sulfonamides; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D000077300:Bosentan