Effect of montelukast, a cysteinyl receptor antagonist, on myofibroblasts in interstitial lung disease.
Montelukast, a potent cysteinyl receptor antagonist, may be an antifibrotic therapeutic agent for lung fibrosis. Seven sarcoidosis patients and 10 with unusual interstitial pneumonia underwent conventional bronchoalveolar lavage, from which myofibroblasts were recovered. Myofibroblast proliferation was assayed, alpha smooth muscle actin levels were measured, TGFbeta mRNA RT-PCR transcripts were semiquantitated, and secretion was evaluated in myofibroblast supernatants. Montelukast at 10(-8) M concentration had a suppressive effect on cell proliferation (31 +/- 18%), which was significantly enhanced by LTD4 10(-8) M. No differences were found between sarcoidosis (31.28 +/- 15.9%) and unusual interstitial pneumonia (30.56 +/- 24.3%) lines. Fetal calf serum (20%) produced an enhancing effect (29.8 +/- 21.6%) in all lines. Myofibroblasts recovered from sarcoidosis patients showed lower alpha-smooth muscle actin contents than unusual interstitial pneumonia lines (0.09 +/- 0.02 vs. 0.34 +/- 0.16, p =0.039, respectively). Montelukast suppressed alpha-actin in short-term cultures in sarcoidosis myofibroblasts and in long-term unusual interstitial pneumonia myofibroblasts. Montelukast at 10(-6) M concentratin decreased the TGFbeta-induced alpha-actin expression in all lines tested. Montelukast decreased mRNA expression of TGFbeta. Montelukast may be a therapeutic agent in pathological conditions involving fibrotic and remodeling processes.
Fireman
Elizabeth
E
Department of Pulmonary and Allergic Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizman Street, Tel Aviv 64239, Israel. fireman@tasmc.health.gov.il
Schwartz
Yehuda
Y
Mann
Abraham
A
Greif
Joel
J
D000085:Acetates / Q000494:pharmacology*; D000199:Actins / Q000032:analysis; D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D012507:Sarcoidosis / Q000188:drug therapy; D013440:Sulfides; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology
D000085:Acetates; D000199:Actins; D003521:Cyclopropanes; D011804:Quinolines; D012333:RNA, Messenger; D013440:Sulfides; D016212:Transforming Growth Factor beta; C093875:montelukast