The specific chymase inhibitor TY-51469 suppresses the accumulation of neutrophils in the lung and reduces silica-induced pulmonary fibrosis in mice.
Chymase is a chymotrypsin-like serine protease that is present in mast cells. Its activities include various effects associated with inflammatory responses. But little is known about the effects of chymase in pulmonary fibrosis. The mouse silicosis model was induced by intratracheal injection of 10 mg silica. The Ashcroft pathological score and the hydroxyproline content of lungs were measured to evaluate the effect of a chymase inhibitor, 2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl] thiazole-4-carboxylic acid (TY-51469). The cellular composition and cytokine levels in bronchoalveolar lavage fluid (BALF) were also examined. Following TY-51469 treatment, the lung fibrosis score and hydroxyproline level were significantly reduced, and the number of neutrophils and the levels of macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and transforming growth factor-β₁ in BALF were reduced on day 21. The administration of TY-51469 at an early stage showed a greater reduction of fibrosis compared to administration at a later stage. The neutrophil number in BALF in mice treated with TY-51469 both at an early stage and late stage was significantly reduced. The level of mouse mast cell proteinase-4 mRNA increased with time in silica-induced fibrosing lung tissue. These results show that the chymase inhibitor TY51469 suppresses the migration of neutrophils, which results in the suppression of lung fibrosis.
Department of Respiratory Medicine, Division of Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan. murakami@med3.m.kanazawa-u.ac.jp
Hazuki
H
Takato
Masahide
M
Yasui
Yukari
Y
Ichikawa
Yuko
Y
Waseda
Kanako
K
Inuzuka
Yoriko
Y
Nishizawa
Atsuro
A
Tagami
Masaki
M
Fujimura
Shinji
S
Nakao
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018932:Chemokine CCL2 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D012822:Silicon Dioxide; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C095218:Ccl9 protein, mouse; D018932:Chemokine CCL2; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D013449:Sulfonamides; C524344:TY 51469; D013876:Thiophenes; D053773:Transforming Growth Factor beta1; D012822:Silicon Dioxide; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases; D006909:Hydroxyproline