Treatment with chondroitinase ABC alleviates bleomycin-induced pulmonary fibrosis.
Pulmonary fibrosis is characterized by an accumulation of inflammatory cells in the lung interstitium, followed by an increased deposition of extracellular matrix. Macrophages play a vital role in this disease by mediating the progression from inflammation to fibrosis, but the mechanisms by which macrophages are retained at these sites are not fully understood. Although the transmigration of leukocytes is regulated by chemokines, glycosaminoglycans modulate the function of chemokines and the migration of leukocytes. Accordingly, we investigated the role of chondroitin sulfate proteoglycans (CSPGs) in a murine bleomycin-induced pulmonary fibrosis models. After intratracheal injection of bleomycin or saline, mice were randomized to receive one intravenous injection and continuous infusion of the CSPG-digesting enzyme chondroitinase ABC (ChABC), or vehicle, for 7 days. CSPGs were readily induced and progressively augmented after the bleomycin challenge. Although CSPGs inhibited the early CCL2-dependent recruitment of macrophages, deposited CSPGs retained macrophages in fibrotic interstitium in a CD44-dependent manner. Treatment with ChABC in vivo dramatically increased survival of the mice and reduced collagen deposition by inhibiting persistent macrophage accumulation. These results indicate a pivotal role for CSPGs in macrophage-mediated lung fibrogenesis and suggest a possible new therapeutic role for ChABC in pulmonary fibrosis.
Kai
Yoshiro
Y
Department of Molecular Preventive Medicine and SORST, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Yoneyama
Hiroyuki
H
Koyama
Jun
J
Hamada
Kaoru
K
Kimura
Hiroshi
H
Matsushima
Kouji
K
D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D019765:Chondroitin ABC Lyase / Q000494:pharmacology / Q000627:therapeutic use*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
D018932:Chemokine CCL2; D011508:Chondroitin Sulfate Proteoglycans; D018960:Hyaluronan Receptors; D001761:Bleomycin; D019765:Chondroitin ABC Lyase