Kai Yoshiro, Yoneyama Hiroyuki, Koyama Jun, Hamada Kaoru, Kimura Hiroshi, Matsushima Kouji
Department of Molecular Preventive Medicine and SORST, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Med Mol Morphol. 2007 Sep;40(3):128-40. doi: 10.1007/s00795-007-0370-y. Epub 2007 Sep 18.
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.
肺纤维化的特征是肺间质中炎症细胞积聚，随后细胞外基质沉积增加。巨噬细胞通过介导从炎症到纤维化的进展在这种疾病中发挥至关重要的作用，但巨噬细胞在这些部位停留的机制尚未完全了解。尽管白细胞的迁移受趋化因子调节，但糖胺聚糖可调节趋化因子的功能和白细胞的迁移。因此，我们研究了硫酸软骨素蛋白聚糖（CSPGs）在小鼠博来霉素诱导的肺纤维化模型中的作用。气管内注射博来霉素或生理盐水后，将小鼠随机分组，接受一次静脉注射并连续输注CSPG消化酶软骨素酶ABC（ChABC）或载体，持续7天。博来霉素攻击后，CSPGs很容易被诱导并逐渐增加。尽管CSPGs抑制了早期CCL2依赖的巨噬细胞募集，但沉积的CSPGs以CD44依赖的方式将巨噬细胞保留在纤维化间质中。体内用ChABC治疗可显著提高小鼠的存活率，并通过抑制巨噬细胞的持续积聚减少胶原蛋白沉积。这些结果表明CSPGs在巨噬细胞介导的肺纤维化中起关键作用，并提示ChABC在肺纤维化中可能具有新的治疗作用。
