Derseh Habtamu B, Perera Kopiyawaththage U E, Dewage Sasika N Vithana, Stent Andrew, Koumoundouros Emmanuel, Organ Louise, Pagel Charles N, Snibson Ken J
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC, Australia.
Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Werribee, VIC, Australia.
Front Pharmacol. 2021 Oct 22;12:700902. doi: 10.3389/fphar.2021.700902. eCollection 2021.
Idiopathic pulmonary fibrosis (IPF) is a progressive chronic lung disease characterized by excessive extracellular matrix (ECM) deposition in the parenchyma of the lung. Accompanying the fibrotic remodeling, dysregulated angiogenesis has been observed and implicated in the development and progression of pulmonary fibrosis. Copper is known to be required for key processes involved in fibrosis and angiogenesis. We therefore hypothesized that lowering bioavailable serum copper with tetrathiomolybdate could be of therapeutic value for treating pulmonary fibrosis. This study aimed to investigate the effect of tetrathiomolybdate on angiogenesis and fibrosis induced in sheep lung segments infused with bleomycin. Twenty sheep received two fortnightly infusions of either bleomycin (3U), or saline (control) into two spatially separate lung segments. A week after the final bleomycin/saline infusions, sheep were randomly assigned into two groups ( = 10 per group) and received twice-weekly intravenous administrations of either 50 mg tetrathiomolybdate, or sterile saline (vehicle control), for 6 weeks. Vascular density, expressed as the percentage of capillary area to the total area of parenchyma, was determined in lung tissue sections immuno-stained with antibodies against CD34 and collagen type IV. The degree of fibrosis was assessed by histopathology scoring of H&E stained sections and collagen content using Masson's trichrome staining. Lung compliance was measured via a wedged bronchoscope procedure prior to and 7 weeks following final bleomycin infusion. In this large animal model, we show that copper lowering by tetrathiomolybdate chelation attenuates both bleomycin-induced angiogenesis and pulmonary fibrosis. Moreover, tetrathiomolybdate treatment downregulates vascular endothelial growth factor (VEGF) expression, and improved lung function in bleomycin-induced pulmonary fibrosis. Tetrathiomolybdate also suppressed the accumulation of inflammatory cells in bronchoalveolar lavage fluid 2 weeks after bleomycin injury. The molecular mechanism(s) underpinning copper modulation of fibrotic pathways is an important area for future investigation, and it represents a potential therapeutic target for pulmonary fibrosis.
特发性肺纤维化（IPF）是一种进行性慢性肺部疾病，其特征是肺实质中细胞外基质（ECM）过度沉积。伴随纤维化重塑，已观察到血管生成失调，并与肺纤维化的发生和发展有关。已知铜是纤维化和血管生成所涉及的关键过程所必需的。因此，我们假设用四硫代钼酸盐降低生物可利用的血清铜可能对治疗肺纤维化具有治疗价值。本研究旨在探讨四硫代钼酸盐对博来霉素注入绵羊肺段诱导的血管生成和纤维化的影响。20只绵羊在两个空间上分开的肺段中每两周接受一次博来霉素（3U）或生理盐水（对照）注入。在最后一次博来霉素/生理盐水注入一周后，绵羊被随机分为两组（每组 = 10只），并接受每周两次静脉注射50 mg四硫代钼酸盐或无菌生理盐水（载体对照），持续6周。用抗CD34和IV型胶原抗体免疫染色的肺组织切片中测定血管密度，以毛细血管面积占实质总面积的百分比表示。通过对苏木精和伊红染色切片进行组织病理学评分以及使用马松三色染色法测定胶原含量来评估纤维化程度。在最后一次博来霉素注入前和注入后7周，通过楔形支气管镜检查程序测量肺顺应性。在这个大型动物模型中，我们表明通过四硫代钼酸盐螯合降低铜可减轻博来霉素诱导的血管生成和肺纤维化。此外，四硫代钼酸盐治疗可下调血管内皮生长因子（VEGF）表达，并改善博来霉素诱导的肺纤维化中的肺功能。在博来霉素损伤后2周，四硫代钼酸盐还抑制了支气管肺泡灌洗液中炎症细胞的积聚。铜调节纤维化途径的分子机制是未来研究的一个重要领域，它代表了肺纤维化的一个潜在治疗靶点。
