University of Minnesota, Department of Medicine, Vascular Research Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN, United States of America.
Hillhurst Biopharmaceuticals, Inc., Montrose, CA, United States of America.
PLoS One. 2018 Oct 11;13(10):e0205194. doi: 10.1371/journal.pone.0205194. eCollection 2018.
Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO-Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle-treated Townes-SS mice to 6.3g/dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 x 106/μL in vehicle-treated SS mice to 2.89 x 106/μL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002-treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 x 103/μL in vehicle-treated versus 20.3 x 103/μL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 expression and decreased NF-κB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration-dependent manner. Collectively, these findings support HBI-002 as a useful anti-inflammatory agent to treat SCD and warrants further development as a therapeutic.
一氧化碳（CO）在低浓度、无毒的情况下，先前已被证明可在镰状细胞病（SCD）的小鼠模型中发挥抗炎保护作用。然而，通过吸入、CO-血红蛋白输注或 CO 释放分子来输送 CO，在日常 CO 给药方面存在问题。口服 CO 饱和液体可避免许多此类问题，并为 SCD 患者的自我给药提供潜在平台。为了测试口服 CO 是否可以调节 SCD 血管阻塞和炎症，一种液体 CO 配方（HBI-002）通过灌胃（10ml/kg）每天一次给予 NY1DD 和 Townes-SS 转基因 SCD 小鼠模型。NY1DD 镰状小鼠和 Townes-AS 对照小鼠的基线 CO-血红蛋白（CO-Hb）水平分别为 1.6%和 1.8%，而 Townes-SS 镰状小鼠的 CO-Hb 水平为 0.6%。在 NY1DD、SS 和 AS 小鼠中，灌胃 HBI-002 后 5 分钟内，CO-Hb 水平分别达到 5.4%、4.7%和 3.0%。经过 10 次治疗，每日一次，在 HBI-002 治疗的 Townes-SS 小鼠中，血红蛋白水平从载体处理的 5.3g/dL 升高至 6.3g/dL。同样，红细胞（RBC）计数从载体处理的 SS 小鼠的 2.36 x 106/μL 升高至 HBI-002 处理的 2.89 x 106/μL。与这些发现一致的是，血细胞比容从载体处理的小鼠的 26.3%升高至 HBI-002 处理的小鼠的 30.0%。HBI-002 处理的 SS 小鼠的网织红细胞计数与载体处理的 SS 小鼠相比没有显著差异，这意味着溶血较少，而不是 RBC 生成增加。白细胞计数从载体处理的 29.1 x 103/μL 下降至 HBI-002 处理的 SS 小鼠的 20.3 x 103/μL。与载体处理的小鼠相比，用 HBI-002 治疗的 Townes-SS 小鼠的 Nrf2 和 HO-1 表达显著增加，NF-κB 激活减少。研究了 HBI-002（每天口服一次，最多 5 天）抑制缺氧-复氧诱导的血管阻塞的能力，以检查其抗炎作用。在 NY1DD 和 Townes-SS 镰状细胞病小鼠中，HBI-002 以时间依赖性方式降低微血管淤滞。总的来说，这些发现支持 HBI-002 作为一种有用的抗炎剂来治疗 SCD，并值得进一步开发作为一种治疗方法。
