New study shows methylene blue may reduce lung damage caused by heart surgery
What Happens to the Lungs During Heart Surgery?
In some major heart surgeries, doctors temporarily stop blood circulation and cool the body to a very low temperature. This technique is called hypothermic circulatory arrest (HCA). It helps protect the brain and other organs during complex procedures like aortic arch repair, but it also comes with risks—especially to the lungs.
One serious complication after this type of surgery is acute lung injury (ALI). It affects more than a third of patients and can lead to breathing problems, longer hospital stays, and in severe cases, death. The injury happens when the lungs are starved of oxygen, then flooded with it again once circulation is restored. This “reboot” can trigger inflammation, stress, and damage to lung tissue.
A Surprising Ally: Methylene Blue
You may know methylene blue as a dye used in science labs, but it’s more than just color. Doctors have used it for decades to treat conditions like carbon monoxide poisoning and infections. It’s also known to fight inflammation and help cells cope with oxidative stress—a kind of damage caused by unstable molecules in the body.
But could this blue dye help protect the lungs during surgery?
A team of scientists in China wanted to find out. In their study, they used a rat model that closely mimics how HCA is done in human surgeries. Their goal was to see if methylene blue could prevent lung damage caused by this procedure—and, if so, how it worked.
How the Study Was Done?
Researchers divided the rats into several groups. Some went through a simulated HCA procedure, while others served as healthy controls. A few of the rats were given methylene blue through an injection 15 minutes before the procedure. The researchers also tested other substances to better understand how methylene blue works in the body.
After surgery, the team measured various health markers, took lung tissue samples, and looked at cells under a microscope.
What They Found?
- Methylene Blue Helped Maintain Normal Body Function
Heart surgery with HCA caused the rats’ blood pressure to drop and their oxygen levels to fall. Their blood also became more acidic. But in rats treated with methylene blue, these changes were much less severe. The dye seemed to help stabilize the body’s systems during and after the procedure.
- It Reduced Visible Damage in the Lungs
Lung samples from untreated rats showed clear signs of injury: swelling, bleeding, thickened walls, and dead cells. The lungs looked inflamed and structurally damaged. However, rats that received methylene blue had healthier-looking lungs with fewer signs of injury and cell death.
- Inflammation Was Lower
The untreated rats had high levels of inflammatory markers in their lungs. These included immune cells and chemicals that signal damage. Methylene blue reduced the number of these markers, meaning it helped control the immune system’s overreaction.
- It Protected the Lungs from Stress
Another cause of lung injury is oxidative stress, which happens when harmful molecules called reactive oxygen species (ROS) build up. Rats that had undergone surgery had high ROS levels and lower amounts of protective enzymes. Methylene blue reversed that: it cut down the harmful molecules and boosted the natural defenses.
- It Shifted Immune Cells to a ‘Healing Mode’
The lungs are home to special immune cells called alveolar macrophages. These cells can either fight infection (the “M1” mode) or help heal tissue (the “M2” mode). After surgery, most of these cells were stuck in the aggressive M1 mode. Methylene blue helped more of them switch to the healing M2 mode, which could explain why the lungs recovered better.
- It Blocked a Dangerous Chain Reaction
One of the most harmful processes in lung injury is something called pyroptosis. It’s a form of cell death where immune cells explode, spilling out substances that make inflammation even worse. This is triggered by a protein complex in cells known as the NLRP3 inflammasome.
In this study, surgery activated this dangerous pathway. But methylene blue blocked it, stopping the chain reaction before it could spiral out of control.
How Do We Know It Was Really Methylene Blue?
To make sure methylene blue was working through the right pathways, the scientists added special substances to some of the rats. One of these boosted the body’s antioxidant defense system (called the Nrf2/HO-1 pathway), while another blocked it. The same was done for the pyroptosis pathway.
When the antioxidant system was blocked, methylene blue didn’t work as well. When the inflammation pathway was turned on, lung damage came back. This confirmed that methylene blue protects the lungs by both boosting antioxidants and preventing inflammatory cell death.
Why This Matters?
This research is exciting because it points to a new way to protect patients during high-risk heart surgeries. Methylene blue is already used in hospitals, and its safety is well-known. That makes it a strong candidate for further study in humans.
While this experiment was done in rats, the findings lay the groundwork for future trials in people. If methylene blue can reduce lung damage in real surgeries, it could improve outcomes for thousands of patients every year.
What is Next?
The researchers noted that they didn’t explore different doses of methylene blue or test it in animals with pre-existing conditions like diabetes or high blood pressure—common in real-life patients. Future studies will need to address these factors.
Still, this study provides a clear starting point: methylene blue shows promise as a low-cost, effective treatment to reduce lung injury in complex surgeries involving hypothermia and circulation stops.
The translation of the preceding English text in Chinese:
新研究显示亚甲蓝可能减少心脏手术引起的肺损伤
心脏手术时肺部会发生什么？
在一些重大心脏手术中，医生会暂时停止血液循环，并将体温降至极低水平。这种技术称为低温循环停顿（HCA），可在进行主动脉弓修复等复杂手术时保护大脑和其他器官，但也带来一定风险——特别是对肺部。
这种手术后的一个严重并发症是急性肺损伤（ALI）。它影响超过三分之一的患者，可能导致呼吸困难、住院时间延长，严重时甚至危及生命。损伤的发生机制是：肺部在手术中缺氧，血液循环恢复后又迅速充氧，这种“重启”会触发炎症、应激反应，并对肺组织造成损害。
意想不到的盟友：亚甲蓝
你或许知道亚甲蓝是一种实验室常用染料，但它的作用远不止染色。几十年来，医生一直用它治疗一氧化碳中毒和感染等疾病。它也被认为具有抗炎作用，并能帮助细胞应对氧化应激——这是一种由体内不稳定分子引发的损伤。
那么，这种蓝色染料能否在手术中保护肺部？
中国的一组科学家想要找到答案。他们在研究中使用了一个模拟人类HCA手术的老鼠模型，旨在探究亚甲蓝是否能预防该手术导致的肺损伤，以及其具体机制。
研究方法
研究人员将老鼠分成几个组。一些接受模拟的HCA手术，另一些作为健康对照组。其中一部分老鼠在手术前15分钟注射了亚甲蓝。研究人员还测试了其他物质，以进一步了解亚甲蓝在体内的作用机制。
术后，团队测量了多种健康指标，采集肺组织样本，并在显微镜下观察细胞情况。
研究发现
亚甲蓝有助于维持身体功能稳定
HCA手术使老鼠的血压下降，血氧水平降低，血液变得更酸性。但注射亚甲蓝的老鼠，这些变化明显减轻。该染料似乎帮助在手术期间和术后稳定了身体系统。
肺部损伤显著减少
未接受治疗的老鼠肺组织出现明显损伤迹象：肿胀、出血、组织增厚、细胞死亡。肺部呈现炎症和结构破坏。但注射亚甲蓝的老鼠肺部看起来更健康，损伤和细胞死亡较少。
炎症水平降低
未处理老鼠肺部的炎症标志物水平很高，包括免疫细胞和损伤信号物质。亚甲蓝减少了这些标志物的数量，说明它帮助抑制了免疫系统的过度反应。
抵御氧化应激的能力增强
氧化应激是另一种肺损伤机制，由体内的活性氧（ROS）堆积引起。手术后的老鼠体内ROS水平升高，而保护性酶类水平下降。亚甲蓝则降低了有害分子的数量，并提升了身体自身的抗氧化防御能力。
促进免疫细胞转为“修复模式”
肺部存在一种特殊的免疫细胞——肺泡巨噬细胞。它们可以处于攻击性强的“M1型”或修复组织的“M2型”。手术后，这些细胞大多停留在M1状态。亚甲蓝促进更多细胞转向修复型的M2状态，这可能是肺部恢复较好的原因之一。
阻断有害的链式反应
肺损伤最危险的过程之一是“焦亡”（pyroptosis），这是一种细胞死亡形式，免疫细胞爆裂后释放出加剧炎症的物质。这一过程由细胞内的NLRP3炎症小体触发。
研究发现，手术激活了这一危险通路，但亚甲蓝成功阻断了它，防止了炎症的恶性循环。
亚甲蓝的作用机制如何验证？
为确保亚甲蓝通过正确的机制发挥作用，研究人员对部分老鼠加入了特定物质。其中一种增强了体内的抗氧化系统（Nrf2/HO-1通路），另一种则抑制它。相似的方法也用于焦亡通路的测试。
结果发现，当抗氧化通路被阻断时，亚甲蓝的效果减弱；当炎症通路被激活时，肺损伤再次出现。这证实了亚甲蓝是通过增强抗氧化能力和防止炎症性细胞死亡来保护肺部的。
研究意义
这项研究令人振奋，因为它为在高风险心脏手术中保护患者提供了新的可能。亚甲蓝已在医院广泛使用，安全性已被证实，使其成为未来人体研究的有力候选药物。
尽管本研究是在老鼠身上进行的，但结果为人体临床试验奠定了基础。如果亚甲蓝能在实际手术中减少肺损伤，它每年可能改善数千名患者的预后。
接下来的研究方向
研究人员指出，他们尚未探索不同剂量的亚甲蓝，也未在患有糖尿病或高血压等常见慢性病的动物中测试其效果。未来的研究需进一步解决这些实际问题。
尽管如此，这项研究已经明确指出：亚甲蓝是一种低成本、潜力巨大的药物，有望用于降低低温循环停顿等复杂手术中的肺损伤风险。
Reference:
Fuyan Ding, Hong Wang, Gang Qiao, Zhidong Zhang
Methylene blue mitigates lung injury in HCA rats by regulating macrophage pyroptosis via Nrf2/HO-1 and NLRP3 pathways.
Biomol Biomed [Internet]. 2025 Feb. 13 [cited 2025 Apr. 14];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11851
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