Xie Peter Y, Morris Christopher J, Bertram Christopher D, Davis Michael J, Jamalian Samira, Jafarnejad Mohammad, Zawieja David C, Moore James E
Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK.
School of Mathematics and Statistics, University of Sydney, NSW, Australia.
Appl Eng Sci. 2025 Jun;22. doi: 10.1016/j.apples.2025.100217. Epub 2025 Apr 4.
The lymphatic system maintains bodily fluid balance by returning interstitial fluid to the venous system. Flow can occur through a combination of extrinsic pumping, due to forces from surrounding tissues, and intrinsic pumping involving contractions of muscle in the lymphatic vessel walls. Lymph transport is important not only for fluid homeostasis, but also for immune function, as lymph is a carrier for immune cells. Lymphatic muscle cells exhibit both cardiac-like phasic contractions to generate flow and smooth-muscle-like tonic contractions to regulate flow. Lymphatic vessels are sensitive to mechanical stimuli, including flow-induced shear stresses and pressure-induced vessel stretch. These forces modulate biochemical pathways, leading to changes in intracellular calcium that trigger contractile proteins. Employing a multiscale computational model of lymphatic muscle coupled to a lumped-parameter model of lymphatic pumping, we developed and validated a feedback control model of subcellular mechanisms that modulate lymphatic pumping. Following verification that the model reproduced results from axial or transmural pressure difference-controlled experiments, we tested the model's ability to match results from experiments imposing upstream/downstream pressure ramps or a sudden increase in downstream resistance. Inter-lymphangion signaling was necessary to reproduce downstream pressure ramp experiments, but otherwise the model predicted behaviors under these more complex conditions. A better understanding of the mechanobiology of lymphatic contractions can help guide future lymphatic vessel experiments, providing a basis for developing better treatments for lymphatic dysfunction.
淋巴系统通过将组织间液回流至静脉系统来维持体液平衡。淋巴液的流动可通过两种方式实现：一是外部泵吸作用，即周围组织产生的压力推动淋巴液流动；二是内部泵吸作用，即淋巴管管壁肌肉的收缩推动淋巴液流动。淋巴运输不仅对维持体液平衡至关重要，而且对免疫功能也十分关键，因为淋巴液是免疫细胞的载体。淋巴管肌肉细胞既表现出类似心脏的阶段性收缩以产生淋巴液流动，又表现出类似平滑肌的紧张性收缩以调节淋巴液流动。淋巴管对机械刺激敏感，包括流动引起的剪切应力和压力引起的血管扩张。这些力会调节生化途径，导致细胞内钙含量发生变化，进而触发收缩蛋白。我们构建了一个多尺度计算模型，将淋巴管肌肉模型与淋巴泵的集总参数模型相结合，开发并验证了一个亚细胞机制的反馈控制模型，该模型可调节淋巴泵功能。在验证该模型能够重现轴向或跨壁压差控制实验的结果后，我们测试了该模型与上游/下游压力斜坡实验或下游阻力突然增加实验结果的匹配能力。淋巴管间信号传导对于重现下游压力斜坡实验结果是必要的，否则该模型可预测这些更复杂条件下的行为。深入了解淋巴收缩的力学生物学有助于指导未来的淋巴管实验，为开发更好的淋巴功能障碍治疗方法提供依据。
