Mechanisms and the therapeutic potential of pulmonary lymphangiogenesis in a murine model of ventilator induced lung injury

在德国，每年有超过40万患者在重症监护病房接受机械通气治疗。呼吸机诱发的肺损伤（VILI）是一种常见的并发症，死亡率很高。预防VILI或治疗这种由损伤性机械通气演变而来的肺损伤的策略是有限的，主要围绕呼吸周期中机械力的限制，从而限制继发性伴随炎症（生物创伤）。机械性创伤和生物性创伤导致肺水肿的产生，肺水肿损害肺部气体交换，有时达到危及生命的低氧血症和高碳酸血症的程度。肺水肿几乎总是由间质和肺泡液流入和流出的不平衡引起的。在这种情况下，肺淋巴系统的排水能力很可能代表了控制肺液体平衡和炎症消退的重要病理生理功能。值得注意的是，淋巴系统促进白细胞从炎症部位外排到引流淋巴结。此外，淋巴管中含有LYVE-1透明质酸受体，可以清除间质中有害的透明质酸分裂产物。我们在引起VILI的高潮气量通气模型中的初步结果表明，有害的机械通气可以激活淋巴系统并诱导淋巴管生成。这些发现提出了VILI期间淋巴供需失衡的新概念，其中水肿形成、炎症细胞流入和透明质酸分裂产物的产生超过了淋巴系统的排水能力（液体、细胞和透明质酸分裂产物的外排）。基于这些发现，我们认为肺淋巴引流能力在VILI的发病和消退中起着至关重要的作用。我们假设可以通过对淋巴系统的药物刺激来增加引流能力，以更好地满足在损伤通气过程中对液体、细胞和分裂产物外排的更高需求。因此，我们的目标是进一步探讨机械通气时淋巴系统的生理学，明确淋巴管生成的机制，并确定VILI期间淋巴功能的调节因素。我们的目的是通过急性和慢性药理淋巴刺激来增加淋巴容量和功能，以测试其在解决损伤性通气期间水肿和炎症的治疗潜力。此外，我们旨在评估LYVE-1功能在清除肺部有害透明质酸中的保护作用。总之，本项目将探索淋巴系统及其引流能力在解决肺水肿和炎症中的作用，并将评估刺激淋巴管生成作为预防和治疗VILI的创新方法的潜在有效性。

In Germany, every year over 400.000 patients receive mechanical ventilation during treatment in the intensive care unit. A common complication, ventilator-induced lung injury (VILI) has a high mortality rate. Strategies to prevent VILI or treat such lung injury once it has evolved from injurious mechanical ventilation, are limited and focus mainly around the limitation of mechanical forces during the respiratory cycle, thereby limiting secondary concomitant inflammation (biotrauma). Mechanical trauma and biotrauma contribute to the generation of pulmonary edema which impairs pulmonary gas exchange, sometimes to the extent of life-threatening hypoxemia and hypercapnia. Pulmonary edema, almost invariably results from imbalances of interstitial and alveolar fluid influx and efflux. In this context, the draining capacity of the pulmonary lymphatic system most likely represents an important pathophysiological function governing the pulmonary fluid balance, and the resolution of inflammation. Of note, the lymphatic system promotes leucocyte efflux from the inflammation site to the draining lymph nodes. In addition, lymphatic vessels are spiked with LYVE-1 hyaluronan receptors that clear the interstitium from injurious hyaluronan split products. Our preliminary results in a model of high tidal volume ventilation that causes VILI, demonstrate that injurious mechanical ventilation can activate the lymphatic system and induce lymphangiogenesis. These findings give rise to a new concept of lymphatic supply-demand imbalances during VILI, where edema formation, inflammatory cell influx and generation of hyaluronan split products exceed the draining capacity of the lymphatic system (efflux of fluid, cells, and hyaluronan split products). Based on these findings, we propose that the pulmonary lymphatic draining capacity plays a crucial role in the pathogenesis and resolution of VILI. We hypothesize that the draining capacity can be increased through pharmacological stimulation of the lymphatic system to better match the higher demand for fluid, cell and split product efflux during injurious ventilation. Therefore, we aim to further explore the physiology of the lymphatic system during mechanical ventilation, to specify mechanisms of lymphangiogenesis and identify factors regulating lymphatic function during VILI. We aim to increase lymphatic capacity and function with acute and chronic pharmacological lymphatic stimulation to test its therapeutic potential for the resolution of edema and inflammation during injurious ventilation. Furthermore, we aim to evaluate the protective effects of LYVE-1 function in clearing harmful hyaluronan from the lungs. In summary, this project will explore the lymphatic system and its draining capacity in the resolution of pulmonary edema and inflammation and will assess the potential effectiveness of stimulated lymphangiogenesis as an innovative approach to the prevention and treatment of VILI.