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40万名患者在重症监护室接受机械通气治疗。呼吸机相关性肺损伤（VILI）是一种常见的并发症，死亡率很高。一旦VILI从损伤性机械通气演变而来，预防VILI或治疗此类肺损伤的策略是有限的，并且主要集中在呼吸周期期间机械力的限制，从而限制继发性伴随炎症（生物创伤）。机械创伤和生物创伤导致肺水肿的产生，肺水肿损害肺气体交换，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体流入和流出的不平衡引起。在这种情况下，肺淋巴系统的引流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流出到引流淋巴结。此外，淋巴管中掺入LYVE-1透明质酸受体，可清除有害透明质酸裂解产物中的氚。我们在导致VILI的大潮气量通气模型中的初步结果表明，损伤性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、炎性细胞流入和透明质酸裂解产物的产生超过了淋巴系统的引流能力（液体、细胞和透明质酸裂解产物的流出）。基于这些发现，我们提出肺淋巴引流能力在VILI的发病和消退中起着至关重要的作用。我们假设，引流能力可以通过淋巴系统的药理学刺激来增加，以更好地匹配损伤性通气期间对液体、细胞和分裂产物流出的更高需求。因此，我们的目的是进一步探讨在机械通气过程中的淋巴系统的生理学，明确淋巴管生成的机制，并确定在VILI调节淋巴功能的因素。我们的目的是增加淋巴容量和功能，急性和慢性药理学淋巴刺激，以测试其治疗潜力的解决水肿和炎症损伤性通气。此外，我们的目的是评估LYVE-1功能在清除肺部有害透明质酸方面的保护作用。总之，该项目将探索淋巴系统及其在解决肺水肿和炎症方面的引流能力，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.