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

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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.