The role of platelet PI3K in acute lung injury

Acute Lung Injury (ALI) is a life-threatening condition, despite improved treatment options. New evidence demonstrates that platelet-leukocyte interactions play a pivotal role in neutrophil activation and migration, which represent hallmarks of ALI and contribute to lung pathology by host tissue damage. Up to today, the role of platelets in bacterial ALI remains incompletely understood. Therefore, it is a central aim of this project to clarify the role of platelets in infectious and non-infectious models of ALI. Moreover we are interested in signaling pathways, in particular phosphatidylinositol 3-kinase (PI3K), potentially regulating innate immune functions of platelets in ALI. Our primary data indicate that surface expression of P-selectin and subsequent platelet-leukocyte aggregate formation can be completely abolished if PI3K is inhibited. Moreover we can show that in a PI3K class Ia knockout mouse (p85a-/-), platelet P-selectin expression in response to TLR stimulation is significantly reduced, while other platelet functions are normal. Based on our preliminary results we hypothesize that in p85a-/- mice inflammatory stimuli-induced platelet-leukocyte interactions are reduced, which should result in a beneficial outcome in the progression of non-infectious ALI, but could have detrimental effects for the host during the clearance of pathogenic bacteria. The PI3K/AKT signaling axis represents a potentially interesting regulatory pathway for pharmacological interventions. Currently, a wide range of selective PI3K inhibitors are tested in preclinical studies and some have entered clinical trials in oncology. However, tightly controlled PI3K signaling is essential for a fully functional host immune response. Inhibition of this pathway might result in serious complications during pathophysiologic conditions of ongoing infections. Therefore, we aim to determine the effects of diminished PI3K activity in platelets in a model of abacterial and bacterial ALI using pharmacologic as well as genetic approaches in mice. Moreover, we aim to determine the impact of platelet specific PI3K deficiency to clarify the role of platelet PI3K in platelet/leukocyte interactions in the progression of ALI. The proposed project will provide important insight into the interaction between platelets and immune cells, particularly in acute lung injury. And it will provide new, physiologically relevant, observations for the importance of PI3K in pathogen-driven intracellular signaling processes in platelets. This is likely to have broader scientific impact across fields such as pharmacology and drug development, in addition it might provide a basis for new therapeutic strategies in different forms of inflammation-associated lung diseases.

Acute lung injury represents a life-threatening condition which is caused by infection or by toxic substances which lead to injuries of the pulmonary vessel wall. Immune cells then hurry into the lungs and try to fight the intruders. This causes damage to the lungs, which limits lung functions and leads to diminished oxygen supply. Studies have shown that blood platelets play a crucial role in recruitment and activation of immune cells. Therefore, influencing blood platelet-immune-cell interaction could be an attractive therapeutical approach in acute lung injury. In this project, we therefore investigated platelet activation via phosphatidylinositol 3-kinase (PI3K) and monitored their effects on various models of lung inflammation. PI3K is important for the activation of blood platelets, as well as other cell types and drugs which block this kinase, are already used in clinics. Our results show that PI3K in blood platelets plays a crucial role in the recruitment of immune cells in the lung. In an experimental model of acid-induced lung injury, which represents a pathological condition where gastric contents enter the lung via the airway, inhibition of platelets via PI3K has a positive effect on the course of disease, as inflammation in the lung gets reduced. If, however, the inflammation of the lungs is caused by bacteria, e.g. pneumonia, it is important that blood platelets can direct immune cells to the site of inflammation in order to limit the spread of bacteria. Thus the survival rate in bacterial pulmonary infections could be increased if functional blood platelets were present. Our data provide new insights into the effect of blood platelets on the immune system and point to the disease-specific function of blood platelets.