Abstract 13088: Protective Impact of Mild Pulmonary Thrombosis on Sepsis-Induced Lung Injury.

Sepsis patients that exhibit lung vascular injury and high mortality often suffer from severe pulmonary thrombosis (e.g. disseminated intravascular coagulation), but the beneficial impact of anti-coagulants in clinical trials of these patients is modest or absent. Although the regulation of sepsis-induced thrombosis has been intensely investigated, the converse impact of thrombosis on post-sepsis vascular injury is incompletely understood. The main aims of this study were to reveal the impact of varying severities of pulmonary thrombosis on sepsis-induced lung injury, and to determine whether hypoxia-inducible factor (HIF) 1α in endothelial and myeloid cells moderates inflammatory lung injury following thrombotic insult. We employed a mouse model of lung thrombosis in which different numbers of polystyrene microbeads are intra-venously seeded into the lung microvasculature, before or after i.p. lipopolysaccharide challenge. In microbead-free mice challenged with lipopolysaccharide, platelet depletion resulted in reduced pulmonary thrombosis and enhanced lung injury and inflammation. Administration of i.v. polystyrene microbeads, however, restored the level of pulmonary thrombosis to that found in platelet-replete mice, and protected against depletion-induced lung injury and inflammation. We then showed in wild type mice, that while severe increases in the level of pulmonary micro-occlusion worsened post-sepsis lung injury and inflammation, induction of a mild level of pulmonary micro-occlusion instead improved post-sepsis lung injury and inflammation. We also showed that the beneficial impact of this mild level of pulmonary thrombosis on post-sepsis lung injury and inflammation is dependent upon HIF1α. Furthermore, the same mild level of pulmonary thrombosis could even be induced after sepsis challenge to accelerate the resolution of lung inflammation, while induction of severe levels of pulmonary thrombosis after sepsis challenge delayed lung recovery. The experimental models used in our study enable for the quantitative control of thrombosis in the lung, while the administration of i.v. microbeads represents a unique strategy for the induction of a beneficial level of micro-occlusion to stabilize HIF1α in the lung vasculature and reduce inflammatory lung injury. In summary, our study provides evidence that the induction of a mild level of thrombotic occlusion protects against inflammatory lung injury, a finding that could help to explain the unconvincing efficacy of anti-coagulation in sepsis patients. [ABSTRACT FROM AUTHOR]