Abstract Number: OC 28.2
Meeting: ISTH 2021 Congress
Background: Sepsis patients commonly suffer from lung thrombosis and sepsis-induced acute lung injury (ALI), but clinical trials of anti-coagulants in sepsis and ALI have failed, and the impact of varying severities of lung thrombosis on ALI is unknown.
Aims: In this study, we aimed to determine the impact of varying levels of lung thrombosis on ALI and to delineate the underlying mechanisms.
Methods: We assessed inflammatory lung injury in mouse models of pulmonary thrombosis combined with sepsis-induced lung injury and thrombocytopenia. We also used RNA sequencing and nanoparticle-mediated endothelial cell (EC)-targeted gene editing to delineate and target thrombosis-induced EC signaling pathways.
Results: In wild type mice, excessive increases in lung thrombosis worsened ALI, but the induction of a mild and innocuous level of lung thrombosis instead reduced ALI and mortality. We then showed that this mild level of lung thrombosis increases the expression of multiple factors that regulate cell survival, including arachidonate 15-lipoxygenase (Alox15) and hypoxia-inducible factor (HIF) 1α in ECs. Next, we used nanoparticle-mediated EC gene editing to show that the protective impact of mild lung thrombosis on ALI is dependent upon EC-specific Alox15 and HIF1α. From a therapeutic perspective, the mild level of lung thrombosis could be induced up to 8 hours after sepsis and still maintain its protective impact on ALI. Furthermore, the induction of mild lung thrombosis completely prevented thrombocytopenia-induced increases and ALI and mortality.
Conclusions: In summary, mild levels of lung thrombosis protect against inflammatory lung injury via Alox15 and HIF1α. Promoting lung EC survival through Alox15 or HIF1α signaling represents a promising therapeutic strategy against ALI/ARDS.
To cite this abstract in AMA style:Evans C, Zhang X, Machireddy N, Zhao Y-. Innocuous Levels of Pulmonary Thrombosis Protect against Inflammatory Lung Injury via Endothelial Alox15 and HIF1α [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/innocuous-levels-of-pulmonary-thrombosis-protect-against-inflammatory-lung-injury-via-endothelial-alox15-and-hif1%ce%b1/. Accessed September 23, 2021.
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