HS3ST1 regulates pulmonary inflammation and is a determinant of clinical outcomes after trauma and hemorrhagic shock

Mokhtari, A. K.; Cotton, M. E.; Thomas, K. A.; Chitrakar, A.; Krocker, J. D.; Pokharel, M.; Osborn, B. K.; Huby Viduarre, M. d. P.; Mankame, A. R.; Wade, C. E.; Wang, Y.-W.; Orlicky, D. J.; Cohen, M. J.; Richter, J. R.; Shworak, N. W.; Cardenas, J.

doi:10.64898/2026.05.07.723543

bioRxiv · 10.64898/2026.05.07.723543

HS3ST1 regulates pulmonary inflammation and is a determinant of clinical outcomes after trauma and hemorrhagic shock

Mokhtari, A. K.·Cotton, M. E.·Thomas, K. A.·Chitrakar, A.·Krocker, J. D.·Pokharel, M.·Osborn, B. K.·Huby Viduarre, M. d. P.·Mankame, A. R.·Wade, C. E.·Wang, Y.-W.·Orlicky, D. J.·Cohen, M. J.·Richter, J. R.·Shworak, N. W.·Cardenas, J.

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Abstract

Mechanisms that promote organ injury after trauma and hemorrhagic shock (T/HS) remain poorly defined. Endothelial heparan sulfates with a 3-O-sulfate (3-OS) modification, controlled by the HS3ST1 gene, have anticoagulant and anti-inflammatory properties through their interaction with antithrombin. Our objective was to determine whether HS3ST1 deficiency drives organ injury and poor outcomes after T/HS. Hs3st1-/- and wild-type (WT) mice were subjected to T/HS followed by resuscitation with lactated ringers (LR) or fresh frozen plasma (FFP). While no differences were observed between WT and Hs3st1-/- LR resuscitated mice, lung injury and leukocyte infiltrates were significantly increased in FFP resuscitated Hs3st1-/-compared to WT mice. In vitro, leukocyte slow rolling and adherence was increased in HS3ST1 KO compared to WT cells. Among 472 T/HS patients, of which 31 (7%) were homozygous for the rs16881446 variant allele (GG), the number of ventilator free days was lower, and mortality was significantly higher in AG and GG patients. The rs16881446 genotype was independently associated with mortality. In conclusion, HS3ST1 deficiency mitigates organ protection from FFP resuscitation, partly through mediating EC:leukocyte engagement, and predicts mortality after T/HS. These findings identify a novel therapeutic target and prognostic tool that can be leveraged towards improved risk stratification after trauma.

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Mokhtari, A. K., Cotton, M. E., Thomas, K. A., Chitrakar, A., Krocker, J. D., Pokharel, M., Osborn, B. K., Huby Viduarre, M. d. P., Mankame, A. R., Wade, C. E., Wang, Y.-W., Orlicky, D. J., Cohen, M. J., Richter, J. R., Shworak, N. W., Cardenas, J.. 2026-05-12. HS3ST1 regulates pulmonary inflammation and is a determinant of clinical outcomes after trauma and hemorrhagic shock. https://doi.org/10.64898/2026.05.07.723543

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