THE INTERACTION BETWEEN ANTITHROMBIN AND ENDOTHELIAL HEPARAN SULFATE MITIGATES PULMONARY THROMBOINFLAMMATION AFTER...

Area of Science:

• Biochemistry
• Immunology
• Physiology

Background:

• Trauma and hemorrhagic shock (T/HS) are linked to multiple organ injuries.
• Antithrombin (AT) exhibits anti-inflammatory and organ-protective effects via interaction with endothelial heparan sulfate (HS).
• A specific 3- O -sulfate modification on HS is crucial for AT's activity.

Purpose of the Study:

• To investigate the impact of T/HS on 3- O -sulfated (3-OS) HS expression.
• To determine if AT-HS interactions are essential for AT's anti-inflammatory properties.

Main Methods:

• Male Sprague-Dawley rats underwent T/HS and resuscitation.
• Pulmonary and plasma HS levels were quantified using liquid chromatography-coupled mass spectrometry.
• Lung injury and inflammatory markers were assessed histologically and biochemically.
• Rats were treated with vehicle or surfen, a HS antagonist, before T/HS and resuscitation with fresh frozen plasma (FFP), lactated Ringer's (LR), or AT-supplemented LR.

Main Results:

• T/HS significantly decreased pulmonary 3-OS HS expression and related sulfotransferase mRNA levels.
• Surfen treatment exacerbated fibrin deposition and inflammatory cell infiltration in FFP-resuscitated rats.
• Blocking AT-HS interactions abrogated FFP's anti-inflammatory effects and worsened lung injury.
• Supplementation with AT during LR resuscitation, combined with surfen, increased lung injury.

Conclusions:

• T/HS markedly reduces pulmonary 3-OS HS expression, which is vital for AT's antithrombotic and anti-inflammatory functions.
• Inhibition of AT-endothelial interactions negates the organ-protective benefits of FFP during T/HS.
• AT's interaction with the endothelium is critical for its anti-inflammatory signaling and organ protection in T/HS.