High-mobility-group box protein 1 A box reduces development of sodium laurate-induced thromboangiitis obliterans in rats

ObjectiveHigh-mobility-group box protein 1 (HMGB1), as a late mediator of inflammation, plays a key role in inflammatory responses by inducing and extending the production of proinflammatory cytokines. The effect of HGMB1 in the inflammatory disease thromboangiitis obliterans (TAO) is unknown. We aimed to investigate the role of HMGB1 in sodium laurate-induced TAO in rats.MethodsMale Wistar rats were randomly divided into five groups (n = 8 each) for treatment: normal, sham-operated, TAO model, and low-dose (15 mg/kg) or high-dose (30 mg/kg) recombinant A box (rA box) infection (administered intraperitoneally once daily for 15 days). The TAO model was induced by sodium laurate and graded by gross appearance on day 15 after femoral artery injection. Histologic changes were measured by histopathology in rat femoral arteries. Plasma levels of HMGB1, thromboxane B2, 6-keto-prostaglandin F1-α, and blood cell counts and blood coagulation levels were measured. Expression of HMGB1, receptor for advanced glycation end-products (RAGE), interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was assessed by immunohistochemistry and immunofluorescence, Western blot analysis, and quantitative reverse-transcription polymerase chain reaction.ResultsThe typical signs and symptoms of TAO were observed on day 15 after sodium laurate injection. The expression of HMGB1, RAGE, interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was markedly increased in rat femoral arteries. Plasma levels of HMGB1 and thromboxane B2 were elevated, but the level of 6-keto-prostaglandin F1-α was decreased. Blood was in a hypercoagulable state, and prothrombin, thrombin, and activated partial thromboplastin times were all significantly shortened, whereas fibrinogen level was increased in TAO rats compared with sham-operated rats. These effects were terminated by the HMGB1 antagonist rA box.ConclusionsHMGB1 is involved in the inflammatory state in a model of TAO induced by sodium laurate in rats, probably via its receptor RAGE. As the antagonist of HMGB1, rA box can attenuate the development of TAO, which may be a potential therapeutic target for the treatment of TAO.

Clinical RelevanceThromboangiitis obliterans (TAO), or Buerger disease, is a segmental nonatherosclerotic inflammatory disorder. Patients with Buerger disease have a lower quality of life because of intermittent claudication, rest pain, ulcers, and superficial thrombophlebitis. The specific etiology and pathologic mechanisms remain not elucidated. High-mobility-group box protein 1, as a late mediator of inflammation, plays a key role in inflammatory responses to tissue injury and infection by inducing and extending the production of proinflammatory cytokines. Here, we explored the role of high-mobility-group box protein 1 in rat model of TAO, discovering a new damage marker in TAO. We also investigated the unique role of recombinant A box in the prevention and treatment of TAO.