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Thromboangiitis obliterans (TAO), also known as Buerger's disease, is a nonatherosclerotic inflammatory disease that influences medium- and small-sized blood vessels of extremities. However, mechanisms underlying TAO are still unclear. As a mediator associated with inflammation, A disintegrin and metalloprotease 10 (ADAM10) was hypothesized to play inhibitory roles in the development of TAO. Thus, the objective of this study is to investigate the effects of ADAM10 in a sodium laurate-induced TAO rat model and elucidate underlying mechanisms. Male Wistar rats were randomly divided into four groups (n = 6) for treatment: sham-operated (SHAM), TAO model (TAO), ADAM10 low dose injection (3 mg/kg; ADAM10-LD) and ADAM10 high dose injection (6 mg/kg; ADAM10-HD). After 14-day treatment, color Doppler ultrasound and hematology analysis indicated TAO rats displayed higher whole blood viscosity and blood platelet count compared with those in the SHAM group. Histologic evaluation and transmission electron microscopy revealed that the ultrastructural damages of vascular smooth muscle and endothelial cells were observed in TAO rats, such as fractured endoplasmic reticulum, decreased cell counts, and fibrillation. On the other hand, the typical signs and symptoms of TAO rats were significantly alleviated via ADAM10 treatment with a dose-dependent pattern. Real-time PCR and western blot results revealed that the expression of high-mobility-group box 1 (HMGB1), receptor for advanced glycation end-products (RAGE) and nuclear factor-kappa B (NF-κB) increased in TAO rats whereas decreased by ADAM10 treatment in both mRNA and protein levels. In conclusion, the results suggest ADAM10 alleviates symptoms of sodium laurate-induced TAO in rats via the RAGE/NF-κB signaling pathway and provides insight into the molecular basis and a potential therapeutic strategy for TAO., (Copyright © 2018. Published by Elsevier Inc.)

Objective: High-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., Methods: Male 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., Results: The 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., Conclusions: HMGB1 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., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Ethnopharmacological Relevance: Thromboangiitis obliterans (TAO) or Buerger's disease is a non atherosclerotic, segmentar inflammatory vasculitis that is incurable at present. Shenfu injection (SFI), a traditional Chinese formulation, have been confirmed to produce protective influences on several organs and limb during ischemia and reperfusion (IR) injury in rats. However, the effects of SFI on TAO remain unclear., Materials and Methods: Adult male Sprague Dawley rats were randomly divided into sham operated group, TAO model group, SFI 2.5mg/kg (low dose), 5mg/kg (medium dose) and 10mg/kg (high dose) groups (n=8). Rats were intravenously administered SFI 2.5, 5 and 10mg/kg or saline once per day for 15 days. TAO model was prepared by injecting sodium laurate into the femoral artery of rats. Then we examined the changes of pathological signs, pathologic grading of thrombus, the indexes of hematology, the contents of thromboxane B2 (TXB2), 6-keto-prostaglandin F(lα) (6-K-PGF(1α)) in plasma following SFI or saline treatment., Results: More pathological signs of lesions, higher grades of pathological thrombosis, increased blood platelet counts, the increase in the TXB2 and TXB2/6-K-PGF(1α) ratio, as well as the decrease of 6-K-PGF(1α) in TAO model group were shown in present experiments; SFI treatment significantly improved the pathological signs of lesions induced by sodium laurate injection, reduced the numbers of thrombus formation, blood platelet counts, the TXB2 and TXB2/6-K-PGF(1α) ratio but increased the 6-K-PGF(1α) compared with TAO model group. However, there were no significant alterations in the counts of red blood cell, leucocyte and neutrophil among these groups., Conclusions: Our preliminary findings first indicated that SFI can produce significant therapeutic effects on experimental Buerger's disease model rats in a dose independent manner. The underlying mechanisms may be due to its modifying hematology, inhibiting platelet aggregation and enhancing anti-thrombotic function of vessel endothelia., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Thromboangiitis obliterans is a vascular disease characterized by a segmental, non-atherosclerotic inflammation of the small and medium-sized arteries and veins. The vascular changes are mainly found on the distal extremities. Involvement of visceral organs is rare. Affected patients are mostly young male smokers, who develop ulcers and gangrene of the toes and fingers as a result of the vascular ischaemia. Diagnosis is made using characteristic clinical criteria as well as pathological findings in arteriography and histopathology. Although the exact underlying causes of Buerger's disease are still unknown, the disease is strongly associated with tobacco smoking. Although most investigators speculate about an autoimmune mechanism, no causative antigens have yet been discovered. The only definite form of therapy is the discontinuation of tobacco use. On the basis of smoking cessation, further therapies (e.g. administration of prostacyclin analoga) are possible. The mortality rate for patients with Buerger's disease is not higher than that for the rest of the adult population, but patients often require minor and major limb amputation due to ulcerations.

Smoking is a major risk factor for peripheral arterial occlusive disease (PAOD) and plays a crucial role in the pathogenesis of the thrombangiitis obliterans (TAO), nicotine and carboxyhemoglobin cause functional disturbances and structural damage of the endothelial cells which may initiate arteriosclerosis. Additional effects of smoking are hyperfibrinogenemia, lowering of HDL-cholesterol and increased oxidation of LDL-cholesterol. By these mechanisms, smoking influences other primary risk factors for arteriosclerosis. Patients with PAOD, who continue to smoke, have a worse clinical prognoses with higher amputation and mortality rates than those who quit smoking. The most urgent goal in the therapy of PAOD and TAO should be an immediate and complete smoking cessation. However most patients continue to smoke despite the knowledge of the hazards to their health. An appropriate approach to this addiction may be an alternative application of nicotine temporarily (transdermal by patches or chewing gum) and behavioral treatment. This combined therapy results in better success rates in terms of smoking cessation.