Conclusions and Perspectives

Although AT is an important natural anticoagulant, it might attenuate inflammatory responses by inhibiting the production of TNF-a. TNF-a is capable of inducing micro-circulatory disturbance leading to various organ failures by activating neutrophils and by inducing microthrombus formation. Since microthrombus formation further increases TNF-a production to form a vicious cycle in the progression of microcirculatory disturbance, inhibition of both neu-trophil activation and microthrombus formation by AT through promotion of endothelial production of PGI2 and inherent anticoagulant activity might be important in improving microcirculatory disturbance. Because of these important properties, AT should be an useful therapeutic agent for microcirculatory disturbance in various disease states.

Glossary

Activated neutrophils: Neutrophils activated by various agonists such as pro-inflammatory cytokines and release neutrophil proteases and oxygen radicals that are capable of damaging endothelial cells.

Antithrombin: One of natural anti-coagulants inhibiting coagulation factors with serine protease properties.

Calcitonin-gene related peptide: A neuropeptide synthesized in dorsal root ganglion cells and released from sensory neurons on activation.

Capsaicin-sensitive sensory neurons: Nociceptive neurons that are activated by a wide variety of noxious physical stimuli and have roles in regulation of local inflammatory responses.

Endothelial cell injury: Damage of endothelial cells induced by of noxious substances such as neutrophil elastase and oxygen free radicals and leads to impairment of the endothelial function to maintain proper microcirculation.

Prostacyclin: One of prostaglandins synthesized in endothelial cells and has potent anti-platelet, vasodilatory and anti-inflammatory activities.

Tumor necrosis factor-a: One of pro-inflammatory cytokines produced by circulating monocytes and macrophages in response to endotoxin and a representative causal substance for coagulation abnormalities and organ failures observed in sepsis.

References

1. Ishiguro, K., Kojima, T., Kadomatsu, K., Nakayama, Y., Takagi, A., Suzuki, M., Takeda, N., Ito, M., Yamamoto, K., Matsushita, T., Kusugami, K., Muramatsu, T., and Saito, H. (2000). Complete antithrombion deficiency in mice results in embryonic lethality. J. Clin. Invest. 106, 873-878.

2. Hirsh, J., Piovella, F., and Pini, M. (1989). Congenital antithrombin III deficiency. Incidence and clinical features. Am. J. Med. 87, 34S-38S.

3. Okajima, K. (2001). Regulation of inflammatory responses by natural anticoagulants. Immunol. Rev. 184, 258-274.

4. Okajima, K., Harada, N., Kushimoto, S., and Uchiba, M. (2002). Role of microthrombus formation in the development of ischemis/ reperfusion-induced liver injury in rats. Thromb. Haemost. 88, 473-480.

5. Okajima, K., Harada, N., and Uchiba, M. (2003). Microthrombus formation enhances tumor necrosis factor-a production in the development of ischemia/reperfusion-induced liver injury in rats. J. Thromb. Haemost. 1, 1316-1317.

6. Isobe, H., Okajima, K., Uchiba, M., Harada, N., and Okabe, H. (2002). Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats. Blood 99, 1638-1645.

7. Mizutani, A., Okajima, K., Uchiba, M., Isobe, H., Harada, N., Mizutani, S. R. N., and Noguchi, T. (2003). Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. Blood 101, 3029-3036.

8. Harada, N., Okajima, K., Uchiba, M., and Katsuragi, T. (2003). Contribution of capsaicin-sensitive sensory neurons to stress-induced increases in gastric tissue levels of prostaglandins in rats. Am. J. Physiol. Gastrointest. Liver. Physiol. 285, G1214-G1224.

9. Harada, N., Okajima, K., Yuksel, M., and Isobe, H. (2005). Contribution of capsaicin-sensitive sensory neurons to antithrombin-induced reduction of ischemia/reperfusion-induced liver injury in rats. Thromb. Haemost. 93, 48-56. 10. Hirose, K., Okajima, K., Taoka, Y., Uchiba, M., Nakano, K., Utoh, J., and Kitamura, N. (2004). Antithrombin reduces the ischemia/ reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses. Thromb. Haemost. 91, 162-170.

Further Reading

Esmon, C. T. (2003). Inflammation and thrombosis. J. Thromb. Haemost. 1, 1343-1348.

Lefer, A. M., and Lefer, D. J. (1993). Pharmacology of the endothelium in ischemia-reperfusion and circulatory shock. Ann. Rev. Pharmacol. Toxicol. 33, 71-90. This excellent review describes the fundamental and important mechanisms of both protection and the development of damage of endothelial cells during ischemia-reperfusion. Opal, S. M., and Esmon, C. T. (2003). Bench-to-bedside review: Functional relationship between coagulation and the innate immune responses and their respective roles in the pathogenesis of sepsis. Crit. Care 7, 23-38. This review article demonstrates the possible coevolution of coagulation and innate immunity from a common ancestral substrate early in eukaryotic development, thereby explaining the molecular mechanisms of pathologic sequelae of sepsis. Taylor, F. B., Jr., Chang, A. C. K., Peer, G. T., Mather, T., Blick, C., Catlett, R., Lockhart, M. S., and Esmon, C. T. (1991). DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coll without preventing shock or organ damage. Blood 78, 364-368. This paper appears to be the first demonstrating that inflammatory responses as well as coagulation abnormalities were important factors in the pathologic process for the development of microcirculatory disturbances seen in sepsis. Vallet, B., and Wiel, E. (2001). Endothelial cell dysfunction and coagulation. Crit. Care Med. 29(7 Suppl), S36-S41. This article shows an important role of coagulation abnormalities induced by tissue factor generation in monocytes in the development of endothelial dysfunction, thus conferring the possible role of microthrombus formation in the formation of a vicious cycle in the progression of microcirculatory disturbance seen in sepsis.

Capsule Biography

Dr. Okajima is Professor of the Department of Biodefense and Chief Investigator of the vascular biology research group. He contributed much to the elucidation of molecular mechanism(s) in the important linkage between the coagulation and inflammation. His work is supported by grants from the Japanese Ministry of Education, Cultures, Sports, Science and Technology and by the departmental funds of Kumamoto University in which he worked before.

Section E

Coronary Slow Flow

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