Abstract

Inducible Enzymes in the Inflammatory Response

(Willoughby, D. A., and Tomlinson, A. (eds.) Birkhauser Verlag, Basel-Boston-Berlin, 1999)

The book considers the role of three inducible enzymes--cyclooxygenase (COX-2), NO-synthase (iNOS), and heme oxygenase (HO-1)--in the development of inflammation.

The first three chapters are introductory and describe biochemistry and regulation of the enzymes. The first chapter (by M. Pairet, J. van Rhyn, M. Distel) contains detailed data on COX-2 including discovery of the enzyme in the late 1980s and regulation of COX-2 expression. Anti-inflammatory activity (including clinical trials) of COX-2 inhibitors is considered including meloxicam, nimesulide, etodolac, flosulide, SC58125, L-745,337, and the newly described celecoxib (SC58635) and MK-966. The authors suggest that anti-inflammatory effects of traditional nonsteroid anti-inflammatory drugs are due to inhibition of COX-2, and that adverse effects of the drugs on the gastrointestinal tract are associated with inhibition of constitutive cyclooxygenase COX-1.

In the second chapter, by A. J. Hobbs and S. Moncada, the role of inducible NO-synthase in inflammation is described. The characterization of NO-synthases includes data on its intracellular localization, isoforms, and mechanism of NO generation. The role of constitutive NO-synthase during the early stages of inflammation and the role of inducible NO-synthase in the development of inflammation are considered. Regulation of NO-synthase expression and the role of NF-kappaB in iNOS expression are briefly described. Description of NO-dependent mechanisms of inflammation includes discussion of the role of macrophages and neutrophils in NO synthesis during various stages of inflammation, role of NO in hemodynamics, cytotoxic activity of NO, and function of NO in pain syndrome associated with inflammation. The authors emphasize multiple roles of NO in development of inflammation and indicate that it is impossible to unequivocally ascribe a pro- or anti-inflammatory role to NO. The available data suggest that NO can play various roles depending on its local concentration of the immunological state of the organism.

The third chapter, by D. Willis, is devoted to heme oxygenase 1 (HO-1) including its biochemical properties, role in heme catabolism, possible role of HO-1 as heat shock protein, biological role of HO-1 in inflammatory pathology, and data on HO-1 expression in various cell types in vitro induced by cytokines and reactive oxygen and nitrogen metabolites as well as by hypoxia and hyperoxia. The protective, anti-inflammatory role of HO-1 is discussed as well as the association of HO-1 expression with termination of inflammation, defense from oxidative damage during endotoxin shock, and defense of organs from graft rejection. Summarizing the data, the author concludes that the known biochemical role of HO-1 in inflammation includes a protective mechanism decreasing tissue damage and HO-1 induction can be a powerful therapeutic instrument in acute inflammation and organ transplantation. Also, considering tumor cells and tissues, inhibition of HO-1 activity in tumor cells can enhance their susceptibility to chemotherapy.

The next chapter describes the role of inducible enzymes in the pathogenesis of rheumatoid arthritis (V. R. Winrow and D. R. Blake) and includes the data on the pathophysiology of rheumatoid arthritis and the mechanism of development of oxidative stress in partial hypoxia in joints affected by rheumatoid arthritis. The authors consider hypoxia as one of the phases of inflammation and describe the enzymes induced by hypoxia and oxidative stress (NO-synthase, cyclooxygenase, heme oxygenase, and xanthine oxidase). The mechanisms of gene expression induced by hypoxia and oxidative stress include redox-regulated transcription factors NF-kappaB and AP-1. Finally, a complex interaction of four inducible enzymes in rheumatoid arthritis is discussed, and it is emphasized that consideration of this interaction is required for development of new therapy.

Chapter 5 (by L. D. K. Buttery and J. M. Polak) describes the role of iNOS and COX-2 in atherosclerosis. The introduction includes a description of the regulation of atherosclerosis by numerous factors, this being why the etiology and pathogenesis of atherosclerosis are still unclear. However, since the discovery of prostacyclin (1970s) and NO (1980s), some data suggest that these mediators are important for atherosclerosis. The authors focus their attention on two enzymes, cyclooxygenase (COX-2) and NO-synthase (iNOS), involved in the formation of prostacyclin and NO. In atherosclerosis, expression of endothelial NO-synthase (eNOS) is lowered and in atherosclerotic lesions, an increased level of inducible NO-synthase (iNOS) is detected; the latter enzyme is preferentially localized in macrophages. Formation of NO suppresses the development of atherosclerosis, but the product of NO reaction with O₂^-·, peroxynitrite, induces oxidative modification of low density lipoproteins, promoting atherosclerosis. The role of COX-2 in atherosclerosis is unclear, but it is co-localized with iNOS in atherosclerotic plaques. Some data indicate that formation of prostacyclin suppresses atherogenesis. However, in atherosclerosis, prostacyclin synthesis can be disrupted on the level of prostacyclin synthase, which is inactivated by peroxynitrite. The authors suggest that iNOS and COX-2 expression in atherosclerosis is a protective response of the organism. The pathological effects are associated with reactive oxygen metabolites and products of their interaction with NO.

Chapter 6 (by M. P. Seed, D. Gilroy, M. Paul-Clark, P. R. Colville-Nash, D. Willis, A. Tomlinson, D. A. Willoughby) is devoted to the role of inducible enzymes COX-2, iNOS, and HO-1 in angiogenesis during inflammation. The chapter includes a short introduction into mechanisms of angiogenesis. Prostaglandins E₂ and E₁ stimulate proliferation of endothelial cells and angiogenesis (formation of new vessels). The role of NO in angiogenesis is less clear because the data on NO effects are contradictorily; NO has been reported to stimulate or inhibit angiogenesis. The role of HO-1 in angiogenesis is even less clear; an indirect influence of HO-1 may be mediated by NO synthesis. Inhibition of COX-1 and COX-2 by nonsteroid anti-inflammatory drugs does not clearly influence angiogenesis, but compounds simultaneously inhibiting NO formation suppress angiogenesis.

Chapter 7 (by S. H. Ferreira, F. Q. Cunha, S. Hyslop) is devoted to the role of COX-2 and iNOS in the development of pain syndrome during inflammation. Sensitization of pain receptors is characteristic for all types of pain syndromes. The introduction includes a description of pain receptors, hyperalgesia, and mediators. The data on frequent pain-relieving effects of COX-2 inhibitors are included in the discussion of the role of cyclooxygenase in hyperalgesia during inflammation. Pain-relieving effects are induced by NO donors and activation of iNOS. Summarizing the data, the authors suggest that prostaglandins are mediators of hyperalgesia, and NO acting via cGMP has an analgesic effect mediated by the regulation of expression of COX-2 and iNOS.

Chapter 8 (by B. C. Kieseier and H.-P. Hartung) is devoted to inflammation in the nervous system. Leukocytes (predominantly, T-cells and macrophages) and reactive metabolites (oxygen radicals, NO, and proteases) are important for inflammation in the nervous system. Enhanced production of NO was documented in various models of neuroinflammation, but the mechanism of NO and iNOS effects in neuroinflammation is unclear. Regulation of activity and the role of matrix metalloproteinases in neuroinflammation is discussed. Data on the role of cyclooxygenases are presented, but the particular roles of COX-1 and COX-2 have not been determined.

The final chapter (by A. Tomlinson and D. A. Willoughby) summarizes data on inducible enzymes in inflammation, and it is concluded that NO produced by iNOS and prostacyclin and prostaglandin E₂ produced via COX-2 are important for the development of inflammation, whereas HO-1 plays a role in termination and limitation of inflammation. The generation of transgenic animals demonstrated that NO and iNOS are important tools in the host defense against infection; animals with altered iNOS induction were extremely sensitive to infection. In experiments with transgenic animals, a role of COX-2 in inflammation was not evident. In HO-1 gene knock-out animals, chronic inflammation developed. The authors suggest that further study of the roles of iNOS, COX-2, and HO-1 in inflammation is of great interest. The interaction between these enzyme has been described in a number of studies, but the data are often contradictory.

The authors of book do not claim an exceptional role of iNOS, COX-2, and HO-1 in inflammation. Other enzymes including metalloproteinases, xanthine oxidase, and transglutaminase are also important in inflammation. These and other inducible enzymes are potential targets for therapy of various types of inflammation. The main conclusion on the role of the three enzymes considers the influence of numerous factors on the pro- or anti-inflammatory role of NOS, COX, and HO-1 and a clear and simple role cannot be unequivocally ascribed to the enzymes. Thus, specific inhibition of potentially harmful metabolites is less promising than the maintenance and reenforcement of the endogenous defensive mechanisms.

G. F. Sud'ina