Gas Biology Research in Clinical Practice. Группа авторов

M.; Nakamura, T. (Aomori)

       Gas and Medical Application: VI. Others

       Acetone Response during Graded and Prolonged Exercise

      Sasaki, H.; Ishikawa, S.; Ueda, H.; Kimura, Y. (Osaka)

       Findings of Skin Gases and Their Possibilities in Healthcare Monitoring

      Tsuda, T.; Ohkuwa, T.; Itoh, H. (Nagoya)

       Phytoncide - Its Properties and Applications in Practical Use

      Nomura, M. (Hiroshima)

       Author Index

       Subject Index

Preface

      Since 2004 we have held annually in Kyoto, Japan, a medical conference on heme oxygenase (HO), titled the ‘HO Research Forum’. To date, more than 80 papers have been presented at these conferences, and our knowledge of HO and carbon monoxide, one of the by-products by HO, has been greatly expanded. Recently, evidence has accumulated suggesting that carbon monoxide plays an important role in many physiological and pathological conditions. Thus, in the last decade there has been an extraordinarily rapid growth in our knowledge of gaseous molecules such as molecular oxygen, nitric oxide, hydrogen sulfide and carbon monoxide. These gaseous molecules have been shown to play important roles in signal transduction in biological systems.

      This book is an attempt to highlight some of the impressive recent advances in gas biology. It was initiated by Dr. Hideo Ueda, but sadly illness prevented him from completing the project. As the subject matter of this book is of importance for most basic and clinical researchers involved in gas biology, we decided to take it on. We were fortunate to receive excellent manuscripts from authors in the field, and readers will find they contain many new insights into leading-edge research on gas biology.

      We would like to thank the many authors and colleagues who have contributed to the success of this publication. Special thanks also go to Dr. Tomohisa Takagi for his assistance. Finally, we thank Karger Publishers for their cooperation and encouragement throughout the publication process.

      Toshikazu Yoshikawa

      Yuji Naito

General

      Yoshikawa T, Naito Y (eds): Gas Biology Research in Clinical Practice.

       Basel, Karger, 2011, pp 1–5

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Roles of Stress-Inducible Carbon Monoxide in the Regulation of Liver Function

      Makoto Suematsu · Mayumi Kajimura · Yasuaki Kabe

      Department of Biochemistry, School of Medicine, Keio University, Japan Science and Technology Agency, ERATO Suematsu Gas Biology Project, Tokyo, Japan

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      Abstract

      Carbon monoxide (CO) is a gaseous product generated by heme oxygenase (HO). As the liver is a gigantic resource of CO derived from heme degradation in vivo, constitutive and inducible CO has been suggested to regulate porto-sinusoidal vascular as well as biliary function. Previous studies revealed that CO generated by HO modulates function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to regulate the biological function of the hepatobiliary systems; the proteins targeted by the gas involve soluble guanylate cyclase, cytochromes P450 and cystathionine β-synthase. Because of the heterogeneous distribution of these enzymes in the liver tissue, CO regulates liver functions through multiple mechanisms that protect the tissue against varied noxious stimuli. The current article overviews the intriguing regulatory mechanisms operated by CO and their medical implications.

      Copyright © 2011 S. Karger AG, Basel

      CO Derived from HO-1 in Macrophages

CO is a nonradical gaseous mediator generated by a mono-oxygenase reaction through heme oxygenase (HO). It was first shown in the early 1970s that both nonparenchymal cells and hepatocytes enable the degradation of heme to bile pigments. Kupffer cells play a role in the removal and degradation of senescent erythrocytes, while hepatocytes catabolize free heme derived from hemoglobin or cytochromes P450 [1]. Distribution of HO-1 and HO-2 in the liver was previously examined by our laboratory in rats and humans, indicating that the two isozymes have distinct topographic patterns: HO-1, the inducible form, is prominent in Kupffer cells, while the constitutive HO-2 is mostly abundant in hepatocytes [2, 3]. Our studies using a specific monoclonal antibody against HO-1 that blocks the isozyme activity revealed that approximately 70% of the whole HO activity in this tissue is derived from HO-2 [3]; considering the percentage of the cell population of Kupffer cells in the liver, these cells possess huge amounts of HO activity as compared with hepatocytes.

Not only in the liver but also in other organs, resident macrophages constitute a major site of the HO-1 distribution. To better understand the tissue iron overload and anemia previously reported in a human patient and mice that lack HO-1, recent studies examined iron distribution and pathology in HO-1(-/-) mice [4], indicating that resident splenic and liver macrophages were mostly absent in HO-1(-/-) mice. This study suggested that erythrophagocytosis causes death of HO-1(-/-) macrophages in vivo and release of nonmetabolized heme likely caused tissue inflammation. In the spleen, initial splenic enlargement progressed to red pulp fibrosis, atrophy and functional hyposplenism in older mice, recapitulating the asplenia of an HO-1-deficient patient which was previously reported in Japan [5]. During constitutive erythrophagocytosis, HO-1-deficient macrophages including Kupffer cells appeared to exhibit cell death by themselves. This study also postulated that failure of tissue macrophages to remove senescent erythrocytes led to intravascular hemolysis and increased expression of hemopexin and haptoglobin, the heme and hemoglobin scavenger proteins, in the liver. Lack of macrophages expressing the Hp receptor, CD163, diminished the ability of Hp to neutralize circulating Hb, and iron overload occurred in kidney proximal tubules, which were able to catabolize heme with HO-2. Thus, in HO-1(-/-) mammals, the reduced function and viability of erythrophagocytosing macrophages appear to be the main causes of tissue damage and iron redistribution.

      CO Derived from HO-2 Targets Hepatic Stellate Cells to Relax Sinusoids

Many years ago, we first showed that CO serves as a vasorelaxing factor that reduces sinusoidal tone and is necessary for maintenance of the microvascular perfusion [6, 7]. This is based on the fact that zinc protoporphyrin IX, a potent inhibitor of HO, abolished CO generation and simultaneously increased the baseline vascular resistance in the perfused liver. The role of endogenous CO in sinusoidal relaxation was also shown in experiments using free oxyhemoglobin which captures both NO and CO, and methemoglobin that