Background: Sepsis is a common cause of acute renal failure (ARF) in clinical practice. However, the precise mechanism of endotoxin-induced ARF is not fully understood. There have been several reports that inhalation of carbon monoxide (CO) gas could be protective against acute rejection in intestine, lung, and kidney transplantation. Thus, we investigated the direct effect of CO in an experimental ARF model of septic shock induced by lipopolysaccharide (LPS). Method: Mice were pretreated with [Ru(CO)3Cl2]2 (CO donor compounds) at various concentrations (0.5, 1.0 and 2.0 µg) which were intravenously injected 24 h before intraperitoneal LPS injection. Biomarkers including myeloperoxidase activity and histochemical staining were evaluated. Results: The elevation of plasma creatinine was suppressed in CO donor-pretreated mice compared with vehicle-treated mice (creatinine 0.35 vs. 0.25; p < 0.05) 24 h after LPS injection. Renal myeloperoxidase activity slightly decreased in CO donor-pretreated mice. In the histological examination, neutrophil infiltration was significantly diminished in CO donor-treated mice. Real-time polymerase chain reaction revealed significant improvements in inflammatory related genes, such as TNFα, MCP-1, RANTES and IL4. Conclusion: Our results suggest the protective effect of the CO donor against endotoxin-induced renal injury; however, further study is needed to elucidate the mechanism.

Keywords:
Carbon monoxide, Endotoxin, Acute renal failure, Lipopolysaccharide
1.
Duckers HJ, Boehm M, True AL, Yet SF, San H, Park JL, Clinton Webb, Lee ME, Nabel GJ, Nabel EG: Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 2001;7:693–698.
2.
Chen K, Gunter K, Maines MD: Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J Neurochem 2000;75:304–313.
3.
Clark JE, Foresti R, Green CJ, Motterlini R: Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J 2000;348:615–619.
4.
Nakao A, Kimizuka K, Stolz DB, Neto JS, Kaizu T, Choi AM, Uchiyama T, Zuckerbraun BS, Nalesnik MA, Otterbein LE, Murase N: Carbon monoxide inhalation protects rat intestinal grafts from ischemia/reperfusion injury. Am J Pathol 2003;163:1587–1598.
5.
Neto JS, Nakao A, Kimizuka K, Romanosky AJ, Stolz DB, Uchiyama T, Nalesnik MA, Otterbein LE, Murase N: Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol 2004;287:F979–F989.
6.
Sarady JK, Zuckerbraun BS, Bilban M, Wagner O, Usheva A, Liu F, Ifedigbo E, Zamora R, Choi AM, Otterbein LE: Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J 2004;18:854–856.
7.
Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, Motterlini R: Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res 2003;93:e2–e8.
8.
Motterlini R, Clark JE, Foresti R, Sarathchandra P, Mann BE, Green CJ: Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ Res 2002;90:E17–E24.
9.
Mizutani A, Okajima K, Uchiba M, Isobe H, Harada N, Mizutani S, Noguchi T: Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. Blood 2003;101:3029–3036.
10.
Yoshida T, Muller E, Stears R, Shirota S, Tsuchiya K, Akiba T, Gullans SR: Osmoadaptation-related genes in inner medulla of mouse kidney using microarray. Biochem Biophys Res Commun 2004;322:250–257.
11.
Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, Chung KR, Chung HT: Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol 2004;172:4744–4751.
12.
Song R, Mahidhara RS, Zhou Z, Hoffman RA, Seol DW, Flavell RA, Billiar TR, Otterbein LE, Choi AM: Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway. J Immunol 2004;172:1220–1226.
13.
Kapturczak MH, Wasserfall C, Brusko T, Campbell-Thompson M, Ellis TM, Atkinson MA, Agarwal A: Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am J Pathol 2004;165:1045–1053.
14.
Sarady JK, Otterbein SL, Liu F, Otterbein LE, Choi AM: Carbon monoxide modulates endotoxin-induced production of granulocyte macrophage colony-stimulating factor in macrophages. Am J Respir Cell Mol Biol 2002;27:739–745.
15.
Ryter SW, Morse D, Choi AM: Carbon monoxide: to boldly go where NO has gone before. Sci STKE 2004;2004(230):RE6.
16.
Thiemermann C: Inhaled CO: deadly gas or novel therapeutic? Nat Med 2001;7:534–535.
17.
Clark JE, Green CJ, Motterlini R: Involvement of the heme oxygenase-carbon monoxide pathway in keratinocyte proliferation. Biochem Biophys Res Commun 1997;241:215–220.
18.
Deramaudt BM, Braunstein S, Remy P, Abraham NG: Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. J Cell Biochem 1998;68:121–127.
19.
Morita T, Kourembanas S: Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. J Clin Invest 1995;96:2676–2682.
20.
Peyton KJ, Reyna SV, Chapman GB, Ensenat D, Liu XM, Wang H, Schafer AI, Durante W: Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood 2002;99:4443–4448.
21.
Song R, Mahidhara RS, Liu F, Ning W, Otterbein LE, Choi AM: Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Am J Respir Cell Mol Biol 2002;27:603–610.
22.
Togane Y, Morita T, Suematsu M, Ishimura Y, Yamazaki JI, Katayama S: Protective roles of endogenous carbon monoxide in neointimal development elicited by arterial injury. Am J Physiol Heart Circ Physiol 2000;278:H623–H632.
23.
Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, Csizmadia E, Tyagi S, Akamatsu Y, Flavell RJ, Billiar TR, Tzeng E, Bach FH, Choi AM, Soares MP: Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med 2003;9:183–190.
24.
Zhou Z, Song R, Fattman CL, Greenhill S, Alber S, Oury TD, Choi AM, Morse D: Carbon monoxide suppresses bleomycin-induced lung fibrosis. Am J Pathol 2005;166:27–37.
25.
Otterbein LE, Soares MP, Yamashita K, Bach FH: Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 2003;24:449–455.
26.
Zhang X, Shan P, Alam J, Davis RJ, Flavell RA, Lee PJ: Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J Biol Chem 2003;278:22061–22070.
27.
Zhang X, Shan P, Otterbein LE, Alam J, Flavell RA, Davis RJ, Choi AM, Lee PJ: Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3. J Biol Chem 2003;278:1248–1258.
28.
Villamor E, Perez-Vizcaino F, Cogolludo AL, Conde-Oviedo J, Zaragoza-Arnaez F, Lopez-Lopez JG, Tamargo J: Relaxant effects of carbon monoxide compared with nitric oxide in pulmonary and systemic vessels of newborn piglets. Pediatr Res 2000;48:546–553.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.