臨床検査51巻5号

2007年05月発行

今月の主題 脂質 脂質関連物質と疾病

脂質メディエーターと呼吸器疾患―気管支喘息，肺線維症を中心に

著者： 長瀬隆英¹

所属機関： ¹東京大学大学院医学系研究科呼吸器内科学

ページ範囲：P.477 - P.481

　気管支喘息，肺線維症などの炎症性肺疾患は，社会的にも極めて重大な疾患であり，治療薬の開発が切実に待たれている．リン脂質およびアラキドン酸を起点とする代謝産物であるPAF，プロスタグランジン，トロンボキサン，ロイコトリエンなどは脂質メディエーターと総称され，ごく微量で多彩な生理活性作用を呈するのが特徴である．脂質メディエーターは気管支喘息をはじめ，様々な呼吸器疾患の発症機序に関与することが明らかになりつつあり，呼吸器疾患の治療標的となることが期待される．〔臨床検査　51：477-481，2007〕

参考文献

1) Prescott SM, Zimmerman GA, McIntyre TM：Platelet-activating factor. J Biol Chem 265：17381-17384, 1990

2) Chao W, Olson MS：Platelet-activating factor：receptors and signal transduction. Biochem J 292：617-629, 1993

3) Izumi T, Shimizu T：Platelet-activating factor receptor：gene expression and signal transduction. Biochim Biophys Acta 1259：317-333, 1995

4) Honda Z, Nakamura M, Miki I, et al：Cloning by functional expression of platelet-activating factor receptor from guinea-pig lung. Nature 349：342-346, 1991

5) Nakamura M, Honda Z, Izumi T, et al：Molecular cloning and expression of platelet-activating factor receptor from human leukocytes. J Biol Chem 266：20400-20405, 1991

6) Ye RD, Prossnitz ER, Zou AH, et al：Characterization of a human cDNA that encodes a functional receptor for platelet activating factor. Biochem Biophys Res Commun 180：105-111, 1991

7) Mutoh H, Bito H, Minami M, et al：Two different promoters direct expression of two distinct forms of mRNAs of human platelet-activating factor receptor. FEBS Lett 322：129-134, 1993

8) Sugimoto T, Tsuchimochi H, McGregor CG, et al：Molecular cloning and characterization of the platelet-activating factor receptor gene expressed in the human heart. Biochem Biophys Res Commun 189：617-624, 1992

9) Bito H, Honda Z, Nakamura M, et al：Cloning, expression and tissue distribution of rat platelet-activating-factor-receptor cDNA. Eur J Biochem 221：211-218, 1994

10) Shindou H, Hishikawa D, Nakanishi H, et al：A single enzyme catalyzes both platelet-activating factor production and membrane biogenesis of inflammatory cells：cloning and characterization of acetyl-CoA：LYSO-PAF acetyltransferase. J Biol Chem 282：6532-6539, 2007

11) Spence DPS, Johnston SL, Calverley PMA, et al：The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma. Am J Respir Crit Care Med 149：1142-1148, 1994

12) Hozawa S, Haruta Y, Ishioka S, et al：Effects of a PAF antagonist, Y-24180, on bronchial hyperresponsiveness in patients with asthma. Am J Respir Crit Care Med 152：1198-1202, 1995

13) Miwa M, Miyake T, Yamanaka T, et al：Characterization of serum platelet-activating factor(PAF)acetylhydrolase：correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children. J Clin Invest 82：1983-1991, 1988

14) Stafforini DM, Satoh K, Atkinson DL, et al：Platelet-activating factor acetylhydrolase deficiency：a missense mutation near the active site of an anti-inflammatory phospholipase. J Clin Invest 97：2784-2791, 1996

15) Sandford A, Weir T, Paré P：The genetics of asthma. Am J Respir Crit Care Med 153：1749-1765, 1996

16) Tjoelker LW, Wilder C, Eberhardt C, et al：Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 374：549-553, 1995

17) Ishii S, Nagase T, Tashiro F, et al：Bronchial hyperreactivity, increased endotoxin lethality and melanocytic tumorigenesis in transgenic mice overexpressing platelet-activating factor receptor. EMBO J 16：133-142, 1997

18) Nagase T, Ishii S, Katayama H, et al：Airway responsiveness in transgenic mice overexpressing platelet-activating factor receptor：roles of thromboxanes and leukotrienes. Am J Respir Crit Care Med 156：1621-1627, 1997

19) Cuss FM, Dixon CM, Barnes PJ：Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet 328：189-192, 1986

20) Solway J, Fredberg JJ：Perhaps airway smooth muscle dysfunction contributes to asthmatic bronchial hyperresponsiveness after all. Am J Respir Cell Mol Biol 17：144-146, 1997

21) Lambert RK, Paré PD：Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness. J Appl Physiol 83：140-147, 1997

22) Stewart AG, Dubbin PN, Harris T, et al：Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells. Proc Natl Acad Sci USA 87：3215-3219, 1990

23) Nagase T, Ishii S, Shindou H, et al：Airway hyperresponsiveness in transgenic mice overexpressing platelet-activating factor receptor is mediated by an atropine-sensitive pathway. Am J Respir Crit Care Med 165：200-205, 2002

24) Shirasaki H, Nishikawa M, Adcock IM, et al：Expression of platelet-activating factor receptor mRNA in human and guinea pig lung. Am J Respir Cell Mol Biol 10：533-537, 1994

in allergen-induced increases in airway smooth muscle in the rat. Am Rev Respir Dis 148：413-417, 1993

26) Ishii S, Kuwaki T, Nagase T, et al：Impaired anaphylactic responses but intact sensitivity to endotoxin in mice lacking a platelet-activating factor receptor. J Exp Med 187：1779-1788, 1998

27) Nagase T, Ishii S, Kume K, et al：Platelet-activating factor mediates acid-induced lung injury in genetically engineered mice. J Clin Invest 104：1071-1076, 1999

28) Hattori M, Adachi H, Tsujimoto M, et al：Miller-Dieker lissencephalopathy gene encodes a subunit of brain platelet-activating factor acetylhydrolase. Nature 370：216-218, 1994

29) Ishii S, Matsuda Y, Nakamura M, et al：A murine platelet-activating factor receptor gene：cloning, chromosomal localization and up-regulation of expression by lipopolysaccharide in peritoneal resident macrophages. Biochem J 314：671-678, 1996

30) Nagase T, Kurihara H, Kurihara Y, et al：Airway hyperresponsiveness to methacholine in mutant mice deficient in endothelin-1. Am J Respir Crit Care Med 157：560-564, 1998

31) Ishii S, Nagase T, Shindou H, et al：Platelet-activating factor receptor develops airway hyperresponsiveness independently of airway inflammation in a murine asthma model. J Immunol 172：7095-7102, 2004

in allergic response and parturition. Nature 390：618-622, 1997

. Nature Immunol 1：42-46, 2000

in bleomycin-induced pulmonary fibrosis. Nature Med 8：480-484, 2002

35) Takai D, Nagase T, Shimizu T：New therapeutic key for cystic fibrosis：a role for lipoxins(Editorial). Nature Immunol 5：357-358, 2004

36) Terawaki K, Yokomizo T, Nagase T, et al：Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses. J Immunol 175：4217-4225, 2005

37) Petrache I, Natarajan V, Zhen L, et al：Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nature Med 11：491-498, 2005