國防大學國防醫學院藥理學研究所碩士論文

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1 (sepsis) (septic sh 40-60% (Titheradge, 1999) (hypotension) (vasoplegia) (multiple organ failure ) ) (lipopolysaccharide, LPS) (endotoxin)

2 LPS-binding protein (LBP) macrophages monocytes Toll-like receptors (cytokines) systemic syndrome 200,000 1,000,000 dalton lipid A (Fig. 1) Szabo (Szabo et al., 1993) LPS (10 mg/kg) 15 (early hypotension) 1 ( delayed hypotension) (Tumor necrosis factor)

3 dalton (picomolar-femtomolar) T 30 (tumor necrosis factor, TNF) T TNF 1987 (Beutler and Cerami, 1987; Chapman et al., 1987; Okusawa et al., 1988; Heard et al., 1992; Dinarello et al., 1993) TNF interleukin-1 (IL-1) (Beutler and Cerami, 1987; Dinarello and Cannon, 1993) LPS (macrophages) (lymphocytes) (neutrophils) TNF IL-1 (Damas et al., 1989; Fleming et al., 1990; Dinarello et al., 1993) TNF polypeptides 157 (subtypes) TNF-alpha (TNF-α) TNF-beta (TNF-β)

4 TNF-α TNF-β T T help (T h ) (cytotoxic lymphocytes) (tumor-specific cytotoxicity) (Skeie et al., 1999) LPS TNF-α (Damas et al., 1989; Nakamura et al., 1991; Wu et al., 2000) 1992 Kosaka TNF-α IL-1 (Kosaka et al., 1992) TNF-α IL-1 interleukin-6 (IL-6) interleukin-8 (IL-8) prostaglandin E 2 (PGE 2 ) platelet-activating factor (PAF) thromboxanes A 2 (TXA 2 ) (Boughton-Smith et al., 1989) TNF-α LPS nitric oxide (NO) (Fig. 2) anti-tnf-α monoclonal antibodies IL-1 receptor antagonists (Ohlsson et al., 1990;

5 Dinarello et al., 1993) IL-1 IL-1α IL 1β IL-1β IL-1α IL-1β IL-1 TNF-α (Dinarello, 1989; Dinarello and Wolff, 1993) TNF-α IL-1 PAF LPS (NO) (NO) NO (Gruetter et al., 1980) 1984 Isomura NO (27 ppm) (Isomura et al., 1984) Furchgott, Moncada Ignarro NO (Furchgott and Zawadzki, 1980; Cherry et al., 1982; Ignarro et al., 1987; Moncada et al., 1987) NO

6 NO NO acetylcholine (ACh) bradykinin (BK) 5-hydroxytryptamine (5-HT) endothelin adenosine 5 -triphosphate (ATP) adenosine 5 -diphosphate (ADP) NO 酶 (NO synthase, NOS) L-arginine L-citrulline NO (Palmer et al., 1988) NO soluble guanylate cyclase (sgc) 酶 GTP cgmp (Fig. 3) cgmp (myosin light chain) NO (nitrite, NO - 2 ) (nitrate, NO - 3 ) NO macrophages NO NO NO 酶酶 Table 1) ( ) NO 酶 (endothelial NO synthase, enos) enos ACh BK

7 calmodulin (Moncada et al., 1990) ( ) NO 酶 (neuronal NO synthase, nnos) nnos enos calmodulin enos nnos 酶 (constitutive NOS, cnos) cnos NO (microvascular permeability) 1989 ( ) NO 酶 (inducible NO synthase, inos) inos inos inos cnos inos calmodulin NO (Table 2) inos NO NO (Moncada et al., 1991;

8 Liu et al., 1996) NO (Yen et al., 1993; Preiser et al., 1994) 1990 Thiemermann Vane NOS N G -monomethyl-l-arginine (L-NMMA) N ω -nitro-l-arginine methyl ester (L-NAME) L-NMMA L-NAME (Thiemermann and Vane, 1990) (mice) (rats) nitrosylated hemoglobin (HbNO) (Wang et al., 1991; Kosaka et al., 1992) NO (free radicals) (Fig. 4)

9 (Lander, 1997) DNA RNA (atherosclerosis) (liver cirrhosis) (Cross et al., 1987; Babior, 2000) (1) (reactive oxygen species, ROS): superoxide (O - 2 ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (. OH) (2) (reactive nitrogen species, RNS). NO ROS RNS (neutrophils) RNS (nonspecific host defense) (Nathan, 1992) ROS RNS (macromolecules) DNA (Lennon et al., 1991) ROS RNS (secondary messengers) (Satriano et al., 1993; Finkel, 1998)

10 (antioxidant defense system) (1) (enzymatic antioxidants) superoxide dismutase (SOD) O - 2 H 2 O 2 catalase (lysosome) H 2 O 2 (Brawn and Fridovich, 1980) glutathione peroxidase (GSH-PX) SOD H 2 O 2 GSSH NADPH GSH (2) (free radical scavenger) melatonin (3) (repair system) polymerase lipase phospholipase A 2, C D arachidonic acid PGs TXs LTs PAF (Huraux et al., 1999) SOD xanthine oxidase (Goode and Webster, 1993) TNF-α

11 IL-1 NO LPS TNF-α TN-Fα NOS NADPH 酶 NO (Hibbs et al., 1987; Hibbs et al., 1988). - NO O 2 (peroxynitrite, ONOO - ) (Beckman et al., 1990; Beckman and Crow,1993) TNF-α IL-1 (nuclear transcription factor-kappa B-I kappa B, NF-κB-IκB) nuclear transcription factor-kappa B (NFκB) DNA promoter inos L-arginine L-citrulline NO TNF-α TNF-α inos (Thiemermann et al., 1993; Szabo, 1995) IL-1 antagonists (Ohlsson et al., 1990) TNF-α IL-1 PAF inos

12 (membrane potential) (K + channels) (hyperpolarization) (voltage-dependent calcium channels) (Bolotina et al., 1994; Nelson and Quayle, 1995) (depolarization) 1991 Moncada 1994 Thiemermann NO NO sgc cgmp (Moncada et al., 1991; Thiemermann, 1994) 1992 Landry Oliver (Landry and Oliver, 1992) K ATP channels K ATP channels K ATP channels hydrogen ions, hypoxia, adenosine lactate (Gorczynski and Duling, 1978; Davies,

13 1990) 1995 Wu GB (Wu et al., 1995) (K ATP channels) (Chen et al., 2000) 苷 (cyclic AMP, camp) β (β-adrenergic agonists ) 1986 Koff β-adrenergic agonists camp IL-1 (Koff et al., 1986) β 2 -adrenergic agonists LPS TNFα IL-1 IL-6 (Spengler et al., 1989; Taffet et al., 1989; Viherluoto et al., 1991; Severn et al., 1992; Talmadge et al., 1993; Hasko et al., 1998; Farmer and Pugin, 2000) Kupffer cells forskolin (an adenylyl cyclase activator) inos NO NFκB inos (Ollivier et al.,1996;

14 Mustafa and Olson, 1998) β 2 -adrenergic agonists LPS IL-10 (Wu et al.; 2000) camp adenylyl cyclase adenylyl cyclase adenylyl cyclase camp 酶 (phosphodiesterase) β 2-adrenergic agonists β 2 -adrenergic receptors (complex) Gs protein adenylyl cyclase ATP camp camp protein kinase A Gs protein adenylyl cyclase GTP GDP adenylyl cyclase camp phosphodiesterase 5 -AMP β 2 -adrenergic agonists TNF-α camp

15 (specific points in the inflammatory cascade of septic shock) (Christman, 1992; Davies and Hagen, 1997) dopamine dobutamine ( ) LPS CD14 binding site LPS-binding proteins LPS (inhibition of secondary mediators) TNF-α, IL-1 TNF-α, IL-1 TNF Phosphodiesterase pentoxifylline, HWA 138 amrinone

16 phosphodiesterase (disseminated intravascular coagulation) antithrombin protein C S inos inos NO inos inos (inos induction) (inos activity) DNA 4 3

17 TBterbutaline β 2 adrenergic agonist + glibenclamide (GB K ATP channel antagonists) melatonin (ML ) + aminoguanidine (AG inos ) AG +TB ( ) ML peptides (pineal gland) ML (Guerrero et al., 1992) ML N-acetyl-5methoxytryptamine (postganglionic retinal nerve fibers) (retinohypothalamic tract) (suprachiasmatic nucleus, SCN) β (β-adrenergic receptors) camp camp arylalkylamine N-acetyltransferase (AA-NAT) ML AA-NAT ML AA-NAT ML (Fig. 5) ML ML hydroxylation

18 (sulfuric acid) (glucuronic acid) ML 2 4 ML ML 1 3 ML ML 1 ML 2 ML 1 GTP ML ML 1 pertussis toxin-sensitive G proteins forskolin camp camp (Ebisawa et al., 1994) ML 1 Mel 1a Mel 1b Mel 1a Mel 1b ML 2 phosphoinositide ML ML calmodulin adenylyl cyclase phosphodiesterase ML RZR-α RZR-β (nuclear retinoid Z receptor, RZR) (Fig. 6) ML ( )

19 ML (jet-lag) ML (immunodepression) (Bubenik et al., 1998) ML ML (antigen-specific) T (Shaji et al., 1998) ML (Rafii-El-Idrissi et al., 1998) ML indole indole (Reiter et al., 1997) ML (Scaiano, 1995) (Fig. 5) 2001 Wu ML TNF-α inos (Wu et al., 2001) inos specific inhibitor ML LPS 60

20 ( ) AG AG nitroguanidine 100 arginine (Fig. 7) NOS inos (Wu et al., 1995) inos inos (Liaudet et al., 1998) 1995 Wu AG (Wu et al., 1995) -adrenergic agonists antioxidants AG LPS ( ) TB TB β -adrenergic agonists ( Fig. 8A) adenylyl cyclase camp

21 2000 Wu TB (0.3 mg/kg) IL-10 TNF-α camp TNF-α camp (Wu et al., 2000) TB inos specific inhibitors K ATP channel antagonists ( LPS 30 ) ( LPS 180 ) ( ) GB GB K ATP channel antagonists Fig. 8B β K ATP channels β voltage-dependent calcium channels insulin 1995 Wu 1999 Sorrentino Gardiner GB

22 (Wu et al., 1995; Sorrentino et al., 1999; Gardiner et al., 1999) GB inos (inos induction) (Wu et al., 1995) β-adrenergic agonists GB LPS 120 Table 3 LPS NO Fig. 9

23 TB +GB ML + AG AG+TB

第四章討論

第四章討論 LPS (sign) LPS ( ) LPS 15 1 SOP LPS ( ) LPS 2 LPS (Szabo et al., 1993) LPS LPS BK PAF endothelin (modulators) enos NO enos NO SOP LPS enos NO LPS TNF-α IL-1 PAF 68 inos TNF-α IL-1 LPS inos NO 2 LPS inos