第四章討論

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1 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

2 inos TNF-α IL-1 LPS inos NO 2 LPS inos NO K ATP channels 1996 Armstead cgmp K ATP channels (Armstead, 1996) NO K ATP channels (Miyoshi et al., 1994; Chen et al., 2000) NO/cGMP K ATP channels (Chen et al., 2000) (baroreflex) LPS (baroreceptor) TNF-α LPS 2 inos NO LPS 69

3 LPS NO LPS TNF-α NO TNF-α 1 NO 2 LPS macrophages TNF-α IL-1 inos NO LPS TNF-α 1 IL-1 inos NO NO NO LPS 15 TB\GB AG\TB ML\AG LPS 15 LPS NO LPS NO AG\TB ML\AG LPS 4 NO LPS 70

$IL-1 inos NO NO NO LPS 15 TB\GB AG\TB$

4 NO TB\GB NO NO GB K ATP channels NO inos TNF-α inos NO TNF-α (1) ML\AG ML TNF-α ( LPS TNF-α ) ML\AG NO ML TNF-α inos AG inos LPS (2) TB\GB LPS 4 TNF-α LPS 2 TNF-α ( TNF-α ) TB\GB NO (3) AG\TB TNF-α LPS 90 AG TNF-α AG\TB LPS AG inos AG 1992 Corbett AG IL-1β NOS arginine (Corbett et al., 1992) AG 71

$TNF-α LPS 2 TNF-α ( TNF-α ) TB\GB NO (3) AG\TB TNF-α LPS 90 AG TNF-α AG\TB$

5 AG inos (1) diamine oxidase histamine (2) advanced glycosylation end products (Nilsson, 1999) (3) catalase (Ou and Wolff, 1994) (4) ROS (Giardino et al., 1998) TB\GB LPS 4 TNF-α macrophages human promonocytic THP-1 cells (in vitro) β-adrenergic agonists incubated 8 24 TNF-α mrna (Severn et al., 1992; Farmer and Pugin, 2000) camp TNF-α camp NO LPS 6 (Imai et al., 1994) TB\GB 6 NO LPS LPS NE ( ) NO 72

$, 1998) TB\GB LPS 4 TNF-α macrophages human promonocytic THP-1 cells (in vitro) β-adrenergic$

6 BK histamine K ATP channels NE NE NE LPS 3 TNFα inos K ATP channels ( ) LPS (glomerular filtration rate, GFR) angiotensin endothelin 1 leukotrienes thromboxane A 2 (Badr, 1992) NO LPS inos mrna NO (Kilbourn et al., 73

angiotensin endothelin 1 leukotrienes thromboxane A 2

7 1990) IL-6 (Fougueray et al., 1993; Donnahoo et al., 1999) NO Schwartz (1) enos inos NO enos (2) LPS enos inos (3) inos (Schwartz et al., 1997) LPS inos NO enos GFR ( macrophages ) ATP CO 2 (Kantrow et al., 1997) GOT GTP albumin GOT 74

8 LPS (hepatotoxicity) TNF-α TNF-α (reactive oxygen nitrogen species) 酶 (Stadler et al., 1992) TNF-α (Barton et al., 2001) NO (Titheradge, 1999) GPT AG\TB ML\AG TNF-α (ML) inos (AG) inos mrna (ML) camp (TB) TB\GB TNF-α NO (Wu et al., 2000) TB TNF-α IL-10 TB IL-10 Kupffer cells 75

$, 2001) NO (Titheradge, 1999) GPT AG\TB ML\AG TNF-α (ML) inos (AG)$

9 TB\GB creatinine NO NO NO TB\GB superoxides (Fig. 13 and Fig. 18) TB IL-6 Nakamura TB LPS IL-6 camp TB PKA-cAMP IL-6 mitogen-activated protein kinase (MAPK) TNF-α IL-6 (Nakamura et al., 1999) TNF-α TB IL-6 TB\GB creatinine creatinine 0.1 mg/dl 25-35%

$al., 1999) TNF-α TB IL-6 TB\GB creatinine creatinine 0.$

10 LPS A/G ratio A/G ratio ( ) A/G ratio (Fig. 21) albumins globulins PAF TxA 2 histamine BK 5-HT albumins ( albumins ) (hypovolemia) albumins albumins 20 6 albumins B cell γ -globulins ( IgA IgG ) A/G ratio albumins globulins A/G ratio albumins globulins 77

albumins ) (hypovolemia) albumins albumins 20 6 albumins B cell

11 LPS LPS alpha-cells (glucagon) cortisol (fight or flight reaction) (1) TNF-α eicosanoids (Mandrup-Poulsen et al., 1990) (2) α β (3) glucagon (glucose uptake) (Stadler et al., 1995) LPS Kupffer (glucose transporters) (Spolarics et al., 1993) NO (Balon and Nadler, 1997) NO (glycogenolysis) (glyconeogenesis) (McCallum and Berry, 1973; Horton et al., 1994 a ; Horton et al., 1994 b ; Casada et al., 1996; Ceppi et al., 1996; Young and Leighton, 1998) TB\GB TB β 2 -adrenergic receptor adenylyl cyclase camp (glycogenolysis) 2 78

, 1993) NO (Balon and Nadler, 1997) NO (glycogenolysis) (glyconeogenesis) (McCallum and Berry, 1973; Horton et al.

12 (negative feedback) 4 LPS GB ( LPS 120 ) beta-cells insulin AG\TB ML\AG LPS ( 3 h) AG\TB AG cnos (Kapur et al., 1997; Tada et al., 2000) AG inos cnos AG cnos ML\AG ML (LPS 1 ) corticosteroids (Ogle and Kitay, 1978) corticosteroids (Vaughan et al., 1972; Shima et al., 1997) NO (1) LPS NO NO NO (2) AG\TB ML\AG LPS NO LPS NO 79

$, 2000) AG inos cnos AG cnos ML\AG ML (LPS 1 ) corticosteroids (Ogle and Kitay,$

13 NO TB\GB GB TB\GB TB ML LPS O - 2 O - 2 O - 2 nitrite O - 2 TB\GB LPS O - 2 NO IL-10 NO (Kuga et al., 1996; Dokka et al., 2001) ML O - 2 O - 2 O - 2 SOD H 2 O 2 酶 hydroxyl radical (OH - ) ML OH - indolyl cation radical O - 2 N-acethyl-N-formyl-5-methoxykynuramine ML ( ) ML ML inos 80

14 Gilad NFκB inos (transcription) (Gilad et al., 1998) Schreck NFκB NFκB inos gene (Schreck et al., 1991) ML\AG O - 2 NO ML O - 2 NFκB inos NO 60 ICR mice TB\GB ML\AG (83%) LPS (16%) 5 AG\TB (42%) LPS (16%) 2.6 ( table 4.) post-treatment 81

$, 1991) ML\AG O - 2 NO ML O - 2 NFκB inos NO 60 ICR mice$

15 pre-treatment 82

國防大學國防醫學院藥理學研究所碩士論文

國防大學國防醫學院藥理學研究所碩士論文 (sepsis) (septic sh 40-60% (Titheradge, 1999) (hypotension) (vasoplegia) (multiple organ failure ) ) (lipopolysaccharide, LPS) (endotoxin) LPS-binding protein (LBP) macrophages monocytes Toll-like receptors

第四章 討論

第四章討論