臺灣博碩士論文加值系統

在重症患者中，急性肺損傷（ALI）或急性呼吸窘迫症候群（ARDS）是一種常見的併發症，並導致嚴重的合併症和死亡率。然而，至目前為止，急性呼吸窘迫症候群的藥物治療仍不盡理想。氧化壓力(oxidative stress)，細胞激素(cytokines)和細胞凋亡(apoptosis)在急性肺損傷或急性呼吸窘迫症候群的病理機轉佔有重要的角色。嗜中性球(Neutrophils)是引起急性肺損傷的關鍵角色。
菸鹼胺磷酸核糖基轉移酶(Nicotinamide phosphoribosyltransferase ;NAMPT)具有調節細胞信息傳遞(cellular signaling)，嗜中性球浸潤，細胞凋亡，氧化壓力和發炎反應的功能。NAMPT被證明是急性肺損傷或急性呼吸窘迫症候群中潛在的新穎生物標記。根據我們的研究發現，NAMPT酶的功能抑製劑FK866在缺血再灌流引發急性肺損傷中具有保護作用。我們證實FK866可以減少肺水腫，發炎細胞激素的產生，嗜中性球浸潤，活性氧化物質(reactive oxygen species)的產生，細胞凋亡的產生及抑制NFκB signaling及MAPK signaling的活化。
褪黑激素(Melatonin)具有多種特性，包括抗細胞凋亡，抗氧化和抗發炎特性。但是，尚不清楚褪黑激素受體促效劑(melatonin receptor agonist)是否在呼吸器導致肺損傷（ventilator-induced lung injury, VILI）中起重要作用。因此，我們將進一步確定褪黑激素受體促效劑在VILI中的角色，並探討可能的保護機制。在我們的研究顯示，呼吸器導致肺損傷顯著增加了肺水腫，嗜中性球浸潤，發炎細胞激素的產生，氧化壓力，細胞凋亡，IκB-α的降解，NF-κB的細胞核遷移(nuclear translocation)以及組織損傷。而透過褪黑激素或褪黑激素受體促效劑（melatonin receptor agonist, Ramelteon）治療可大大減輕這些影響。然而，褪黑激素或Ramelteon的保護作用會被Luzindole（褪黑激素受體拮抗劑melatonin receptor antagonist）所阻斷。
此外，褪黑激素或Ramelteon在呼吸機引發肺損傷中會誘導IL-10表現增加，而此作用是經由褪黑激素受體，因為使用Luzindole可以消除這些保護作用。當我們給予抗IL-10抗體(anti-IL-10 antibody)時，會抵消褪黑激素和Ramelteon對呼吸器導致肺損傷的保護作用，這表明褪黑激素受體促效劑是藉由上調IL-10的產生，改善呼吸器導致的肺損傷。


關鍵詞：急性肺損傷；呼吸器導致肺損傷；缺血再灌流引發急性肺損傷；菸鹼胺磷酸核糖基轉移酶；褪黑激素受體；褪黑激素受體促效劑;白介素10

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a relatively frequent complication in critically ill patients and is responsible for significant co-morbidity and mortality. However, effective pharmacological therapies have not yet been identified for ARDS. Oxidative stress, cytokines, and apoptosis have significant contribution in the pathogenesis of ALI/ARDS. Neutrophils are key players in ALI.
Nicotinamide phosphoribosyltransferase (NAMPT) regulate cellular signaling, neutrophils infiltration, apoptosis, oxidative stress response, and inflammation. NAMPT was demonstrated as a potential novel biomarker in ALI/ARDS. In our study, FK866, an inhibitor of NAMPT enzymatic function, had beneficial effects in ischemia-reperfusion (I/R)-induced acute lung injury. We demonstrated that FK866 attenuated lung I/R injury by decreasing lung edema, production of inflammatory cytokines, neutrophils infiltration, reactive oxygen species, apoptosis, and NFκB and MAPK signaling.
Melatonin has multiple properties, including anti-apoptotic, anti-oxidative, and anti-inflammatory properties. However, it is not clear whether melatonin receptor agonist play an important role in ventilator-induced lung injury (VILI). Therefore, we determined the role of melatonin receptor agonist in VILI and explore the possible mechanism for protection. In our study, VILI significantly increased lung edema, neutrophil infiltration, inflammatory cytokine production, oxidative stress, apoptosis, IκB-α degradation, nuclear translocation of NF-κB, and tissue injury. These effects were significantly attenuated by treatment with melatonin or ramelteon (melatonin receptor agonist). However, the protective effect of melatonin or ramelteon was blocked by the administration of luzindole (melatonin receptor antagonist).
Additionally, melatonin- or ramelteon-induced IL-10 expression in VILI was mediated by melatonin receptors since luzindole treatment abrogates the effect. When we administered an anti-IL-10 antibody, the protective effects of melatonin and ramelteon against VILI were abrogated, which indicated that melatonin receptors upregulated IL-10 production and improved VILI.


Keywords: Acute lung injury; ventilator-induced lung injury; ischemia-reperfusion lung injury; nicotinamide phosphoribosyltransferase; melatonin receptor; melatonin receptor agonist; interleukin-10

CONTENTS
Contents I
List of Table and Figure IV
Abstract in Chinses VI
Abstract in English VIII
INTRODUCTION
■Acute lung injury 1
■Ischemia reperfusion lung injury 3
■Ventilator-induced lung injury 4
■Role of nicotinamide phosphoribosyltransferase in ALI 5
■Role of melatonin receptors in ALI 8
■IL-10 in lung injury 9
■Relationship between melatonin and IL-10 10
■Aims and objectives of this study 11
METHODS
■Animals 13
■Isolated perfused rat lung model 13
■Experimental design of study 1 14
■Experimental design of study 2 15
■Hypoxia-reoxygenation (H/R)of A549 cells 17
■Vascular filtration coefficient 17
■Arterial blood gas analysis 18
■Measurement of the lung weight/body weight (LW/BW) and wet/dry (W/D)
weight ratios 18
■Histopathological analysis 19
■Determination of serum malondialdehyde (MDA) 19
■Protein carbonyl content in lung tissue 20
■Immunohistochemical analyses 20
■Measurement of protein and cytokine levels in BALF 20
■Immunoblotting 21
■Statistical analysis 22
RESULTS
Study 1.Evaluation of the protective effect and mechanism of action of the NAMPT inhibitor FK866 on I/R lung injury in rats 23
■Effect of FK866 on indices of lung edema 23
■Effect of FK866 on PAP 23
■Effect of FK866 on NAMPT protein expression in lung tissue 24
■Effect of FK866 on CINC-1, TNF-α, and IL-6 concentrations, and total
cell counts in the BALF 24
■Effect of FK866 on the carbonyl content, malondialdehyde level, and
numbers of MPO-positive cells in lung tissue 25
■Effect of FK866 on lung pathology 25
■Effects of FK866 on Bcl-2 and caspase-3 protein expression in lung
tissue 25
■Effect of FK866 on the mitogen-activated protein kinase (MAPK)
signaling pathway and MKP-1 in lung tissue 26
■Effect of FK866 on the NF-κB signaling pathway 26
■Effect of FK866 in A549 epithelial cells subjected to H/R 27
Study 2. Protective effect and mechanism of action of melatonin receptor agonists on VILI in rats 27
■Effect of melatonin and ramelteon on oxygenation 27
■Effect of melatonin and ramelteon on lung edema 28
■Effect of melatonin and ramelteon on serum MDA and the carbonyl
content and MPO-positive cell in lung tissue 28
■Effect of melatonin and ramelteon on TNF-α, IL-1β, IL-6, and
CXCL-1 concentrations in BALF 29
■Effect of melatonin and ramelteon on IL-10 and STAT3 expression 29
■Effect of melatonin and ramelteon on iNOS expression 30
■Effect of melatonin and ramelteon on lung pathology 30
■Effect of melatonin and ramelteon on the NF-κB signaling pathway 30
■Effect of melatonin and ramelteon on apoptosis 31
■Effect of an anti-IL-10 antibody on the ability of melatonin and
ramelteon to prevent VILI-induced changes in IL-10 in BALF 31
■Effect of an anti-IL-10 antibody on the ability of melatonin and
ramelteon to prevent VILI-induced lung edema 32
■Effect of an anti-IL-10 antibody on the ability of melatonin and
ramelteon to prevent VILI-induced changes in cytokine
concentrations in BALF 32
■Effect of an anti-IL-10 antibody on the ability of melatonin and
ramelteon to prevent VILI-induced pathology 33
■Effect of an anti-IL-10 antibody on the ability of melatonin and
ramelteon to prevent VILI-induced apoptosis and NF-κB signaling
pathway activation 34
DISCUSSION 35
CONCLUSIONS 51
TABLE and FIGURES 52
REFERENCES 77
List of Table and Figures
■Table 1. Effect of melatonin and ramelteon on oxygenation 52
■Figure 1. Effect of FK866 on pulmonary edema 53
■Figure 2. Effect of FK866 on pulmonary artery pressure (ΔPAP) 54
■Figure 3. Effect of FK866 on NAMPT protein expression in lung tissue 55
■Figure 4. Effect of FK866 on CINC-1, TNF-α, and IL-6 levels, and total
cell counts in bronchoalveolar lavage fluid (BALF) 56
■Figure 5. Effect of FK866 on protein carbonyl contents, MDA levels, and
numbers of MPO-positive cells in lung tissue 57
■Figure 6. Effect of FK866 on lung pathology 58
■Figure 7. Effect of FK866 on the expression of caspase-3 and Bcl-2 in lung
tissue 59
■Figure 8. Effect of FK866 on MAPK and MKP-1 expressions in lung tissue 60
■Figure 9. Effect of FK866 on NF-κB activation and Akt phosphorylation in
lung tissues 61
■Figure 10. Effect of FK866 on A549 cells subjected to
hypoxia-reoxygenation 62
■Figure 11. Effect of melatonin and ramelteon on lung edema 63
■Figure 12. Effect of melatonin and ramelteon on serum malondialdehyde (MDA)
levels, carbonyl content and myeloperoxidase (MPO)-positive cell numbers in
lung tissue 64
■Figure 13. Effect of melatonin and ramelteon on TNF-α, IL-1β, IL-6, and
CXCL-1 concentrations in BALF 65
■Figure 14. Effect of melatonin and ramelteon on IL-10 levels in BALF and
STAT3 expression in the lung tissue 66
■Figure 15. Effect of melatonin and ramelteon on iNOS expression. iNOS
levels in the lung tissue 67
■Figure 16. Effect of melatonin and ramelteon on lung pathology 68
■Figure 17. Effect of melatonin and ramelteon on the NF-κB signaling
pathway 69
■Figure 18. Effect of melatonin and ramelteon on apoptosis 70
■Figure 19. Effect of an anti-IL-10 antibody on melatonin-and
ramelteon-mediated BALF IL-10 levels 71
■Figure 20.Effect of anti-IL-10 antibody on melatonin- and
ramelteon-mediated VILI protection against lung edema. 72
■Figure 21. Effect of an anti-IL-10 antibody on the melatonin- and
ramelteon-mediated cytokines concentrations in BALF 73
■Figure 22. Effect of an anti-IL-10 antibody on the melatonin-and
ramelteon-mediated lung pathology 74
■Figure 23. Effect of an anti-IL-10 antibody on the melatonin-and
ramelteon-mediated apoptosis and NF-κB signaling pathway 75
■Supplemental Figure 1.Effect of vehicle on the VILI-mediated lung injury 76

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