臺灣博碩士論文加值系統

呼吸道的發炎反應已被證實為呼吸系統疾病，包括：氣喘、慢性阻塞性肺疾病等的一個特殊表徵。在正常的生理環境或是病理狀態下，氣管平滑肌細胞也已被證實為神經傳導物質、發炎反應調控因數或外來物質作用的一種目標細胞(end-effect cells)。除此之外，氣管平滑肌細胞本身也是細胞激素、趨化激素、生長因數以及細胞外基質分泌的重要來源，在細胞病理狀態下的調節及結構重組中扮演重要的角色。當呼吸道發炎時，氣管會表現cytosolic phospholipase A2 (cPLA2)及vascular cell adhesion molecule-1 (VCAM-1)等發炎性蛋白質進而調控整個發炎反應過程。再者，細胞激素及趨化激素已被證實可以調控cPLA2及VCAM-1的表現，因而調節呼吸道疾病的病程。研究調查指出，過敏原、毒害環境、病毒或細菌感染可以造成白血球細胞及淋巴細胞浸潤的現象進而導致細胞傷害或是支氣管的發炎反應。Lipopolysaccharide (LPS)已被發現存在於塵璊之中，是調控發炎反應的重要物質之ㄧ。LPS本身是格蘭氏陰性菌細胞壁外膜的主要成分，是格蘭氏陰性細菌感染引發宿主免疫反應的主要調控分子。雖然LPS已被證實可以刺激內皮細胞經由mitogen-activated protein kinases (MAPKs)、phosphoinositide 3-kinases (PI3-K)/AKT及其他訊息傳遞因數調控cPLA2及VCAM-1表現，然而對於LPS刺激氣管平滑肌細胞表現cPLA2及VCAM-1的分子機轉仍然並未被證實。因此，本篇論文主要是探討LPS刺激氣管平滑肌細胞表現cPLA2及VCAM-1等發炎蛋白的相關分子機制。我們將會建立細胞內訊號分子以及細胞核內共同活化因子(co-activators)間的相對關係模式。我們的假設為LPS經由增加cPLA2及VCAM-1的表現量而影響氣管平滑肌細胞與白血球細胞之間的相互作用，進而促使呼吸道發炎反應的產生。為了說明這些問題，我們將一一探討細胞內的相關訊息傳遞因數，如：protein kinase Cs（PKCs）、MAPKs、Src、proline-rich tyrosine kinase (PyK2)、epidermal growth factor (EGFR)、PI3-K/Akt、 nuclear factor-κB (NF-κB)、activator protein-1 (AP-1)和histone acetyltransferase (HAT)等，是否參與在LPS刺激氣管平滑肌細胞引發cPLA2及VCAM-1表現的機轉當中。
在本篇論文的第一個部份主要是探討LPS刺激氣管平滑肌細胞調控cPLA2表現的機轉。LPS以時間依賴性(time-dependent)的方式刺激cPLA2的表現以及PGE2的釋放，此種現象可以受到前處理genistein (tyrosine kinase抑制劑)、D609 (phosphatidycholine-phospholipase C抑制劑) 、U73122 (phosphatidylinositol-phospholipase C抑制劑)、GF109203X和staurosporine (PKC抑制劑)、BAPTA/AT plus EDTA (鈣離子敖合劑)、PD98059 (MEK1/2抑制劑)、SB202190 (p38抑制劑)、SP600125 (c-Jun terminal kinase (JNK)抑制劑)、LY294002與wortmannin (PI3-K抑制劑)等抑制劑與p42或p38 dominant negative mutants transfection所抑制。LPS刺激誘發cPLA2表現和PGE2釋放等現象也會受到前處理helenalin (NF-κB選擇性抑制劑)或是NF-B inducing kinase (NIK)、 IκB kinase (IKK)-α和IKK-β dominant negative mutants transfection等作用而減低。並且，LPS刺激也可以直接促進IκB-α分解使得NF-κB轉移到細胞核內。另外，LPS刺激cPLA2的磷酸化增加會受到PD98059、GF109203X和staurosporine等抑制劑前處理所抑制，顯示LPS可以經由p42/p44 MAPK和PKC調控PLA2的活性。再者，經由AACOCF3 (選擇性cPLA2抑制劑)抑制LPS所誘發的cPLA2與COX-2表現和PGE2釋放等現象證明cPLA2在此發炎反應中所扮演的角色。經由上述這些結果確認LPS刺激氣管平滑肌細胞可以經由PLC、鈣離子、PKC、tyrosine kinase、MAPKs、PI3-K和NF-κB等訊號分子調控cPLA2表現。

在本篇論文的第二個部分主要是探討MAPKs和NF-κB在LPS刺激VCAM-1表現過程中所扮演的角色。LPS以時間依賴性的方式刺激VCAM-1蛋白質及mRNA表現量增加，此項作用可被MEK1/2 (U0126)、p38、JNK、NF-κB等專一性抑制劑或是MEK、p42、p38等siRNA前處理的方式所抑制。經由前處理抑制劑U0126，SB202190或是MEK、p42、p38等siRNA transfection也會減弱LPS所誘發的p42/p44MAPK和p38磷酸化作用。另外，LPS刺激也會造成IκB-α分解，和NF-κB轉移到細胞核內。此項作用能夠受到helenalin，U0126，SB202190，SP600125等藥理性抑制劑前處理所抑制。再者，LPS刺激VCAM-1的表現量增加可以促進多型性核白血球(PMNs)黏附到人類氣管平滑肌細胞，而前處理抑制劑helenalin，U0126或SP600125則可以抑制此情形。因此，經由上述這些結果推測，在人類氣管平滑肌細胞中，LPS的刺激可以經由p42/p44MAPK，p38 和 JNK調控NF-κB的活性增加，進而引發VCAM-1基因的大量表現。

論文的第三部份主要是探討LPS是否能經由Src/EGFR/PI3-K/Akt/p300等一連串的訊息傳遞途徑調控VCAM-1基因表現。LPS刺激VCAM-1基因大量的表現所強化的嗜中性白血球黏附作用可被抑制劑LY294002和Wortmannin所抑制。LPS造成Src、PYK2、EGFR及AKT的磷酸化作用以及VCAM-1基因的表現也可被Src (PP1)、EGFR (AG1478)、PI3-K、AKT (SH-5)、p300 (curcumin)等藥理性抑制劑，或是Src，AKT，p300等siRNA 以及p110 shRNA transfection前處理方式所抑制。利用免疫螢光，免疫沉澱，和ChIP (Chromatin immunoprecipition) assay等實驗進ㄧ步發現，LPS的刺激可以造成AKT的活化作用並且轉移到細胞核內，並且與細胞核內蛋白p300以及VCAM-1 promoter region連結在一起，進而調控VCAM-1的 promoter 活性促使VCAM-1 mRNA表現量增加。經由以上的結果，我們發現，當LPS刺激人類氣管平滑肌細胞，可以經由transactivation pathway (Src/PYK2/EGFR)來調控AKT的磷酸化以及增強p300活性，進而導致VCAM-1的基因表現增加。

在論文的最後一個部分，我們將焦點集中於AP-1是否也參與在LPS刺激VCAM-1的表現過程當中。前處理AP-1的抑制劑(tanshinone)，不管是在人類氣管平滑肌細胞或是在ICR老鼠等活體外或體內的試驗當中，都可明顯減少LPS所誘發的VCAM-1基因表現以及白血球細胞的吸附聚集現象。LPS可以刺激c-Fos的表現量增加，並且受到前處理GF109203X，Ro-318220、Gö-6976 (conventional PKCs抑制劑)、U0126和SB202190等抑制劑所抑制。另外給予GF109203X、Ro31-8220、Gö-6976、U0126、SB202190和SP600125等抑制劑，皆可以減弱LPS刺激氣管平滑肌細胞所誘發的c-Jun表現量。LPS刺激之下c-Fos和c-Jun的表現量可以進而促使AP-1 promoter的活性增加。活化的AP-1會結合到VCAM-1 promoter region，導致VCAM-1 promoter 的活性增加，促使VCAM-1 mRNA以及蛋白質的表現，進而強化人類氣管平滑肌細胞與白血球之間的黏附作用。此現象也可以藉由前處理GF109203X、Ro31-8220或Gö-6976等抑制劑而受到抑制作用。這些實驗結果說明，在人類氣管平滑肌細胞中，LPS也能夠透過活化PKCs/MAPKs/AP-1等一連串的訊息傳遞路徑來調節VCAM-1的表現。

本篇論文深入探討LPS在人類氣管平滑肌細胞中的作用機制，證實我們於研究開始時所設立的假設，發現LPS能夠經由增加氣管平滑肌細胞與白血球細胞之間的交互作用，進而促使發炎反應的發生，而參與整個呼吸道疾病病程的發展。希望能藉由增加對於cPLA2和VCAM-1等發炎基因調控相關訊息傳遞機轉的瞭解，發展出更適當的抗發炎的新療程。

Airway inflammation has been proved as significant feature of airway diseases including asthma and chronic obstructive pulmonary disease (COPD). Tracheal smooth muscle cells (TSMCs) function as end-effector cells involving in response to stimulation of various neurotransmitters, proinflammatory mediators, and exogenous substance released under homeostatic or pathologic conditions. In addition, TSMCs are the source of proinflammatory cytokines, chemokines, growth factors, and ECM, which further play a significant role in regulating cellular pathology and structure remodeling. During the airway inflammation, cytosolic phospholipase A2 (cPLA2) and vascular cell adhesion molecule-1 (VCAM-1) are the proinflammatory proteins expressed by the airway resident cells, and contribute to the development and perpetuation of inflammation. Several factors including cytokines and chemokines have been shown to regulate the expression of cPLA2 and VCAM-1 and hence, mediate the pathogenesis of airway diseases. Besides, investigation also indicats that noxious, infectious, and allergic insult lead to cellular damage and/or bronchial inflammation with activated leukocytes and lymphocytes infiltration as character. LPS has shown present in the organic dusts, and is one of the major candidates for inflammatory reaction. LPS is the key component of the outer membranes of Gram-negative bacteria and provided a ruling role in the host response to Gram-negative bacterial infection. Although LPS has been reported to induce VCAM-1 or cPLA2 expression in endothelial cells or macrophages through mitogen-activated protein kinases (MAPKs), Phosphoinositide 3-kinases (PI3-K)/Akt, and other signaling molecules, the mechanisms underlying LPS-induced VCAM-1 and cPLA2 expression in TSMCs remains unknown. Thus this thesis focused on investigating the signaling pathway correlating to LPS-induced VCAM-1 and cPLA2 expression in HTSMCs (human tracheal smooth muscle cells) or CTSMCs (canine tracheal smooth muscle cells). We will establish the relationship between the intracellular signal molecules and nuclear co-activators participating in LPS-induced cPLA2 or VCAM-1 expression. Our hypothesis is that up-regulation of cPLA2 or VCAM-1 stimulated by LPS may contribute to leukocytes/TSMCs interaction and promote inflammatory response in airways. To addressing these questions, the experiments were performed to investigate the roles of protein kinase Cs (PKCs), MAPKs, Src, Proline-rich tyrosine kinase 2 (PYK2), epidermal growth factor receptor (EGFR), PI3-K/Akt, nuclear factor-κB (NF-B), activator protein-1 (AP-1) and histone acetyltransferase (HAT) activity in LPS-induced cPLA2 or VCAM-1 expression in TSMCs.
At the first part of this thesis, the mechanisms underlying LPS-induced cPAL2 expression were investigated. LPS indcued expression of cPLA2 and release of PGE2 in a time-dependent manner which were further attenuated by inhibitors of tyrosine kinase (genistein), phosphatidylcholine-phospholipase C (D609), phosphatidylinositol-phospholipase C (U73122), PKC (GF109203X and staurosporine), removal of Ca2+ by BAPTA/AM plus EDTA, MEK1/2 (PD98059), p38 (SB202190), c-Jun-N-terminal kinase (JNK; SP600125), PI3-K (LY294002 and wortmannin) and dominant negative mutants of ERK2 and p38 transfection. LPS-induced cPLA2 expression and PGE2 synthesis was also inhibited by a selective NF-κB inhibitor (helenalin) and transfection with dominant negative mutants of NF-B inducing kinase (NIK), IκB kinase (IKK)-α, and IKK-β, consistent with that LPS-stimulated both IκB-α degradation and NF-κB translocation into nucleus in these cells. LPS-stimulated cPLA2 phosphorylation was inhibited by PD98059, GF109203X, and staurosporine, indicating the regulation by p42/p44 MAPK and PKC. Moreover, LPS-induced up-regulation of cPLA2 and COX-2 linked to PGE2 synthesis was inhibited by AACOCF3 (a selective cPLA2 inhibitor), implying the involvement of cPLA2 in these responses. These findings suggested that phosphorylation and expression of cPLA2 correlated with the release of PGE2 from LPS-challenged TSMCs, at least in part, mediated through PLC, Ca2+, PKC, tyrosine kinase, MAPKs, PI3-K and NF-κB signaling pathways.
At the second part of this thesis, the roles of MAPKs and NF-κB pathways in LPS-induced VCAM-1 expression were investigated. LPS induced expression of VCAM-1 protein and mRNA in a time-dependent manner which was significantly inhibited by inhibitors of MEK1/2 (U0126), p38, JNK, NF-κB or transfection with siRNA of MEK, p42, or p38. Consistently, LPS-stimulated phosphorylation of p42/p44 MAPK and p38 was attenuated by pretreatment with U0126 or SB202190 and transfection of MEK, p42, or p38 siRNAs, respectively. LPS-stimulated translocation of NF-κB into the nucleus and degradation of IκB-α was also blocked by helenalin, U0126, SB202190, or SP600125. Moreover, the resultant enhancement of VCAM-1 expression increased the adhesion of polymorphonuclear cells to monolayer of HTSMCs which was blocked by pretreatment with helenalin, U0126, or SP600125 prior to LPS exposure. Thus, these results suggested that in HTSMCs, activation of p42/p44 MAPK, p38, and JNK pathways, at least in part, mediated through NF-κB, were essential for LPS-induced VCAM-1 gene expression.
At the third part of this thesis, the participation of Src/EGFR/PI3-K/Akt/p300 cascade in LPS-induced VCAM-1 expression was proved. LPS-induced up-regulation of VCAM-1 enhanced the adhesion of neutrophils onto HTSMC monolayer, which was inhibited by LY294002 and wortmannin. LPS-stimulated Src, PYK2, EGFR, and Akt phosphorylation and VCAM-1 expression were attenuated by the inhibitors of Src (PP1), EGFR (AG1478), PI3-K, Akt (SH-5) and p300 (curcumin), respectively, or transfection with siRNAs of Src, Akt or p300 and shRNA of p110. LPS-stimulated activated Akt translocated into nucleus and associated with p300 and VCAM-1 promoter region was further confirmed by immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation assays. LPS-induced p300 activation enhanced VCAM-1 promoter activity and VCAM-1 mRNA expression. These results suggested that in HTSMCs, Akt phosphorylation mediated through transactivation of Src/PYK2/EGFR promoted the transcriptional p300 activity and eventually led to VCAM-1 expression induced by LPS.
The last part of investigation was focus on the role of AP-1 in LPS-insduced VCAM-1 expression. Tanshinone (inhibitor of AP-1) significantly attenuated LPS-induced VCAM-1 expression and leukucytes recruitments in vitro in HTSMCs and in vivo in ICR mice. LPS stimulated c-Fos expression which was inhibited by pretreatment with GF109203X, Ro31-8220, Gö-6976 (inhibitor of conventional PKCs), U0126, and SB202190, whereas LPS-induced c-Jun expression was attenuated by GF109203X, Ro31-8220, Gö-6976, U0126, SB202190 and SP600125. Up-regulation of c-Fos and c-Jun expression related to the increase of AP-1 promoter activity in response to the stimulation of LPS. LPS stimulated AP-1 activation and bound to VCAM-1 promoter region thus led to increase of VCAM-1 promoter activity, expression of VCAM-1 mRNA and protein and enhancement of adhesiveness between HTSMCs, which could be attenuated by pretreatment with GF109203C, Ro31-8220, Gö-6976. These data revealed that LPS-mediated VCAM-1 expression through PKCs/MAPKs/AP-1 cascade in HTSMCs.
This thesis went deep into the mechanisms of LPS action in TSMCs, supporting the hypothesis that LPS contributed to leukocyte/TSMCs interaction and promoted inflammatory responses involving in the development of airway diseases. Increased understanding of signal transduction mechanisms underlying cPLA2 and VCAM-1 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies.

Table of Contents
Page (頁數)
指導教授推薦書…………………………………………….....i
口試委員會審定書…………………………………………....ii
博士論文著作授權書………………………………………...iii
Acknowledgements (誌謝)……………………………….....iv
Abbreviations (縮寫表)……………………………….......v
Pharmacological inhibitors (藥理性抑制劑)…………..vii
Abstract in Chinese (中文摘要)………………………..viii
Abstract in English (英文摘要)………………………….xii
Table of Contents (目錄)………………………………...xvi
CHAPTER I INTRODUCTION……………......………….....1
SECTION 1. Background and significance……………….2
SECTION 2. Specific aims…………………………………18
SECTION 3. Figures and tables…………………….....19
CHAPTER II MATERIALS AND METHODS…………………....57
SECTION 1. Materials……………………………………..58
SECTION 2. Methods……………………………………....60
CHAPTER III ………………………………………………....69
Induction of cytosolic phospholipase A2 by lipopolysaccharide in canine tracheal smooth muscle cells: Involvement of MAPKs and NF-κB pathways
SECTION 1: Background……………………………………….70
SECTION 2: Results………………………………………....73
SECTION 3: Discussion……………………………………...79
SECTION 4: Figures and legends………………..…………83
CHAPTER IV …………………………………......…………100
Involvement of MAPKs and NF-κB in LPS-induced VCAM-1 expression in human tracheal smooth muscle cells
SECTION 1: Background……………………………………..101
SECTION 2: Results……………………...………………..103
SECTION 3: Discussion………………………………………108
SECTION 4: Figures and legends………………………….112
CHAPTER V …………………….............……………..127
Lipopolysaccharide induces VCAM-1 expression and neutrophil adhesion to human tracheal smooth muscle cells: Involvement of Src/EGFR/PI3-K/Akt pathway
SECTION 1: Background…………………………..........128
SECTION 2: Results………………………………………….130
SECTION 3: Discussion………………………………………135
SECTION 4: Figures and legends………………………...140
CHAPTER VI …………………………………………………..157
Lipopolysaccharide up-regulates VCAM-1 expression in human tracheal smooth muscle cells via PKC/MAPKs/AP-1 activation
SECTION 1: Background……………………………………..158
SECTION 2: Results………………………………………...161
SECTION 3: Discussion………………………………………165
SECTION 4: Figures and legends………………………...169
CHAPTER VII CONCLUSION AND PERSPECTIVES...........188
SECTION 1: Conclusion..............................189
SECTION 2: Perspectives............................192
SECTION 3: Schemes…………...........…………………193
PUBLICATIONS……………………………………………......194
REFERENCES .........................................196

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