ACKNOWLEDGEMENTS First of all, I would like to express my heartfelt gratitude to my supervisor, Associate Professor Madhav Bhatia for providing me the great opportunity to work on this project and for his invaluable advice, guidance, continuous support and encouragement throughout the study I would also like to thank Ms Shoon Mei Leng, the senior laboratory officer, for her assistance, support and her excellent work in maintaining our orderly conducive laboratory environment My appreciation is also extended to every member of the Life Sciences Institute Cardiovascular Biology Program, Akhil Hegde, Cao Yang, He Min, Jenab Nooruddinbhai Sidhapuriw, Koh Yung Hua, Raina Devi Ramnath, Ramasamy Tamizhselvi, Selena Sio Weishan, and Zhi Liang for insightful discussions, technical advice and help in one way or another Last but not least, I would like to give my special thanks to my parents Without their support and encouragement, this project could not have been completed i    TABLE OF CONTENTS ACKNOWLEDGEMENTS I SUMMARY VI LIST OF FIGURES IX ABBREVIATIONS XIII PUBLICATIONS XV CHAPTER I INTRODUCTION 1.1 GENERAL OVERVIEW .1 1.2 ACUTE PANCREATITIS 1.2.1 Pathophysiology of acute pancreatitis and associated lung injury 1.2.1.1 Inflammatory mediators in acute pancreatitis and associated lung injury 1.2.1.2 Leukocytes in acute pancreatitis and associated lung injury 1.2.1.2.1 Leukocyte trafficking during inflammation 1.2.1.2.2 Neutrophils 1.2.1.2.3 Macrophages 1.2.2 Experimental models of acute pancreatitis 1.2.2.1 Principle of caerulein-induced acute pancreatitis model 1.2.2.2 Induction and characteristics of caerulein-induced acute pancreatitis model .10 1.3 SP 11 1.3.1 SP in acute pancreatitis and associated lung injury 11 1.3.2 SP in immunoregulation 12 1.3.2.1 SP in immunoregulation: neutrophils 12 1.3.2.2 SP in immunoregulation: macrophages 13 1.4 CHEMOKINES .14 1.4.1 Chemokines and their receptors in acute pancreatitis and associated lung injury .15 1.5 INTRACELLULAR SIGNALING MOLECULES 16 1.5.1 NF-κB 17 1.5.2 MAPKs .18 1.5.3 PKC isoforms .19 1.5.4 PI3K-Akt 19 1.6 RESEARCH RATIONALE AND OBJECTIVES .21 1.6.1 Research rationale .21 1.6.2 Objectives 22 CHAPTER II: SP REGULATES CHEMOKINE EXPRESSION IN LEUKOCYTES DURING ACUTE PANCREATITIS AND ASSOCIATED LUNG INJURY 24 2.1 INTRODUCTION 24 2.2 MATERIALS AND METHODS 25 2.2.1 Animals 25 2.2.2 Reagents 26 2.2.3 Caerulein-induced acute pancreatitis and associated lung injury model 26 2.2.4 Total RNA isolation and RT-PCR 27 ii    2.2.5 Immunohistochemistry .28 2.2.6 Statistical analysis .29 2.3 RESULTS 30 2.3.1 Effects of caerulein hyperstimulation and CP96,345 treatment on pancreatic and lung MCP-1 expression .30 2.3.2 Effects of caerulein hyperstimulation and CP96,345 treatment on pancreatic and lung RANTES expression .30 2.3.3 Effects of caerulein hyperstimulation and CP96,345 treatment on pancreatic and lung MIP-1α expression .31 2.3.4 Effects of caerulein hyperstimulation and CP96,345 treatment on pancreatic and lung MIP-2 expression .31 2.3.5 Effects of caerulein hyperstimulation and CP96,345 treatment on immunohistochemical localization of MCP-1, MIP-1α and MIP-2 in the pancreas and lungs 32 2.4 DISCUSSION 32 CHAPTER III IN VITRO EVIDENCE OF INDUCTION OF CHEMOKINE PRODUCTION AND CHEMOKINE RECEPTOR EXPRESSION IN MOUSE NEUTROPHILS BY SP AND THE CELLULAR MECHANISM 46 3.1 INTRODUCTION 46 3.2 MATERIALS AND METHODS 47 3.2.1 Animals 47 3.2.2 Reagents 47 3.2.3 Isolation of mouse primary neutrophils .48 3.2.4 Cell treatment 49 3.2.5 Cell migration assay 49 3.2.6 Total RNA isolation and RT-PCR 50 3.2.7 ELISA 51 3.2.8 Flow cytometry 51 3.2.9 Immunofluorescence staining 51 3.2.10 Nuclear extract preparation 52 3.2.11 NF-κB DNA-binding activity assay 52 3.2.12 Whole cell lysate preparation and Western blot analysis 53 3.2.13 Statistical analysis .54 3.3 RESULTS 54 3.3.1 SP treatment activated mouse primary neutrophils 54 3.3.2 SP treatment activated the transcription factor NF-κB in mouse primary neutrophils .55 3.3.3 SP treatment enhanced chemokine expression in mouse primary neutrophils 56 3.3.4 SP treatment induced chemokine receptor expression in mouse primary neutrophils 57 3.3.5 SP treatment enhanced chemotactic responses of mouse primary neutrophils to rMIP-2 and rMIP-1α 58 3.4 DISCUSSION 59 CHAPTER IV IN VITRO EVIDENCE OF INDUCTION OF CHEMOKINE PRODUCTION IN MOUSE MACROPHAGES BY SP AND THE CELLULAR MECHANISMS – ROLE OF NF-KB AND ERK1/2 .72 4.1 INTRODUCTION 72 4.2 MATERIALS AND METHODS 73 4.2.1 Reagents 73 iii    4.2.2 Cell culture and treatment 73 4.2.3 Isolation of peritoneal macrophages 74 4.2.4 ELISA 74 4.2.5 Whole cell lysate preparation and Western blot analysis 75 4.2.6 Nuclear extract preparation 75 4.2.7 NF-κB DNA-binding activity assay .75 4.2.8 EMSA 75 4.2.9 Statistical analysis .76 4.3 RESULTS 76 4.3.1 SP induced chemokine production in mouse macrophages 76 4.3.2 NK-1R but not NK-2R antagonists abolished SP-induced chemokine production in mouse macrophages .78 4.3.3 SP enhanced NF-κB but not AP-1 activity via the NK-1R in mouse macrophages .78 4.3.4 SP activated NF-κB via the classical and atypical pathways in mouse macrophages .79 4.3.5 Inhibition of NF-κB activation abolished SP-induced chemokine production in mouse macrophages .80 4.3.6 SP activated ERK1/2 in mouse macrophages 80 4.3.7 Inhibition of ERK1/2 activation attenuated SP-induced chemokine production in mouse macrophages .81 4.3.8 Inhibition of ERK1/2 activation prevented SP-induced phosphorylation and nuclear translocation of NF-κB p65 in mouse macrophages 81 4.4 DISCUSSION 82 CHAPTER V THE CELLULAR MECHANISMS OF SP-INDUCED CHEMOKINE PRODUCTION IN MOUSE MACROPHAGES – ROLE OF PKC ISOFORMS AND PI3K-AKT 101 5.1 INTRODUCTION 101 5.2 MATERIALS AND METHODS 101 5.2.1 Reagents 101 5.2.2 Cell culture and treatment 102 5.2.3 Isolation of peritoneal macrophages 102 5.2.4 ELISA .102 5.2.5 Whole cell lysate preparation and Western blot analysis 102 5.2.6 Subcellular fractionation 102 5.2.7 Nuclear extract preparation 103 5.2.8 NF-κB DNA-binding activity assay 103 5.2.9 Statistical analysis .103 5.3 RESULTS 103 5.3.1 SP induced PKCα, δ and ε activation via NK-1R in mouse macrophages .103 5.3.2 PKCα, δ and ε were involved in SP-induced chemokine production in mouse macrophages 104 5.3.3 PKCα, δ and ε were involved in SP-induced ERK1/2 activation in mouse macrophages 105 5.3.4 PKCα, δ and ε were involved in SP-induced NF-κB activation in mouse macrophages 106 5.3.5 SP induced activation of PI3K-Akt pathway via NK-1R in mouse macrophages 106 5.3.6 PI3K-Akt pathway was involved in SP-induced ERK1/2 and NF-κB activation and chemokine production in mouse macrophages 107 5.3.7 PKCs and PI3K-Akt were two independent convergent pathways activated by SP in mouse macrophages .108 5.3.8 SP induced PKC and PI3K-Akt pathways in primary peritoneal macrophages 108 5.3.9 Signal transduction pathways induced by SP in mouse macrophages .109 iv    5.4 DISCUSSION .109 CHAPTER VI NKA INDUCES CHEMOKINE PRODUCTION BY MOUSE MACROPHAGES VIA ERK1/2- AND PI3K-AKT-NFKB PATHWAYS 139 6.1 INTRODUCTION 139 6.2 MATERIALS AND METHODS 140 6.2.1 Reagents 140 6.2.2 Cell treatment 141 6.2.3 Isolation of primary peritoneal macrophages 141 6.2.4 Whole cell lysate preparation and Western blot analysis 141 6.2.5 Nuclear extract preparation 141 6.2.6 NF-κB DNA-binding activity assay 142 6.2.7 Total RNA isolation and RT-PCR 142 6.2.8 Immunofluorescence staining 142 6.2.9 ELISA .143 6.2.10 Statistical analysis 143 6.3 RESULTS 143 6.3.1 NKA upregulated NK-1R expression in mouse macrophages lacking detectable NK-2R 143 6.3.2 NKA induced chemokine production via NK-1R in mouse macrophages 144 6.3.3 NKA induced NF-κB activation via NK-1R in mouse macrophages 145 6.3.4 NKA activated ERK1/2 and PI3K-Akt pathways in mouse macrophages 146 6.3.5 ERK1/2 and PI3K-Akt pathways were involved in NKA-induced NF-κB activation and chemokine production in mouse macrophages 146 6.4 DISCUSSION .147 CHAPTER VII SUMMARY OF CONTRIBUTIONS AND FUTURE RESEARCH 171 7.1 SUMMARY OF CONTRIBUTIONS 171 7.2 FUTURE RESEARCH 174 REFERENCES 177 v    SUMMARY The neuropeptide substance P (SP) is a well-recognized inflammatory mediator in acute pancreatitis However, the mechanism remains elusive Aiming to delineate its mechanistic actions, the present study attempts to trace the signal transduction cascade activated by SP in the regulation of release of inflammatory molecules that contribute to disease progression In a mouse model of caerulein-induced acute pancreatitis and associated lung injury, blockade of the biological actions of SP with a specific antagonist of its neurokinin-1 receptor (NK-1R) significantly attenuated the chemokine (MCP-1, MIP-1α, and MIP-2) expression in pancreas and lungs, which correlated with less leukocyte infiltration and alleviated tissue damages Resident/infiltrating leukocytes (neutrophils and macrophages) were identified as major chemokine-expressing cells in both pancreas and lungs These preliminary observations suggested a potential mechanistic connection between SP, leukocytes and chemokines in acute pancreatitis – SP acting via resident/recruited leukocytes in tissues to induce the release of chemokines, which further aggravate the condition In vitro studies on isolated cultured mouse neutrophils and macrophages supported that SP, via NK-1R, exerts a direct stimulatory effect on chemokine (MCP-1, MIP-1α, and MIP-2) production by both cell types In neutrophils, SP-NK-1R also induced the expression of CD11b (a neutrophil activation marker) and chemokine receptors (CCR1 and CXCR2) As a functional consequence, SP-stimulated neutrophils exhibited vi    enhanced migratory responses towards chemokines which implied an additional role for SP in promoting leukocyte activation and migration in vivo Mouse macrophages were also used as a model system to elucidate cellular mechanisms of SP-induced chemokine production SP triggered a cascade of molecular events in the cells A key signaling molecule involved was the transcription factor NF-κB SP induced both classical and atypical pathways of NF-κB activation in mouse macrophages Inhibition of NF-κB abolished SP-induced chemokine production by macrophages Furthermore, extracellular signal-regulated kinase (ERK)1/2 lie upstream of NF-κB in SP-induced signal transduction cascade ERK1/2 were activated in the cells between and 30 following SP stimulation A specific ERK1/2 inhibitor prevented activation of NF-κB and chemokine production induced by SP Two kinase pathways, PKCs and PI3K-Akt were further identified to be important for mediating SP-induced ERK1/2 activation PKC isoforms, including the conventional PKCα and novel PKCδ and ε, were selectively activated by SP-NK-1R at early time points (3 min) Inhibition of PKCα, δ, or ε attenuated SP-NK-1R-indcued ERK1/2, NF-κB activation and chemokine production PI3K-Akt pathway was activated at a later time point (15 min) than PKCs and also preceded through ERK1/2 and NF-κB activation to induce chemokine production in macrophages PKCs and PI3K-Akt were two independent pathways and acted synergistically to trigger downstream events PKCs were likely to induce early ERK1/2 activation while PI3K-Akt contributed to the pathway at later time points Collectively, these data indicate that SP-NK-1R triggers two convergent signaling pathways, one led by PKC isoforms and the other by PI3K-Akt, which induce ERK1/2 and NF-κB activation, leading to upregulated chemokine expression in leukocytes vii    Neurokinin A (NKA), another neuropeptide of the tachykinin family, was found to have similar inductive effects on chemokine production in macrophages, mediated via PI3KAkt- and ERK1/2-dependent NF-κB activation viii    LIST OF FIGURES Figure 2.1 CP96,345 treatment attenuated caerulein-induced increase in MCP-1 mRNA expression in the pancreas and lungs Figure 2.2 Effects of caerulein hyperstimulation and CP96,345 treatment on immunohistochemical localization of MCP-1 in the pancreas and lungs Figure 2.3 CP96,345 treatment had no effect on caerulein-induced upregulation of RANTES mRNA expression in the pancreas Figure 2.4 CP96,345 treatment suppressed caerulein-induced upregulation of MIP-1α mRNA expression in the pancreas and lungs Figure 2.5 Effects of caerulein hyperstimulation and CP96,345 treatment on immunohistochemical localization of MIP-1α in the pancreas and lungs Figure 2.6 CP96,345 treatment attenuated caerulein-induced increase in the MIP-2 mRNA expression in the pancreas and lungs Figure 2.7 Effects of caerulein hyperstimulation and CP96,345 treatment on immunohistochemical localization of MIP-2 in the pancreas and lungs Figure 3.1 SP upregulated CD11b integrin (neutrophils activation marker) expression in primary mouse neutrophils Figure 3.2 SP stimulated NF-κB binding activity, IκBα degradation and NF-κB translocation in primary mouse neutrophils Figure 3.3 Effect of SP stimulation on MIP-1α and MIP-2 expression by primary mouse neutrophils Figure 3.4 Effect of SP stimulation on CCR1, CCR2 and CXCR2 expression in primary mouse neutrophils Figure 3.5 SP stimulation enhanced chemotactic responses of primary mouse neutrophils to rMIP-2 and rMIP-1α Figure 4.1 SP enhanced chemokine production in RAW 264.7 macrophages Figure 4.2 SP enhanced chemokine production in primary peritoneal macrophages ix    Figure 4.3 Effect of NK receptor antagonists on SP-induced MIP-2 and MCP-1 upregulation Figure 4.4 SP enhanced NF-κB p65 but not AP-1 DNA-binding activity via the NK-1R Figure 4.5 SP activated NF-κB via the classical and atypical pathways in RAW 264.7 macrophages Figure 4.6 Inhibition of NF-κB activation abolished SP-induced chemokine production in RAW 264.7 cells Figure 4.7 SP induced ERK1/2 activation in RAW 264.7 cells and primary peritoneal macrophages Figure 4.8 Inhibition of ERK1/2 activation attenuated SP-induced chemokine production in RAW 264.7 cells Figure 4.9 SP-induced 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classification system and their role in immunity. Immunity 12:121-127, 2000 192    ... infiltrating leukocytes (neutrophils and macrophages) in the pancreas are the main sources of chemokine production in caerulein-induced acute pancreatitis in mice and the alveolar macrophages, epithelial... partially associated with the suppression of SP expression in the pancreas and lungs in the condition (Lau and Bhatia, 2006) Despite the clear pathogenetic role of SP in acute pancreatitis, the. .. acute pancreatitis 10    1.3 SP SP is an 11-amino acid peptide product of the preprotachykinin-A (PPT-A) gene It belongs to the tachykinin family of neuropeptides which also include neurokinin