Conclusion. These data provide a clue that AT1 receptor blocker could effectively attenuate severe form of pancreatitis and its-associated systemic inflammation in experimental models of AP. The underlying mechanisms may be involved in Ang II-induced NADPH oxidase derived oxidative stress, particularly NFkappaB and ERK1/2-dependent CREB activation. The pro-inflammatory pathways would commonly converge to transcribe an array of genes such as IL-6, thus regulating the severity of pancreatitis and the onset of its complications. All these in vivo and in vitro data provide substantial evidence that Ang II is involved in AT1 receptor-mediated signaling cascade in regulating the pathogenesis of AP. The findings provide a new insight on potential application of AT 1 receptor blockade for a therapeutic approach in the management of AP. (Abstract shortened by UMI.) / Recent advance in basic research has revealed that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of AP. In this regard, the present study aimed at investigating the effectiveness of RAS blockade in clinically relevant AP animal model and AP-associated systemic inflammation. More importantly, the underlying mechanistic pathways involved in angiotensin II (Ang II)-induced pro-inflammatory actions were elucidated using both in vivo and in vitro systems. / Results. Major components of RAS were up-regulated in obstructive pancreatitis model. Blockade of AT1 receptor attenuated pancreatic injury induced by the two models. Moreover, losartan could significantly ameliorate AP-associated systemic inflammation. Analysis of protein expression levels revealed that losartan treatment improved AP-associated elevation of NADPH oxidase p67 and p22 subunits. Double-immunostaining confirmed that expression of NADPH oxidase was localized to pancreatic acinar cells. AT1 receptor antagonism not only reduced oxidative stress but also suppressed nuclear factor kappaB (NFkappaB) activation, as evidenced by reversal effects on IkappaBbeta depletion, augmentation of phosphor NFkappaB p65, and enhanced nuclear kappaB binding activity. Blockade of AT1 receptor could also suppress the levels of kappaB-related protein expression, including intercellular adhesion molecule-1, cyclooxygenase-2, and IL-1. On the other hand, pancreatic mRNA and protein levels of IL-6 were enhanced by obstructive AP, which were antagonized by AT1 receptor blocker. Losartan treatment could reverse extracellular-regulated kinase (ERK) 1/2 and cAMP-responsive element binding protein (CREB) phosphorylation brought by obstructive AP. In vitro studies, exogenous application of Ang II induced ERK1/2 and CREB activation in AR42J cells. Concomitantly, IL-6 expression was augmented dose- and time-dependently in response to Ang II, which was reversed by treatment of AT1 receptor blocker (losartan) and ERK1/2 inhibitor (PD98059). Ang II induced NFkappaB activation was reversed by pre-treatment of AT1 receptor blocker and NADPH oxidase inhibitor but not ERK1/2 inhibitor in vitro. Moreover, Ang II-induced superoxide generation was detected. Treatment of antioxidant prevented Ang II-induced ERK1/2 activation. On top of these, in vitro experiments revealed that Ang II could sustain the activation of caerulein-induced NFkappaB and ERK1/2 in an AT1 receptor-mediated manner, but not secretagogue-induced hypersecretion. / Chan, Yuk Cheung. / Adviser: Po Siny Lzung. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3246. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 228-262). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences