Project title
腎素-血管張力素系統在週期性機械拉力引起肺臟細胞活化以及發炎反應扮演角色之探討
Internal ID
NSC97-2314-B002-136-MY2
Principal Investigator
Start Date
August 1, 2008
End Date
July 31, 2009
Organizations
Partner Organizations
Role of the Renin-Angiotensin System in the Development of Cellular Activation and Proimflammatory Response of the Lung Cells Induced by Cyclic Mechanical Stretch = 腎素-血管張力素系統在週期性機械拉力引起肺臟細胞活化以及發炎反應扮演角色之探討 = 腎素-血管張力素系統在週期性機械拉力引起肺臟細胞活化以及發炎反應扮演角色之探討
Description
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are one of the causes of acute respiratory failure. The pathogenesis of ALI/ARDS has been considered complex, but recently it has been shown that ventilation with inadequate setting may result in significant lung injury, so-called ventilator-induced lung injury (VILI). Although the exact mechanism for VILI remains to be elucidated, investigators have shown that induced lung inflammation is main etiology, especially for the nuclear factor-κB pathway. Recently, the involvement of the renin-angiotensin system (RAS) in acute lung injury has gained some interests. One of out recently published studies showed that polymorphism of the ACE gene affects the outcome of ARDS (Jerng JS et al. Critical Care Medicine 2006; 34: 1001- 6), suggesting that the RAS may be activated and play an important role in the pathogenesis as well as evolution of ALI/ARDS. Another one of our recent studies also showed that the RAS may be activated in the model of ventilator-induced lung injury, and the use of angiotensin-converting enzyme inhibitor may attenuate the development of lung injury. (Jerng JS et al, Thorax 2007; 62: 527- 35). Our findings suggest that the signaling pathway of angiotensin II may be important in the development of ALI/ARDS. However, the exact mechanism for the involvement of RAS in the development of VILI remains to be elucidated, especially about the question for the possible cell types responsible for the reaction to mechanical stretch. Therefore we propose for investigation with an in vitro cell stretch system. By using the commercialized Flexcell system, we will apply stretching force on cultured human cells of respiratory origin, and target at the RAS in these cell lines. In the first year, we will establish this in vitro cell stretch system, and confirm that the stretching induces a proinflammatory response of the cells; we will also assess the activity of the RAS in the cells. In the second year we will study the cellular reaction to the treatment with angiotensin, and compare it with the reaction to cyclic stretching. The study will focus on NF-κB, and whether blocking of RAS will attenuate the activation of NF-κB. In the third year we will focus on the signaling pathways other than NF-κB in response to cyclic stretching. We will also study the interaction of RAS with these pathways during cyclic stretching. By using molecular methods, we wish to elucidate the role of the rennin-angiotensin system in the development of ventilator-induced lung injury, and provide further evidence of the complex interaction between RAS and the intracellular signaling pathways.