The Role of Renin-Angiotensin System in Acute Lung Injury and Acute Respiratory Dysfunction Syndrome_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

SHEN Lihan ¹ , MO Hongying ² , CAI Lihua ¹ , QIN Bingjun ¹ , XIAO Zhenglun. ²

Intensive Care Unit, Dongguan People’s Hospital. Dongguan, Guangdong,523018, ChinaCorresponding Author: SHEN Li-han, E-mail: shenlihan@ hotmail. com;

Corresponding author：

Keywords：

Acute lung injury; Acute respiratory dysfunction syndrome; Cecal ligation and puncture; Renin-angiotensin system; Angiotensin Ⅱ; Angiotensin-converting enzyme

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Objective To explore the role of renin-angiotensin system( RAS) in acute lung injury( ALI) /acute respiratory dysfunction syndrome( ARDS) by using amouse cecal ligation and puncture ( CLP)model.Methods The ALI/ARDS animal models were assessed bymeasuring blood gas, wet/dry lung weight ratio( W/D) , and lung tissue histology 18 hours after CLP operation. After the ALI/ARDS models was successfully established, immunohistochemistry, western blotting and radioimmunity were used to investigate the changes of several key enzymes of RAS, such as ACE, ACE2 and Ang Ⅱ. In addition, two groups of animals received a separate intraperitoneal injection of angiotensin-converting enzyme ( ACE) inhibitor captopril or recombinant mouse ACE2 ( rmACE2) after CLP, then the changes of RAS in ALI/ARDS models
were observed. Results The extensive lung injuries can be observed in the lung tissues from CLP-treated animals 18 hours after operation. The CLP-induced ALI/ARDS led to an increase in the wet/dry weight ratio of the lung tissues, and a decrease in the PaO2 /FiO2 [ ( 194. 3 ±23. 9) mm Hg vs ( 346. 7 ±20. 5) mm Hg,P lt;0. 01] . Immunohistochemistry and western blotting tests of the lung tissues from CLP-treated animals showed a decrease in the ACE2 protein level. However, in both the CLP and sham mice there were no significant differences between the two groups. CLP markedly increased Ang Ⅱ level in lungs and plasma of mice, and RAS drugs significantly impacted the Ang Ⅱ levels of mice. Compared with the CLP group,captopril or rmACE2 led to a decrease of the Ang Ⅱ level in mice [ Lung: ( 1. 58 ±0. 16) fmol /mg,( 1. 65 ±0. 21) fmol /mg vs ( 2. 38 ±0. 41) fmol /mg; Plasma: ( 178. 04 ±17. 87) fmol /mL, ( 153. 74 ±10. 24) fmol /mL vs ( 213. 38 ± 25. 44) fmol /mL] . Conclusions RAS activation is one of the characteristics of CLP-induced ALI/ARDS in mice models. ACE and ACE2 in RAS have a different role in the regulation of AngⅡ synthesis, while ACE has a positive effect in generating AngⅡ, and ACE2 shows a negative effect.

Citation： SHEN Lihan,MO Hongying,CAI Lihua,QIN Bingjun,XIAO Zhenglun.. The Role of Renin-Angiotensin System in Acute Lung Injury and Acute Respiratory Dysfunction Syndrome. Chinese Journal of Respiratory and Critical Care Medicine, 2010, 9(3): 310-314. doi: Copy

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5.	Otsuka M, Takahashi H, Shiratori M, et al. Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist. Thorax, 2004, 59: 31-38.
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8.	Li W, Moore MJ, Vasilieva N, et al. Angiotensin- converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 2003 ,426: 450-454.
9.	Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects fromsevere acute lung failure. Nature, 2005, 436: 112-116 .
10.	Imai Y, Kuba K, Penninger JM. Angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Cell Mol Life Sci, 2007, 64 :2006-2012.
11.	Singleton KD, Beckey VE, Wischmeyer PE. Glutamine prevents activation of NF-KB and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome ( ARDS) following sepsis. Shock, 2005, 24: 583-589.
12.	Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol, 1997 , 17: 467 -491.
13.	Goss CH, Brower RG, Hudson LD, et al. Incidence of acute lung injury in the United States. Crit Care Med, 2003 , 31: 1607-1611.
14.	Douglas GC, O′Bryan MK, Hedger MP, et al. The novel angiotensinconverting enzyme( ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology, 2004, 145: 4703 -4711.
15.	Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem, 2000 , 275 :33238 -33243.
16.	Yamamoto T, Wang L, Shimakura K, et al. Angiotensin II-inducedpulmonary edema in a rabbit model. Jpn J Pharmacol, 1997 , 73: 33 -40.
17.	Ruiz-Ortega M, Esteban V, Rupérez M, et al. Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens, 2006, 15: 159 -166.
18.	Filippatos G, Tilak M, Pinillos H, et al. Regulation of apoptosis by angiotension Ⅱ in the heart and lungs. Int J Mol Med, 2001, 7: 273 -280.
19.	He X, Han B, Mura M, et al. Angiotensin-converting enzyme inhibitor captopril prevents oleic acid-induced severe acute lung injury in rats. Shock, 2007, 28: 106 -111.

1. Tsushima K, King LS, Aggarwal NR, et al. Acute lung injury review.Intern Med, 2009, 48: 621 -630.
2. 宋鹏, 李琦, 王长征, 等. 17 例重症急性呼吸窘迫综合征临床资料回顾性分析. 中国呼吸与危重监护杂志, 2006, 5: 35-38.
3. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med, 2006 , 20: 1671-1684.
4. Orte C, Polak JM, Haworth SG, et al. Expression of pulmonary vascular angiotensin- converting enzyme in primary and secondary plexiform pulmonary hypertension. J Pathol, 2000, 192: 379 -384.
5. Otsuka M, Takahashi H, Shiratori M, et al. Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist. Thorax, 2004, 59: 31-38.
6. 陆艳辉, 惠汝太, 赵彦芬, 等. ACE 基因插入/ 缺失多态与国人肺血栓栓塞症的关联研究. 中华结核和呼吸杂志, 2001 , 24: 265 -268.
7. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/ deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome.Am J Respir Crit Care Med, 2002, 166: 646 -650.
8. Li W, Moore MJ, Vasilieva N, et al. Angiotensin- converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 2003 ,426: 450-454.
9. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects fromsevere acute lung failure. Nature, 2005, 436: 112-116 .
10. Imai Y, Kuba K, Penninger JM. Angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Cell Mol Life Sci, 2007, 64 :2006-2012.
11. Singleton KD, Beckey VE, Wischmeyer PE. Glutamine prevents activation of NF-KB and stress kinase pathways, attenuates inflammatory cytokine release, and prevents acute respiratory distress syndrome ( ARDS) following sepsis. Shock, 2005, 24: 583-589.
12. Weber KT. Fibrosis, a common pathway to organ failure: angiotensin II and tissue repair. Semin Nephrol, 1997 , 17: 467 -491.
13. Goss CH, Brower RG, Hudson LD, et al. Incidence of acute lung injury in the United States. Crit Care Med, 2003 , 31: 1607-1611.
14. Douglas GC, O′Bryan MK, Hedger MP, et al. The novel angiotensinconverting enzyme( ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology, 2004, 145: 4703 -4711.
15. Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem, 2000 , 275 :33238 -33243.
16. Yamamoto T, Wang L, Shimakura K, et al. Angiotensin II-inducedpulmonary edema in a rabbit model. Jpn J Pharmacol, 1997 , 73: 33 -40.
17. Ruiz-Ortega M, Esteban V, Rupérez M, et al. Renal and vascular hypertension-induced inflammation: role of angiotensin II. Curr Opin Nephrol Hypertens, 2006, 15: 159 -166.
18. Filippatos G, Tilak M, Pinillos H, et al. Regulation of apoptosis by angiotension Ⅱ in the heart and lungs. Int J Mol Med, 2001, 7: 273 -280.
19. He X, Han B, Mura M, et al. Angiotensin-converting enzyme inhibitor captopril prevents oleic acid-induced severe acute lung injury in rats. Shock, 2007, 28: 106 -111.

Chinese Journal of Respiratory and Critical Care Medicine

The Role of Renin-Angiotensin System in Acute Lung Injury and Acute Respiratory Dysfunction Syndrome

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