Effects of Ambroxol on JNK Signaling Pathway in Gastric Aspiration Induced Lung Injury in Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZhangYanmin , JiaXiaomin ,  ZhaoJie , LiHaiquan , MaLei , XuJunma , HangWenlu

Department of Respiratory Medicine, Second Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, 221006, China;

Corresponding?author：

ZhaoJie, Email: 15952186238@163.com

Keywords：

Ambroxol; Acute lung injury; c-Jun N-terminal protein kinase

DOI：

10.7507/1671-6205.2015091

Video：

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Objective To investigate the effect of ambroxol hydrochloride on c-Jun N-terminal kinase (JNK) signal pathway in gastric aspiration lung injury. Methods Forty healthy male Sprague Dawley rats were randomly divided into a control group, an injury group, a SP600125 (JNK specific inhibitor) group and an ambroxol group. The model of gastric aspiration lung injury was established by aspiration of gastric contents. The rats in the SP600125 group preoperatively received intravenous injection of JNK specific inhibitor SP600125 (3 mg/100 g). The rats in the ambroxol group received intravenous injection of ambroxol hydrochloride (50 mg/kg) 2 hours after the damage occurred. The neutrophil count and malondialdehyde (MDA) activity in bronchoalveolar lavage fluid (BALF), the lung wet weight/dry weight ratio (W/D), and myeloperoxidase (MPO) activity were measured. The protein expressions of JNK and phosphorylated JNK (p-JNK) and inducible nitric oxide synthase (iNOS) in lung tissue were detected by Western blot method. The changes of lung tissue structure were observed under light microscope. Results In the injury group, the neutrophil counts and MDA activity in BALF, W/D, MPO activity, p-JNK and iNOS protein expression increased significantly, lung tissue appeared obvious histopathological injury compared with the control group. In the SP600125 group and the ambroxol group, neutrophil count and MDA activity in BALF, lung W/D, MPO activity, p-JNK and iNOS protein expression were significantly decreased compared with the injury group (P < 0.05), and the damage of the lung tissue pathology was reduced. The expression of JNK protein in lung tissue was not different in all groups (P > 0.05). Conclusions JNK is involved in inflammatory reaction of gastric aspiration lung injury. The protective effect of ambroxol may be related to the inhibition of JNK signaling pathway and the inhibition of iNOS expression.

Citation： ZhangYanmin, JiaXiaomin, ZhaoJie, LiHaiquan, MaLei, XuJunma, HangWenlu. Effects of Ambroxol on JNK Signaling Pathway in Gastric Aspiration Induced Lung Injury in Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2015, 14(4): 368-371. doi: 10.7507/1671-6205.2015091 Copy

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5.	官澤文, 文文, 賴國祥, 等.氨溴索注射液對大鼠氣管內注藥所致氣管黏膜損傷的保護作用.中國呼吸與危重監護雜志, 2012, 11:274-277.
6.	李慧, 徐效峰, 丘紹校.大劑量氨溴索對急性肺損傷/急性呼吸窘迫綜合征療效的系統評價.中國呼吸與危重監護雜志, 2012, 11:459-464.
7.	張衍民, 賈曉民, 趙杰, 等.氨溴索對吸入性肺損傷大鼠肺組織PBEF表達的影響及其抗炎作用.國際呼吸雜志, 2012, 32:409-412.
8.	張衍民, 賈曉民, 趙杰.氨溴索在大鼠胃內容物吸入性肺損傷中的抗炎作用.臨床肺科雜志, 2012, 17:222-223.
9.	Krishnan R, Bruce A, Alan O, et al.Predictive modeling and inflammatory biomarkers in rats with lung contusion and gastric aspiration.J Trauma, 2009, 67:1182-1190.
10.	Davidson BA, Vethanayagam RR, Grimm MJ, et al.NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury.J Immunol, 2013, 190:1714-1724.
11.	Maniatis NA, Sfika A, Nikitopoulou I, et al.Acid-induced acute lung injury in mice is associated with P44/42 and c-Jun N-terminal kinase activation and requires the function of tumor necrosis factorαreceptor I.Shock, 2012, 38:381-386.
12.	Li W, Liu F, Wang C, et al.Novel insights into phosgene-induced acute lung injury in rats:role of dysregulated cardiopulmonary reflexes and nitric oxide in lung edema pathogenesis.Toxicol Sci, 2013, 131:612-628.
13.	Wu X, Li S, Zhang J, et al.Meta-analysis of high doses of ambroxol treatment for acute lung injury/acute respiratory distress syndrome based on randomized controlled trials.J Clin Pharmacol, 2014, 54:1199-1206.

1. Koh Y.Update in acute respiratory distress syndrome.J Intensive Care, 2014, 2:2.doi:10.1186/2052-0492-2-2.
2. Force ADT, Ranieri VM, Rubenfeld GD, et al.Acute respiratory distress syndrome:the Berlin definition.JAMA, 2012, 307:2526-2533.
3. 俞森洋.對急性呼吸窘迫綜合征診斷新標準(柏林定義)的解讀和探討.中國呼吸與危重監護雜志, 2013, 12:1-4.
4. Zhou E, Li Y, Wei Z, et al.Schisantherin A protects lipopolysaccharide-induced acute respiratory distress syndrome in mice through inhibiting NF-κB and MAPKs signaling pathways.Int Immunopharmacol, 2014, 22:133-140.
5. 官澤文, 文文, 賴國祥, 等.氨溴索注射液對大鼠氣管內注藥所致氣管黏膜損傷的保護作用.中國呼吸與危重監護雜志, 2012, 11:274-277.
6. 李慧, 徐效峰, 丘紹校.大劑量氨溴索對急性肺損傷/急性呼吸窘迫綜合征療效的系統評價.中國呼吸與危重監護雜志, 2012, 11:459-464.
7. 張衍民, 賈曉民, 趙杰, 等.氨溴索對吸入性肺損傷大鼠肺組織PBEF表達的影響及其抗炎作用.國際呼吸雜志, 2012, 32:409-412.
8. 張衍民, 賈曉民, 趙杰.氨溴索在大鼠胃內容物吸入性肺損傷中的抗炎作用.臨床肺科雜志, 2012, 17:222-223.
9. Krishnan R, Bruce A, Alan O, et al.Predictive modeling and inflammatory biomarkers in rats with lung contusion and gastric aspiration.J Trauma, 2009, 67:1182-1190.
10. Davidson BA, Vethanayagam RR, Grimm MJ, et al.NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury.J Immunol, 2013, 190:1714-1724.
11. Maniatis NA, Sfika A, Nikitopoulou I, et al.Acid-induced acute lung injury in mice is associated with P44/42 and c-Jun N-terminal kinase activation and requires the function of tumor necrosis factorαreceptor I.Shock, 2012, 38:381-386.
12. Li W, Liu F, Wang C, et al.Novel insights into phosgene-induced acute lung injury in rats:role of dysregulated cardiopulmonary reflexes and nitric oxide in lung edema pathogenesis.Toxicol Sci, 2013, 131:612-628.
13. Wu X, Li S, Zhang J, et al.Meta-analysis of high doses of ambroxol treatment for acute lung injury/acute respiratory distress syndrome based on randomized controlled trials.J Clin Pharmacol, 2014, 54:1199-1206.

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Effects of Ambroxol on JNK Signaling Pathway in Gastric Aspiration Induced Lung Injury in Rats

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