Effects of hypoxia‑inducible factor‑1α and matrix metalloproteinase‑9 on alveolar‑capillary barrier disruption and lung edema in rat models of severe acute pancreatitis‑associated lung injury

Qi,Bing; Chen,Hai‑Long; Shang,Dong; Dong,Ying; Zhang,Gui‑Xin; Yu,Lei

doi:10.3892/etm.2014.1810

Effects of hypoxia‑inducible factor‑1α and matrix metalloproteinase‑9 on alveolar‑capillary barrier disruption and lung edema in rat models of severe acute pancreatitis‑associated lung injury

Authors:
- Bing Qi
- Hai‑Long Chen
- Dong Shang
- Ying Dong
- Gui‑Xin Zhang
- Lei Yu
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Affiliations: Dalian Medical University, Dalian, Liaoning 116044, P.R. China, Department of Acute Abdominal Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116021, P.R. China
Published online on: June 26, 2014 https://doi.org/10.3892/etm.2014.1810
Pages: 899-906

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Abstract

The aim of this study was to investigate the effects of hypoxia‑inducible factor‑1α (HIF‑1α) and matrix metalloproteinase‑9 (MMP‑9) on alveolar‑capillary barrier disruption and lung edema in rat models of severe acute pancreatitis‑associated lung injury (PALI). A total of 40 male Sprague‑Dawley rats were randomly divided into a sham surgery group (n=10) and three PALI groups, in which acute pancreatitis was induced by the retrograde infusion of 5% sodium taurocholate (1 ml/kg). The PALI groups were as follows: i) Untreated PALI group (n=10); ii) 2‑methoxyestradiol (2ME2) group (5 mg/kg body mass; n=10); and iii) 2ME2 group (15 mg/kg body mass; n=10). In the two 2ME2 groups, the HIF‑1α inhibitor 2ME2 was administered intraperitoneally 1 h after the induction of AP. The severity of the pancreatitis was evaluated by the serum amylase levels and pathology. The severity of the lung injury was evaluated by the wet/dry ratio, blood gas analysis and pathology. The alveolar‑capillary barrier disruption was assessed by Evans blue dye extravasation. The protein and mRNA expression levels of HIF‑1α and MMP‑9 were studied using enzyme‑linked immunosorbent assays (ELISAs), western blot analysis and reverse transcription‑polymerase chain reaction. The active tumor necrosis factor‑α levels were measured using an ELISA. The HIF‑1α inhibitor 2ME2 attenuated the severity of the pancreatitis and PALI, while the lung edema and alveolar‑capillary barrier disruption were significantly ameliorated compared with those in the untreated PALI group. Administration of the higher dose of 2ME2 significantly suppressed the protein expression of MMP‑9 in the lung tissues. The results indicate that HIF‑1α has a major function in alveolar‑capillary barrier disruption and lung edema in PALI via a molecular pathway cascade involving MMP‑9. Inhibition of HIF‑1α by 2ME2 attenuates alveolar‑capillary barrier disruption and lung edema. Pharmacological blockade of this pathway in patients with PALI may provide a novel therapeutic strategy.

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1	Bhatia M, Wong FL, Cao Y, et al: Pathophysiology of acute pancreatitis. Pancreatology. 5:132–144. 2005. View Article : Google Scholar
2	Bhatia M: Novel therapeutic targets for acute pancreatitis and associated multiple organ dysfunction syndrome. Curr Drug Targets Inflamm Allergy. 1:343–351. 2002. View Article : Google Scholar : PubMed/NCBI
3	Wang G, Chen HL, Ren F, Li J and Li YQ: Expression of Cav-1, AQP1 and AQP5 in lung of acute pancreatitis-associated lung injury rats and the therapeutic role of Qingyitang. Zhonghua Yi Xue Za Zhi. 90:2564–2569. 2010.(In Chinese).
4	Higashida T, Kreipke CW, Rafols JA, et al: The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg. 114:92–101. 2011.
5	Gao ZM, Chen HL and Liu XD: Expression and function of aquaporin-1 in acute lung injury induced by severe acute pancreatitis in rats. Shi Jie Hua Ren Xiao Hua Za Zhi. 15:453–457. 2007.(In Chinese).
6	Renzulli P, Jakob SM, Täuber M, Candinas D and Gloor B: Severe acute pancreatitis: Case-oriented discussion of interdisciplinary management. Pancreatology. 5:145–156. 2005. View Article : Google Scholar : PubMed/NCBI
7	Chen P, Huang L, Sun Y and Yuan Y: Upregulation of PIAS1 protects against sodium taurocholate-induced severe acute pancreatitis associated with acute lung injury. Cytokine. 54:305–314. 2011. View Article : Google Scholar : PubMed/NCBI
8	Sochor M, Richter S, Schmidt A, Hempel S, Hopt UT and Keck T: Inhibition of matrix metalloproteinase-9 with doxycycline reduces pancreatitis-associated lung injury. Digestion. 80:65–73. 2009. View Article : Google Scholar : PubMed/NCBI
9	Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF and Eltzschig HK: A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood. 111:2024–2035. 2008. View Article : Google Scholar : PubMed/NCBI
10	Pirrone F, Pastore C, Mazzola S and Albertini M: In vivo study of the behaviour of matrix metalloproteinases (MMP-2, MMP-9) in mechanical, hypoxic and septic-induced acute lung injury. Vet Res Commun. 33(Suppl 1): 121–124. 2009. View Article : Google Scholar : PubMed/NCBI
11	Kobayashi Y, Matsumoto M, Kotani M and Makino T: Possible involvement of matrix metalloproteinase-9 in Langerhans cell migration and maturation. J Immunol. 163:5989–5993. 1999.PubMed/NCBI
12	Martinez-Hernandez A and Amenta PS: The basement membrane in pathology. Lab Invest. 48:656–677. 1983.
13	Keck T, Balcom JH 4th, Fernández-del Castillo C, Antoniu BA and Warshaw AL: Matrix metalloproteinase-9 promotes neutrophil migration and alveolar capillary leakage in pancreatitis-associated lung injury in the rat. Gastroenterology. 122:188–201. 2002. View Article : Google Scholar : PubMed/NCBI
14	Shimoda LA and Semenza GL: HIF and the lung: role of hypoxia-inducible fctors in pulmonary development and disease. Am J Respir Crit Care Med. 183:152–156. 2011. View Article : Google Scholar : PubMed/NCBI
15	Semenza G: Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 64:993–998. 2002. View Article : Google Scholar : PubMed/NCBI
16	Bai X, Sun B, Pan S, et al: Down-regulation of hypoxia-inducible factor-1alpha by hyperbaric oxygen attenuates the severity of acute pancreatitis in rats. Pancreas. 38:515–522. 2009. View Article : Google Scholar : PubMed/NCBI
17	Gomez G, Englander EW, Wang G and Greeley GH Jr: Increased expression of hypoxia-inducible factor-1alpha, p48, and the Notch signaling cascade during acute pancreatitis in mice. Pancreas. 28:58–64. 2004. View Article : Google Scholar : PubMed/NCBI
18	Becker PM, Alcasabas A, Yu AY, Semenza GL and Bunton TE: Oxygen-independent upregulation of vascular endothelial growth factor and vascular barrier dysfunction during ventilated pulmonary ischemia in isolated ferret lungs. Am J Respir Cell Mol Biol. 22:272–279. 2000. View Article : Google Scholar
19	Standiford TJ, Kunkel SL, Lukacs NW, et al: Macrophage inflammatory protein-1 alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia. J Immunol. 155:1515–1524. 1995.PubMed/NCBI
20	Schmidt J, Rattner DW, Lewandrowski K, et al: A better model of acute pancreatitis for evaluating therapy. Ann Surg. 215:44–56. 1992. View Article : Google Scholar : PubMed/NCBI
21	Wang H, Liu JW, Li ZL, et al: Development of a rat model of severe acute pancreatitis associated lung injury. Shi Jie Hua Ren Xiao Hua Za Zhi. 21:211–219. 2013.(In Chinese).
22	Chen C, Ostrowski RP, Zhou C, Tang J and Zhang JH: Suppression of hypoxia-inducible factor-1α and its downstream genes reduces acute hyperglycemia-enhanced hemorrhagic transformation in a rat model of cerebral ischemia. J Neurosci Res. 88:2046–2055. 2010.
23	Koeppen M, Eckle T and Eltzschig HK: The hypoxia-inflammation link and potential drug targets. Curr Opin Anaesthesiol. 24:363–369. 2011. View Article : Google Scholar : PubMed/NCBI
24	Hartmann G, Tschöp M, Fischer R, et al: High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine. 12:246–252. 2000. View Article : Google Scholar : PubMed/NCBI
25	Rosenberger P, Schwab JM, Mirakaj V, et al: Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol. 10:195–202. 2009. View Article : Google Scholar : PubMed/NCBI
26	Hartwig W, Werner J, Jimenez RE, et al: Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury. Am J Physiol. 277:G1008–G1016. 1999.PubMed/NCBI
27	Zhou H, Chen X, Zhang WM, Zhu LP and Cheng L: HIF-1α inhibition reduces nasal inflammation in a murine allergic rhinitis model. Plos One. 7:e486182012.
28	Mabjeesh NJ, Escuin D, LaVallee TM, et al: 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell. 3:363–375. 2003. View Article : Google Scholar : PubMed/NCBI
29	Salama SA, Kamel MW, Botting S, et al: Catechol-o-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells. PLoS One. 4:e73562009. View Article : Google Scholar
30	Pastor CM, Matthay MA and Frossard JL: Pancreatitis-associated acute lung injury: new insights. Chest. 124:2341–2351. 2003. View Article : Google Scholar : PubMed/NCBI