Effect of hypoxic preconditioning on rat lungs exposed to simulated high altitude hypoxia_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Fuxiang ¹ ,  XIA Qianming ¹ , LI Hongyan ¹ , QUAN Yan ¹ , XIAO Zhenliang ² , ZHANG Yan ¹ , LIAN Hengning ¹ , HU Shen ¹

Department of Respiratory Disease，Chengdu Command General Hospital.Chengdu，Sichuan，610083，ChinaCorresponding author：XIA Qian-ming，E-mail：xiaqm55055@yahoo.com.cn;

Corresponding author：

XIA Qianming, Email: xiaqm55055@yahoo.com.cn

Keywords：

High altitude pulmonary edema; Hypoxic preconditioning; Hypoxia inducible factor-1

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Objective To investigate the influence of hypoxic preconditioning on pulmonary structure of rats exposed to simulated high altitude hypoxia and to explore the role of hypoxia inducible factor-1α（HIF-1α）.Methods Fifty-six Wistar rats were randomly divided into 7 groups(n=8 in each group),ie,a normal control group(N group)，an acute hypoxic control group(H0 group)，an acute hypoxic group(H1 group)，a 3 000 m hypoxic preconditioning group(C3.0 group)，a 3 000 m hypoxic preconditioning + acute hypoxic group (C3.1 group)，a 5 000 m hypoxic preconditioning group(C5.0 group)，and a 5 000 m hypoxic preconditioning + acute hypoxic group(C5.1 group).After treated with hypoxic preconditioning，the animals were exposed to simulated altitude of 6 000 m for 24 hours.Then the protein and mRNA expression of HIF-1α in lung of N，H0，C3.0 and C5.0 groups were assessed by Western blot and RT-PCR，respectively.The lung structure in N，H1，C3.1 and C5.1 groups was observed by light microscope and electron microscope.Results Pulmonary interstitial edema was apparently observed in H1 group，while significantly relieved in two hypoxic preconditioning groups.HIF-1α protein was not detected in rat lungs by Western blot analysis.Compared to N group，the levels of HIF-1α mRNA significantly increased in C3.0 group and C5.0 group(both P lt;0.01).Conclusions Hypoxic preconditioning can relieve hypoxic pulmonary interstitial edema and increase HIF-1α mRNA expression in rat lungs.HIF-1 may be involved in the process of hypoxic preconditioning in rat lungs.

Citation： LI Fuxiang,XIA Qianming,LI Hongyan,QUAN Yan,XIAO Zhenliang,ZHANG Yan,LIAN Hengning,HU Shen. Effect of hypoxic preconditioning on rat lungs exposed to simulated high altitude hypoxia. Chinese Journal of Respiratory and Critical Care Medicine, 2008, 08(3): 199-204. doi: Copy

1.	Duplain H，Sartori C，Scherrer U.High-altitude related illness.Rev Med Suisse，2007，3：1766-1769.
2.	Gidday JM，Shah AR，Maceren RG，et al.Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning.J Cereb Blood Flow Metab，1999，19：331-340.
3.	Vannucci RC，Towfighi J，Vannucci SJ.Hypoxic preconditioning and hypoxic-ischemic brain brain damage in the immature rat：pathologic and metabolic correlates.J Neurochem，1998；71：1215-1220.
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5.	Lando D，Gorman JJ，Whitelaw ML，et al.Oxygen-denpendent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation.Eur J Biochem，2003，270：781-790.
6.	Bergeron M，Gidday JM，Yu AY，et al.Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain.Ann Neurol，2000，48：285-296.
7.	Kietzmann T，Cornesse Y，Brechtel K，et al.Perivenous expression of the mRNA of the three hypoxia-inducible factor-subunits，HIF1 alpha，HIF2 alpha and HIF3 alpha，in rat liver.Biochem J，2001，354：531-537.
8.	Schwab M，Jayet PY，Allemann Y，et al.High altitude pulmonary edema.An experiment of nature to study the underlying mechanisms of hypoxic pulmonary hypertension and pulmonary edema in humans.Medicina (B Aires)，2007，67：71-81.
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11.	Cremona G，Asnaghi R，Baderna P，et al.Pulmonary extravascular fluid accumulation in recreational climbers：a prospective study.Lancet，2002，359：303-309.
12.	胡瑞成，戴爱国，谭双香.缺氧诱导因子1α、诱导型一氧化氮合酶在缺氧性肺动脉高压大鼠肺动脉的表达.中国组织化学与细胞化学杂志，2002，11：314-318.
13.	Yu AY，Frid MG，Shimoda LA，et al.Temporal，spatial，and oxygen-regulated expression of hypoxia-inducibe factor-1 in the lung.Am J Physiol，1998，275：L818-L826.
14.	杨曦明，谢印芝，张东祥，等.血管内皮细胞生长因子与高原肺水肿发病的关系.中华医学杂志，2000，80：931-935.
15.	黄庆愿，高钰琪，史景泉，等.低氧习服过程中大鼠心脏的适应性改变.中国病理生理杂志，2001，17：606-609.
16.	Bernaudin M，Tang Y，Reilly M，et al.Brain genomic response following hypoxia and re-oxygenation in the neonatal rat.J Biolog Chem，2002，277：39728-39738.
17.	夏前明，李福祥，全燕，等.低氧习服过程肺组织一氧化氮水平和钠-钾ATP酶活性的变化.中国临床康复，2005，104-106.
18.	Schoene RB，Goldberg S.The quest for an animal of high altitude pulmonary edema.Int J Sports Med，1992，13Suppl 1：s59-s61.
19.	Komatsu DE，Hadjiargyrou M.Activation of the transcription factor HIF-1 and its target genes，VEGF，HO-1，iNOS，during fracture repair.Bone，2004，34：680-688.
20.	Sartori C，Allemann Y，Duplain H，et al.Salmeterol for the prevention of high-altitude pulmonary edema.N Engl J Med，2002，346：1631-1636.

1. Duplain H，Sartori C，Scherrer U.High-altitude related illness.Rev Med Suisse，2007，3：1766-1769.
2. Gidday JM，Shah AR，Maceren RG，et al.Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning.J Cereb Blood Flow Metab，1999，19：331-340.
3. Vannucci RC，Towfighi J，Vannucci SJ.Hypoxic preconditioning and hypoxic-ischemic brain brain damage in the immature rat：pathologic and metabolic correlates.J Neurochem，1998；71：1215-1220.
4. Dehnert Ch，Schneider M，Mairbaurl H，et al.Acute mountain sickness and high-altitude pulmonary edema.How to protect the mountain climber from the effects of the "altitude haze".MMW Fortschr Med，2003，145：33-35.
5. Lando D，Gorman JJ，Whitelaw ML，et al.Oxygen-denpendent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation.Eur J Biochem，2003，270：781-790.
6. Bergeron M，Gidday JM，Yu AY，et al.Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain.Ann Neurol，2000，48：285-296.
7. Kietzmann T，Cornesse Y，Brechtel K，et al.Perivenous expression of the mRNA of the three hypoxia-inducible factor-subunits，HIF1 alpha，HIF2 alpha and HIF3 alpha，in rat liver.Biochem J，2001，354：531-537.
8. Schwab M，Jayet PY，Allemann Y，et al.High altitude pulmonary edema.An experiment of nature to study the underlying mechanisms of hypoxic pulmonary hypertension and pulmonary edema in humans.Medicina (B Aires)，2007，67：71-81.
9. Sharp FR，Ran R，Lu A，et al.Hypoxic preconditioning protects against ischemic brain injury.NeuroRx，2004，1：26-35.
10. 王仁鹏，吕银慧，张文军，等.急性低压缺氧对大鼠肺泡超微结构的影响.第三军医大学学报，1994，16：19-22.
11. Cremona G，Asnaghi R，Baderna P，et al.Pulmonary extravascular fluid accumulation in recreational climbers：a prospective study.Lancet，2002，359：303-309.
12. 胡瑞成，戴爱国，谭双香.缺氧诱导因子1α、诱导型一氧化氮合酶在缺氧性肺动脉高压大鼠肺动脉的表达.中国组织化学与细胞化学杂志，2002，11：314-318.
13. Yu AY，Frid MG，Shimoda LA，et al.Temporal，spatial，and oxygen-regulated expression of hypoxia-inducibe factor-1 in the lung.Am J Physiol，1998，275：L818-L826.
14. 杨曦明，谢印芝，张东祥，等.血管内皮细胞生长因子与高原肺水肿发病的关系.中华医学杂志，2000，80：931-935.
15. 黄庆愿，高钰琪，史景泉，等.低氧习服过程中大鼠心脏的适应性改变.中国病理生理杂志，2001，17：606-609.
16. Bernaudin M，Tang Y，Reilly M，et al.Brain genomic response following hypoxia and re-oxygenation in the neonatal rat.J Biolog Chem，2002，277：39728-39738.
17. 夏前明，李福祥，全燕，等.低氧习服过程肺组织一氧化氮水平和钠-钾ATP酶活性的变化.中国临床康复，2005，104-106.
18. Schoene RB，Goldberg S.The quest for an animal of high altitude pulmonary edema.Int J Sports Med，1992，13Suppl 1：s59-s61.
19. Komatsu DE，Hadjiargyrou M.Activation of the transcription factor HIF-1 and its target genes，VEGF，HO-1，iNOS，during fracture repair.Bone，2004，34：680-688.
20. Sartori C，Allemann Y，Duplain H，et al.Salmeterol for the prevention of high-altitude pulmonary edema.N Engl J Med，2002，346：1631-1636.

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