Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Pretreatment of Diltiazem Ameliorates Endotoxin-Induced Acute Lung Injury by Suppression of Neutrophilic Oxidative Stress

내독소로 유도된 급성폐손상에서 Diltiazem 전처치가 호중구성 산화성 스트레스에 미치는 효과

  • Jang, Yoo Suk (Department of Physiology, School of Medicine, Daegu Catholic University) ;
  • Lee, Young Man (Department of Physiology, School of Medicine, Daegu Catholic University) ;
  • Ahn, Wook Su (Department of Chest Surgery, School of Medicine, Daegu Catholic University) ;
  • Lee, Sang Chae (Department of Internal Medicine, School of Medicine, Daegu Catholic University) ;
  • Kim, Kyung Chan (Department of Internal Medicine, School of Medicine, Daegu Catholic University) ;
  • Hyun, Dae Sung (Department of Internal Medicine, School of Medicine, Daegu Catholic University)
  • 장유석 (대구 가톨릭대학교 의과대학 생리학교실) ;
  • 이영만 (대구 가톨릭대학교 의과대학 생리학교실) ;
  • 안욱수 (대구 가톨릭대학교 의과대학 흉부외과학교실) ;
  • 이상채 (대구 가톨릭대학교 의과대학 내과학교실) ;
  • 김경찬 (대구 가톨릭대학교 의과대학 내과학교실) ;
  • 현대성 (대구 가톨릭대학교 의과대학 내과학교실)
  • Received : 2006.01.17
  • Accepted : 2006.04.19
  • Published : 2006.04.30
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Abstract

Background : Acute respiratory distress syndrome (ARDS) is characterized by severe inflammatory pulmonary edema of unknown pathogenesis. To investigate the pathogenesis of ARDS associated with neutrophilic oxidative stress, the role of phospholipase $A_2$ ($PLA_2$) was evaluated by the inhibition of calcium channel. Methods : In Sprague-Dawley rats, acute lung injury (ALI) was induced by the instillation of E.coli endotoxin (ETX) into the trachea. At the same time, diltiazem was given 60 min prior to tracheal instillation of ETX. Parameters of ALI such as lung and neutrophil $PLA_2$, lung myeloperoxidase (MPO), BAL neutrophils, protein, surfactant were measured. Production of free radicals from neutrophils was measured also. Morphological studies with light microscope and electron microscope were carried out and electron microscopic cytochemistry for detection of free radicals was performed also. Results : Diltiazem had decreased the ALI parameters effectively in ETX given rats and decreased the production of free radicals from neutrophils and lung tissues. Morphological studies denoted the protective effects of diltiazem. Conclusion : Diltiazem, a calcium channel blocker, was effective in amelioration of ALI by the suppression of neutrophilic oxidative stress mediated by $PLA_2$ activation.

연구배경 : 급성호흡곤란증후군의 병인론 중 산화성 스트레스는 페 모세혈관손상의 중요한 기전의 일부이다. 본 연구에서는 호중구에 의한 유리 산소기의 형성이 $PLA_2$의 활성화와 관계가 있음을 근거로 하여 calcium channel blocker인 diltiazem이 내독소에 의한 급성 폐손상에 미치는 영향을 알아보고자 하였다. 방법 : 체중 300 gm 내외의 수컷 Sprague-Dawley흰쥐에서 내독소를 이용하여 급성 폐손상을 유도하고 동시에 내독소 투여 60분전에 diltiazem (3 mg/kg)을 복강 내로 투여하였다. 급성 폐손상이 유도된 흰쥐에서 폐장의 $PLA_2$, 사람에게서 분리된 호중구에서의 $PLA_2$, 폐장의 MPO의 활성도, 폐세척액내의 호중구의 수, surfactant, 단백함량, 호중구에서의 유리 산소기의 생성 등을 측정하였다. 또한 광학 현미경 및 전자 현미경을 이용하여 형태학적인 변화를 관찰하였고, 동시에 전자현미경 세포화학법을 이용하여 폐장내의 유리 산소기의 생성도 검사 하였다. 결과 : 내독소 투여 후 5 시간 후에는 급성 폐손상이 유발되고 폐장 및 호중구의 $PLA_2$, MPO, 폐세척액내의 호중구수, 단백함량 및 surfactant의 함량이 높게 측정되었다. 형태학적으로는 내독소에 의한 급성 페손상이 확인되었고 전자현미경을 이용한 세포화학적 검사에서는 폐장 내 유리 산소기의 생성이 증가되었음을 확인하였다. Diltiazem은 이러한 모든 변화를 감소시키고, 호중구에서의 산소기의 생성도 감소시켜 내독소에 의한 급성 폐손상을 감소 시켰다. 결론 : Diltiazem을 이용한 $PLA_2$의 억제는 내독소에 의한 급성 페손상에서 호중구에 의한 산화성 스트레스를 경감함으로써 그 손상을 줄일 것으로 사료된다.

Keywords

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