F. Clinical effectiveness of Clo on eosinophil count in patients with asthma
V. CONCLUSION
This thesis investigated the association of Cys-LT related pathways and platelet-eosinophil interactions in asthma. In allergic inflammation, the expression of CysLT-related receptors, including CysLTR1, CysLTR2 and P2Y12R were up-regulated at the ratio of 1:0.65:1.34, suggesting the 1:1 ratio for Clo:Mon treatment in the subsequent in vivo studies. In a secondary challenge asthma mouse model, we detected increased PEA formation, platelet and eosinophil activation status along with increased airway inflammation, which were suppressed by Clo/Mon treatment. Clo/Mon may function by inhibiting the ADP-induced PEA formation and platelet activation. In conclusion, we demonstrated the synergistic effects of Clo and Mon in suppressing platelet-eosinophil interaction in airway inflammation.
The combination of two antagonists may be potential in asthma treatment, especially in more severe eosinophilic asthma.
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54
-국문요약-
천식에서 몬테루카스트와 클로피 도그렐의 치료효능
Trinh Hoang Kim Tu
(지도교수: 박해
심)
배경
Cysteinyl leukotrienes (LT), C4, D4, E4는 면역관련 세포들에서 배출되는 지질 매개물질로써 cysteinyl leukotriene 수용체인 CysLTR1, CysLTR2, P2Y12R과 결합하여 기도염증, 기도과민성, 알레르기 염증에서 혈관 투과성의 증가 에 관여한다. 혈소판과 호산구 표면에 존재하는 P2Y12R은 세포의 활성 화에 관여한다고 알려져 있으며, 또한 혈소판은 호산구의 이동과 활성을 증가시킬 수 있는 세포내 과립을 배출하고 호산구와 혈소판을 응집시켜 천식 염증을 조절할 수 있다고 알려져 있다. 특히 호산구와 응집된 혈소 판은 CysLT 과생산의 주요한 원인이 되기 때문에 염증반응을 증가시키 는 원인이 된다. 최근까지 여러 동물 실험과 임상 연구를 통해서 prasugrel이나 clopidogrel 같은 항 혈소판제재는 기도 과민성, 혈소판 활성, 호산구의 탈 과립화를 억제하는 것이 밝혀졌다.
따라서, 우리는 CysLTR1의 길항제인 montelukast와 P2Y12R의 길항제인 clopidogrel을 복합요법이 마우스를 이용한 천식 모델에서 기도 염증을 억제하는데 상승작용을 할 것이라고 가설을 세우고 이 연구를 진행하였
55 다.
목적
첫째, 마우스 천식 모델에서 CysLT와 관련된 수용체들의 분포와 특성을 조사하였다. 둘째, 마우스 천식 모델에서 montelukast와 clopidogrel 복합요 법의 상승작용을 평가하였고, 이 복합요법 상승작용의 기전을 밝히는 것 을 목적으로 하였다. 마지막으로 clopidogrel을 사용한 천식 환자들에서 그 효과에 대한 임상적 관찰을 진행하였다.
재료 및 방법
CysLT와 관련된 수용체들 발현과 상호작용 평가를 위하여 난황단백으로 천식을 유도한 BALB/c 마우스를 이용하였다. 각 수용체의 역할을 알아 보기 위하여 CysLTR1의 길항제인 montelukast, CysLTR2의 길항제인 HAMI 3379, P2Y12R의 길항제인 clopidogrel을 각각 주입하고 폐조직과 염 증 세포의 수용체 발현을 보기 위하여 western blot, flow cytometry, double
fluorescence staining의 방법으로 평가하였다.
Montelukast와 clopidogrel 복합요법의 치료 효과 평가를 위하여 BALB/c 마우스에실험 제 0일과 14일에 난황단백으로 감작을 시킨 뒤 실험 28일 부터 30일에 0.2% 난황단백으로 1차 유발을 시키고 실험 42일부터 44일
56
까지 2차로 난황단백으로 유발을 시킨 호산구 천식 모델을 이용하였다. 2 차 난황단백 유발 30분전에 clopidogrel (10mg/kg), montelukast (10mg/kg),
clopidogrel (10mg/kg)과 montelukast (10mg/kg) 동시 투여 또는 dexamethasone (1 mg/kg)을 투여하여 약제의 효과를 판단하였다.
마우스의 기도과민성 측정을 위하여 메타콜린을 사용하여 Flexivent시스 템으로 측정하였고, 폐포세척액에서 인터루킨-4, -5, -13, 인터페론 감마, platelet factor 4, 호산구 페록시다아제를 ELISA를 이용하여 측정하였다.
폐 조직을 이용하여 조직학적 변화를 관찰하였다. 또한 혈소판과 호산구 를 분리하여 복합 배양으로 adenosine diphosphate (ADP) 10µM, LTC4 (200 nM), LTE4 (200 nM), Montelukast (1 µM), Clopidogrel (1 µM), Montelukast &
Clopidogrel (1 µM)의 효과를 in vitro방법으로 분석하였다. 혈액과 폐포세 척액에서 혈소판-호산구의 응집과 P-selection의 발현은 flow cytometry와
immunohistochemistry을 이용하여 관찰하였다.
Clopidogrel을 사용한 천식 환자들의 효과 판정을 위하여 1998년부터 2015년까지 아주대병원 전자 의무 기록이 있는 환자들을 후향적으로 분 석하였다. 포함기준으로 천식, 알레르기 비염이 있으면서 clopidogrel을 7 일 이상 사용한 환자를 대상으로 하였고, 연구기간 동안 호산구 측정을 하지 않은 환자들은 제외하였다. 총 596명의 환자를 포함하여 환자들에 서 호산구 수와 혈중 호산구 분획을 비교하였다.
57 결과
난황단백으로 감작 후 유도한 마우스 천식 모델의 폐 조직에서 CysLTR1 과 P2Y12R는 통계적으로 유의하게 발현이 상승하였다 (P<0.05).
난황단백으로 감작 후 유도한 마우스 천식 모델의 폐 조직에서 CysLTR1 과 P2Y12R는 통계적으로 유의하게 발현이 상승하였다 (P<0.05).