Apoptosis-dependent acute pulmonary injury after intratracheal instillation of angiotensin Ⅱ

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ZHUANG Jia-Ju(Department of Physiology,Bethune Military Medical College,Shijiazhuang 050081,China)
LI Xiao-Peng(Department of Physiology,Michigan State University,East Lansing 48824,Michigan,USA)
Bruce David Uhal(Department of Physiology,Michigan State University,East Lansing 48824,Michigan,USA)
Koh Rhun Yian(Department of Physiology,Michigan State University,East Lansing 48824,Michigan,USA)
Journal Title:
Volume 60, Issue 06, 2008
Key Word:
apoptosis;alveolar epithelial cell;acute pulmonary injury;type Ⅱ pneumocyte

Abstract: To test the hypothesis that exogenous purified angiotensin Ⅱ(ANG)might cause apoptosis of alveolar epithelial cells (AECs)and acute lung injury,male Wistar rats were intratracheally instilled with purified ANG(10 pmol/L),ANG plus the caspase inhibitor ZVAD.fmk(60 μmol/L),ANG plus the ANG receptor AT1 antagonist Iosartan(LOS,100 μmol/L)or sterile phosphate-buffered saline(PBS)vehicle alone.Six or 20 h later,the lungs were lavaged in situ for determination of bronchoalveolar lavage(BAL)fluid content of hemoglobin(Hb)and fluorescent(BODIPY)-albumin,a bolus of which was injected intravenously 15 min prior to BAL.Terminal deoxvnucleotidyl transferase.mediated nick-end labeling(TUNEL)revealed that instillation of ANG,but not PBS alone,increased labeling of fragmented DNA in bronchiolar epithelial cells and in AECs(P<0.05)at 6 h post-ANG.Increased TUNEL was abrogated by concurrent instillation of ZVAD-fmk or LOS.Significant increased numbers of caspase-positive cells were observed by anti.caspase 3 immunolabeling afterinstillationofANG(P<0.01);the salnedoses of LOS or ZVAD-fmk that blocked TUNEL also blocked the activation of caspase 3(P<0.01).Intratracheal instillation of ANG also remarkably increased BAL BODIPY-albumin(P<0.01)and Hb(P<0.05),both of which were eliminated by ZVAD-fmk or LOS.These data indicate that exposure of AECs to ANG in vivo is sufficient to induce apoptosis and alveolar epithelial barrier injury mediated by ANG receptor AT1.

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