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Protective actions of des‐aspartate‐angiotensin I in mice model of CEES‐induced lung intoxication
Author(s) -
Ng Eugene TeckLeong,
Sim MengKwoon,
Loke WengKeong
Publication year - 2011
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1599
Subject(s) - angiotensin ii , pharmacology , angiotensin ii receptor type 1 , losartan , chemistry , receptor , nadph oxidase , renin–angiotensin system , nasal administration , medicine , enzyme , endocrinology , biochemistry , blood pressure
The present study investigated the protective actions of des‐aspartate‐angiotensin I (DAA‐I) in mice that were intranasally administered 2‐chloroethyl ethyl sulfide (CEES), a half sulfur mustard. The protection was dose‐dependent, and an oral dose of 75 mg kg −1 per day administered 18 h post exposure and for the following 13 days, offered maximum protection that increased survival by a third. DAA‐I attenuated the early processes of inflammation seen in the CEES‐inoculated mice. DAA‐I attenuated (i) elevated pulmonary ROS, and gp91‐phox protein of NADPH oxidase, a non phagocytic enzyme that generates superoxide and subsequent ROS; (ii) intercellular adhesion molecule‐1 (ICAM‐1) that is involved in the extravasation of circulating leucocytes; and (iii) myeloperoxidase activity, which is a surrogate enzymatic measurement of neutrophil infiltration. These actions led to improved histological lung structures, and survival of type‐1 pneumocytes. The action of DAA‐I on animal survival was blocked by losartan, a selective angiotensin AT1 receptor blocker, indicting that the AT1 receptor mediates the protection. The presence of elevated PGE2 and PGI2 in lung supernatants of DAA‐I treated CEES‐inoculated mice indicates that the two prostaglandins are involved in signaling the protective actions of DAA‐I. This finding complements earlier studies showing that DAA‐I acts on an indomethacin‐sensitive angiotensin AT1 receptor. The findings of the present study are the first demonstration of an angiotensin peptide as an effective antidote for CEES intoxication. DAA‐I is also an effective therapeutic intervention against CEES that was instituted at 18 h post exposure, and challenges conventional assumptions of limited efficacy with delayed action against alkylating agents. Copyright © 2010 John Wiley & Sons, Ltd.