Protective actions of des-aspartate-angiotensin I in mice model of CEES-induced lung intoxication

• Published in: Journal of applied toxicology 2011-08, Vol.31 (6), p.568-578
• Main Authors: Ng, Eugene Teck-Leong, Sim, Meng-Kwoon, Loke, Weng-Keong
• Format: Article
• Language: English
• Subjects: 2-chloroethyl ethyl sulfide; Angiotensin I - analogs & derivatives; Angiotensin I - pharmacology; Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; des-aspartate-angiotensin I; Dinoprostone - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Epoprostenol - metabolism; ICAM-1; Intercellular Adhesion Molecule-1 - metabolism; losartan; Losartan - pharmacology; Lung - drug effects; Lung - pathology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mustard Gas - analogs & derivatives; Mustard Gas - toxicity; NADPH Oxidases - metabolism; Peroxidase - metabolism; PGE2; Reactive Oxygen Species - metabolism; Receptors, Immunologic - metabolism; ROS; Signal Transduction; Toxicology
• ISSN: 0260-437X; 1099-1263; 1099-1263
• DOI: 10.1002/jat.1599

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. Des‐aspartate‐angiotensin I (DAA‐I attenuated the fatality of mice that were intranasally administered 2‐chloroethyl ethyl sulphide (CEES). DAA‐I attenuated the early processes of inflammation seen in the lung of CEES‐inoculated mice. The protection was dose‐dependent. An oral dose of 75 mg/kg/day administered 18 hours post exposure and for the following 13 days, offered maximum protection that increased survival by a third. The protection was blocked by losartan, a selective angiotensin AT1 receptor blocker, indicating that the AT1 receptor mediates the protection.