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

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.