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

Abstract

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.

Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

“…The effect waned off within a week after cessation of DAA-I treatment. These findings are in agreement with those of earlier studies showing that the actions of DAA-I were losartan- and indomethacin-sensitive [ 7 , 8 , 11 , 13 , 19 , 20 ].…”

Targeting Tumor Necrosis Factor Alpha to Mitigate Lung Injury Induced by Mustard Vesicants and Radiation

“…59 CEES also causes pulmonary oxidative stress, characterized by increases in superoxide dismutase (SOD), Ym-1, and lipid peroxidation end products and decreases in intracellular glutathione levels. [60][61][62] Inflammatory proteins, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, TNFα, TNFR1, and CCR2 are also increased in the lung after CEES. 56,61,62 These responses are linked to functional alterations, including decreases in lung compliance and increases in elastance.…”

A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects

“…Accordingly, DAA-I has been shown to be efficacious in animal models of cardiac hypertrophy [1], neointima formation [2], arteriosclerosis [2], renal failure [3], post-infarction injuries [4, 5], diabetes [6, 7], viral infection [8], chemical-induced inflammation [9], heat stroke [10], cancer [10] and gamma radiation lethality [11], where it has been found to significantly attenuate the severity of the pathology. At effective doses, DAA-I has no observable effects on the basal physiological and biochemical parameters that were measured in these studies and was found to lack secondary responses that could be considered adverse or side effects.…”