We evaluated the efficacy of aerosolized
acetylcholinesterase (AChE) reactivator
oxime MMB-4 in combination with the
anticholinergic atropine sulfate for protection against respiratory toxicity and
lung injury following microinstillation inhalation exposure to
nerve agent soman (GD) in guinea pigs. Anesthetized animals were exposed to GD (841 mg/m(3), 1.2 LCt(50)) and treated with endotracheally aerosolized
MMB-4 (50 µmol/kg) plus
atropine sulfate (0.25 mg/kg) at 30 sec post-exposure. Treatment with
MMB-4 plus
atropine increased survival to 100% compared to 38% in animals exposed to GD. Decreases in the pulse rate and blood O(2) saturation following exposure to GD returned to normal levels in the treatment group. The
body-weight loss and lung
edema was significantly reduced in the treatment group. Similarly, bronchoalveolar cell death was significantly reduced in the treatment group while GD-induced increase in total cell count was decreased consistently but was not significant. GD-induced increase in bronchoalveolar
protein was diminished
after treatment with
MMB-4 plus
atropine. Bronchoalveolar lavage AChE and BChE activity were significantly increased in animals treated with
MMB-4 plus
atropine at 24 h. Lung and diaphragm tissue also showed a significant increase in AChE activity in the treatment group. Treatment with
MMB-4 plus
atropine sulfate normalized various respiratory dynamics parameters including respiratory frequency, tidal volume, peak inspiratory and expiratory flow, time of inspiration and expiration, enhanced pause and pause post-exposure to GD. Collectively, these results suggest that aerosolization of
MMB-4 plus
atropine increased survival, decreased respiratory toxicity and
lung injury following GD inhalation exposure.