Sarin is an
organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production,
sarin is the
nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of
sarin exposure is through inhalation and, depending on the dose,
sarin leads to acute
respiratory failure and death. The mechanism(s) of
sarin-induced
respiratory failure is poorly understood.
Sarin irreversibly inhibits
acetylcholine esterase, leading to excessive synaptic levels of
acetylcholine and, we have previously shown that
sarin causes marked ventilatory changes including weakened response to
hypoxia. We now show that LD50
sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased
hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60%
oxygen chambers after
sarin exposure improved the survival from about 50% to 75% at 24h; however, many animals died within hours after removal from the
oxygen chambers. On the other hand, if LD50
sarin-exposed animals were administered the
bronchodilator epinephrine, >90% of the animals survived. Moreover, while both
epinephrine and
oxygen treatments moderated cardiorespiratory parameters, the proinflammatory
cytokine surge, and elevated expression of
hypoxia-induced factor-1α, only
epinephrine consistently reduced the
sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD50
sarin inhalation, and
epinephrine may limit the ventilatory, inflammatory, and lethal effects of
sarin.