title: Blood and bronchoalveolar lavage fluid acetylcholinesterase levels following microinstillation inhalation exposure to sarin in Guinea pigs.
abstract: We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m(3)) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt(50) for sarin using the microinstillation technique was determined to be close to 677.4 mg/m(3). Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m(3) sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m(3) sarin exposure but a marginal inhibition at 169.3 mg/m(3). In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m(3) in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m(3) and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.
authors.affiliation: Division of Biochemistry, Department of Biochemical Pharmacology, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Magnus M
authors.initials: MM
authors.lastname: Che
authors.forename: Michele
authors.initials: M
authors.lastname: Conti
authors.forename: Megan
authors.initials: M
authors.lastname: Boylan
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Sciuto
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gordon
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood*; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000097:blood*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008136:Longevity / Q000187:drug effects; D008168:Lung / Q000187:drug effects*; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D012524:Sarin / Q000633:toxicity*
chemical_list: D000336:Aerosols; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase