More than 20,000
burn injury victims suffer from
smoke inhalation injury in the United States annually. In an ovine model of
acute lung injury, γ-
tocopherol had a beneficial effect when nebulized into the airway. We hypothesize that γ-
tocopherol scavenges
reactive oxygen species (ROS) and
reactive nitrogen species resulting from
burn and
smoke inhalation injury and that these ROS/
reactive nitrogen species activate the
arginase pathway, leading to increased
collagen deposition and decreased pulmonary function. To test this hypothesis, ewes were operatively prepared for chronic study, then they were randomly divided into groups (n = 8): uninjured, injured, or injured with nebulization (γ-
tocopherol [950 mg/g] and α-
tocopherol [40 mg/g] from hours 3 to 48 after the injury). The injury, under deep
anesthesia, consisted of a 20% total body surface
burn and 36 breaths of cotton
smoke; all animals were killed after 3 weeks. Treatment increased lung γ-
tocopherol at 3 weeks after γ-
tocopherol nebulization compared with injured sheep (1.75 ± 0.62 nmol/g vs. 0.45 ± 0.06, P < 0.05). The expression of
dimethylarginine dimethylaminohydrolase-2, which degrades asymmetrical
dimethylarginine, a
nitric oxide synthase inhibitor, significantly increases with γ-
tocopherol treatment compared with injured sheep (P < 0.05).
Arginase activity (0.15 ± 0.02 μM
urea/μg
protein vs. 0.24 ± 0.009, P < 0.05),
ornithine aminotransferase (11,720 ± 888 vs. 13,170 ± 1,775), and
collagen deposition (0.62 ± 0.12 μM
hydroxyproline/μg
protein vs. 1.02 ± 0.13, P < 0.05) significantly decrease with γ-
tocopherol compared with injured animals without γ-
tocopherol. The decreases in
arginase and
collagen with γ-
tocopherol are associated with significantly increased diffusion capacity (P < 0.05) and decreased
lung wet-to-dry ratio (P < 0.05).
Smoke-induced chronic pulmonary dysfunction is mediated through the ROS/asymmetrical
dimethylarginine/
arginase pathway, and ROS scavengers such as γ-
tocopherol may be a potential therapeutic management of
burn patients with inhalation injury.