Modulation of inflammation by reactive oxygen species: implications for aging and tissue repair

Following tissue injury, adequate inflammatory vascular responses are essential for subsequent tissue repair. The aims of this study were to investigate the role of reactive oxygen species (ROS, generated at the injury site) in modulating the inflammatory response under acute- and chronic-injury conditions. The effect of age and the implications of this modulation for tissue repair was investigated. Using laser Doppler flowmetry, inflammatory vascular responses were monitored in the base of vacuum-induced blisters in the hind footpad of anesthetized rats (65 mg/kg Nembutal). Inflammation was amplified by superfusion of substance P (SP) over the blister base. The inflammatory response was examined in acute blisters induced on either naïve skin (acute-injury model) or on skin innervated by a chronically injured nerve (chronic-injury model). Furthermore, the acute-injury model was examined during early and late phases, 0 and 5 h after blister induction, respectively. The involvement of ROS was assessed by either combined superfusion of the antioxidants: superoxide dismutase and catalase over the blister base in acute-injury, or intramuscular injection of tirilazad in chronically injured rats. The results showed that antioxidant treatment had no effect on the response during early and late phases of acute inflammation in young rats. However in old rats, the vascular response was significantly attenuated (60%) or significantly increased (40%) during the early and late phases of acute inflammation, respectively. Under chronic-injury conditions, antioxidant treatment significantly enhanced the response in both young and old rats. We then examined the effect of antioxidant, tirilazad, on the healing of a full thickness thermal injury induced in the intrascapular region (using a CO₂ laser) of the rat. Following burn injury, tirilazad was injected around the wound site starting on day 1 (early treatment) or day 6 (late treatment). Tirilazad had opposing actions on wound closure with early and late treatments delaying (24.6 ± 0.6 d) or accelerating (14.2 ± 0.3 d) wound closure compared with the group of aged controls (20.3 ± 0.8 d). The results suggest that ROS have a paradoxical role exerting either a positive or negative effect on the inflammatory response with age. We contend that the role of ROS in modulating inflammation should be considered when designing treatment protocols to accelerate tissue repair.