Skin injuries reduce survival and modulate corticosterone, C-reactive protein, complement component 3, IgM, and prostaglandin E 2 after whole-body reactor-produced mixed field (n + γ-photons) irradiation

Abstract

Skin injuries such as wounds or burns following whole-body γ-irradiation (radiation combined injury (RCI)) increase mortality more than whole-body γ-irradiation alone. Wound-induced decreases in survival after irradiation are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to systemic bacterial infection. Among these factors, radiation-induced increases in interleukin-6 (IL-6) concentrations in serum were amplified by skin wound trauma. Herein, the IL-6-induced stress proteins including C-reactive protein (CRP), complement 3 (C3), immunoglobulin M (IgM), and prostaglandin E2 (PGE2) were evaluated after skin injuries given following a mixed radiation environment that might be found after a nuclear incident. In this report, mice received 3 Gy of reactor-produced mixed field (n + γ-photons) radiations at 0.38 Gy/min followed by nonlethal skin wounding or burning. Both wounds and burns reduced survival and increased CRP, C3, and PGE2 in serum after radiation. Decreased IgM production along with an early rise in corticosterone followed by a subsequent decrease was noted for each RCI situation. These results suggest that RCI-induced alterations of corticosterone, CRP, C3, IgM, and PGE2 cause homeostatic imbalance and may contribute to reduced survival. Agents inhibiting these responses may prove to be therapeutic for RCI and improve related survival.

Figure 1

Survival after radiation combined injury depended on injury type and timing of injury. N = 24 mice per group and per time point. A representative data set is presented here. No SD is included. Similar results were reproducible in other independent experiments. (a) Skin wounding before or after irradiation reduced 30-day survival after irradiation. Wounding after irradiation decreased 30-day survival more than wounding before irradiation. (b) Skin burning after but not before irradiation reduced 30-day survival after irradiation. wnd: wounding; brn: burning; rad: radiation at 3 Gy (n/n + γ = 0.94).

Figure 2

Corticosterone increased then decreased in mouse plasma after irradiation and wounding but not irradiation and burning. N = 3–6 per group at each time point. The control corticosterone concentration was 334 ± 24 ng/mL. (a) Skin wound trauma transiently enhanced the radiation-induced increase in plasma corticosterone concentrations at days 1–5 and then reduced it below the baseline at days 5–9. *P < 0.05; **P < 0.01 versus control group. (b) Skin burn trauma reduced the radiation-induced increase in plasma corticosterone concentrations within 1 d, increased at day 3, reduced again between days 7–9, and returned to the baseline line at day 11. *P < 0.05; **P < 0.01 versus control group. wnd: wounding; brn: burning; rad: radiation at 3 Gy (n/n + γ = 0.94).

Figure 3

Skin injuries altered CRP responses to radiation. N = 3–6 per group and per time point. The control CRP concentration was 4.0 ± 0.1 μg/mL. (a) Skin wound trauma transiently decreased serum CRP concentrations at days 2 and 3, then increased it at days 4–7, reduced to baseline, and rose again at days 16–24. *P < 0.05; **P < 0.01 versus control group. (b) Skin burn trauma increased serum CRP concentrations at days 1, 5, and 20 after irradiation. *P < 0.05; **P < 0.01 versus control group. wnd: wounding; brn: burning; rad: radiation at 3 Gy (n/n + γ = 0.94).

Figure 4

Skin injuries altered C3 responses to radiation.  N = 3–5 per group and per time point. (a) Skin wound trauma enhanced and sustained the radiation-induced increase in serum C3 concentrations. The control C3 concentration was 325 ± 10 μg/mL. *P < 0.05; **P < 0.01; ***P < 0.001 versus control group. (b) Skin burn trauma increased and sustained serum C3 concentrations after irradiation. The control C3 concentration was 310 ± 11 μg/mL. *P < 0.05; **P < 0.01, ***P < 0.001 versus control group. wnd: wounding; brn: burning; rad: radiation at 3 Gy (n/n + γ = 0.94).

Figure 5

Skin injuries enhanced the radiation-induced decrease in IgM concentrations. N = 6 per group and per time point. (a) Skin wound trauma enhanced and sustained the radiation-induced decrease in serum IgM concentrations. *P < 0.05; **P < 0.01; ***P < 0.001 versus control group. (b) Skin burn trauma decreased and sustained serum IgM concentrations after irradiation. *P < 0.05; **P < 0.01, ***P < 0.001 versus control group. wnd: wounding; brn: burning; rad: radiation at 3 Gy (n/n + γ = 0.94).

Figure 6

Skin injuries sustained prostaglandin E₂ response to radiation. N = 2–6 per group and per time point. The control PGE₂ concentration was 15 ± 2 pg/mL. (a) Skin wound trauma sustained the radiation-induced increase in PGE₂ concentrations. *P < 0.05; **P < 0.01 versus control group. (b) Skin burn trauma transiently enhanced serum PGE₂ concentrations after irradiation. *P < 0.05; **P < 0.01 versus control group. wnd: wounding; brn: burning; rad: radiation at 3 Gy (n/n + γ = 0.94).