Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy

AIM: To determine the mechanistic role of fibrinogen, a key regulator of inflammation and fibrosis, in early and delayed radiation enteropathy. METHODS: Fibrinogen wild-type (Fib(+/+)), fibrinogen heterozygous (Fib(+/-)), and fibrinogen knockout (Fib(-/-)) mice were exposed to localized intestinal irradiation and assessed for early and delayed structural changes in the intestinal tissue. A 5-cm segment of ileum of mice was exteriorized and exposed to 18.5 Gy of x-irradiation. Intestinal tissue injury was assessed by quantitative histology, morphometry, and immunohistochemistry at 2 wk and 26 wk after radiation. Plasma fibrinogen level was measured by enzyme-linked immunosorbent assay. RESULTS: There was no difference between sham-irradiated Fib(+/+) and Fib(+/-) mice in terms of fibrinogen concentration in plasma and intestinal tissue, intestinal histology, morphometry, intestinal smooth muscle cell proliferation, and neutrophil infiltration. Therefore, Fib(+/-) mice were used as littermate controls. Unlike sham-irradiated Fib(+/+) and Fib(+/-) mice, no fibrinogen was detected in the plasma and intestinal tissue of sham-irradiated Fib(-/-) mice. Moreover, fibrinogen level was not elevated after irradiation in the intestinal tissue of Fib(-/-) mice, while significant increase in intestinal fibrinogen level was noticed in irradiated Fib(+/+) and Fib(+/-) mice. Importantly, irradiated Fib(-/-) mice exhibited substantially less overall intestinal structural injury (RIS, P = 0.000002), intestinal wall thickness (P = 0.003), intestinal serosal thickness (P = 0.009), collagen deposition (P = 0.01), TGF-β immunoreactivity (P = 0.03), intestinal smooth muscle proliferation (P = 0.046), neutrophil infiltration (P = 0.01), and intestinal mucosal injury (P = 0.0003), compared to irradiated Fib(+/+) and Fib(+/-) mice at both 2 wk and 26 wk. CONCLUSION: These data demonstrate that fibrinogen deficiency directly attenuates development of early and delayed radiation enteropathy. Fibrinogen could be a novel target in treating intestinal damage.