Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy

Abstract

AIMTo determine the mechanistic role of fibrinogen, a key regulator of inflammation and fibrosis, in early and delayed radiation enteropathy.METHODSFibrinogen 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.RESULTSThere 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.CONCLUSIONThese data demonstrate that fibrinogen deficiency directly attenuates development of early and delayed radiation enteropathy. Fibrinogen could be a novel target in treating intestinal damage.

Biomarkers of radiation‐induced vascular injury

“…Fibrinogen deficiency suppresses the development of early and delayed radiation-induced enteropathy, characteristically mediated by endothelial injury, suggesting a role for fibrinogen in mediation of endothelial injury. 35,36 Oxidized low-density lipoprotein (ox-LDL) augments radiation-induced phenotypic changes like upregulation of alpha-smooth muscle actin (α-SMA), fibroblast-specific protein-1 (FSP-1), and vimentin. This transition to mesenchymal phenotype favors acceleration of atherosclerosis.…”

“…Fibrinogen acts as an acute indicator of radiation‐induced activation of the coagulation cascade. Fibrinogen deficiency suppresses the development of early and delayed radiation‐induced enteropathy, characteristically mediated by endothelial injury, suggesting a role for fibrinogen in mediation of endothelial injury . Oxidized low‐density lipoprotein (ox‐LDL) augments radiation‐induced phenotypic changes like upregulation of alpha‐smooth muscle actin (α‐SMA), fibroblast‐specific protein‐1 (FSP‐1), and vimentin.…”

Fibrinogen, a Promising Marker to Evaluate Severity and Prognosis of Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Retrospective Observational Study.

“…COPD is associated with chronic in ammation both locally and systemically, which increases further during acute exacerbations (2). It has been known that the levels of some in ammatory biomarkers are associated with acute exacerbation (3), disease progression and severity of air ow obstruction (4)(5)(6)(7). The identi cation of these biomarkers not only provided a method to predict prognosis but also shed light upon a better understanding of the pathogenesis of COPD.…”

Fibrinogen is a promising biomarker for chronic obstructive pulmonary disease: evidence from a meta-analysis

“…Much attention has been focused on the potential implication of circulating inflammatory biomarkers in the development of COPD. One of the most widely evaluated inflammatory biomarkers is fibrinogen, a key modulator of inflammation and fibrosis development, as well as tissue injury [ 7 ]. The association between circulating fibrinogen and COPD risk has been investigated by a large number of studies, with inconsistent and inconclusive findings.…”