Intestinal Radiation-Induced Fibrosis (RIF)

Fibrosis is the presence of excessive collagen in an organ or tissue. In the intestine, it is characterized by the fibrogenic differentiation of resident mesenchymal cells and accumulation of extracellular matrix (ECM).

PATHOLOGY Radiation-induced morphological alterations: Acute Late toxicity Acute sensitivity to radiation may result from a genetic predisposition triggered either by mutation (ATM, Rad21, DNA ligase IV, XRCC1, and NBS gene sequences), and/or single nucleotide polymorphisms (ATM, Rad21, TGFß1, and SOD2 SNPs). Gervaz P et al., Cur Mol Med 2009, 9: 273.

Acute Injury loss of lamina propria lymphocytes acute vasculopathy neutrophils and eosinophils invasion eosinophilic infiltrates extending from the surface to the submucosa have formed, and maximal histological changes are present, with dramatic mucosal ulceration.

the correlation between the severity of early lesions and the probability of developing late complications (?)

Chronic Injury intestinal strictures ulcerations and fistulas number of crypts is reduced a collagenous infiltration in the lamina propria arterioles and venules become narrowed with subintimal fibrosis and fibrinoid necrosis.

The muscularis propria is thickened and dystrophic with infiltration of connective septa. The myenteric plexus is mostly hypertrophied. The subserosa also revealed a severe fibrosis containing newly formed microvessels, myofibroblasts, inflammatory cells, and zones composed of stromal accumulation.

Myenteric plexus Longitudinal muscle Circular muscle Submucosa Submucosal plexus

The muscularis propria is thickened and dystrophic with infiltration of connective septa. The myenteric plexus is mostly hypertrophied. The subserosa also revealed a severe fibrosis containing newly formed microvessels, myofibroblasts, inflammatory cells, and zones composed of stromal accumulation.

PHYSIOPATHOLOGY The traditional target cell model of late radiation adverse effects postulated irreversible and dose- dependent damage to the replicatory capacity of cells, leading to loss of parenchymal cells and vascular endothelium.

It is now recognized that the radiation-induced fibrosis is a dynamic process involving a genetically regulated cytokine response mediated by a wide range of intestinal cells, including inflammatory, vascular, epithelial and other stromal components within the ECM.

Gervaz P et al., Cur Mol Med 2009, 9: 273.

Radiation-induced wound healing signals trigger delayed fibrosis Gervaz P et al., Cur Mol Med 2009, 9: 273.

Major Fibrogenic Cytokines Transforming Growth factor ß1 (TGF-ß1) Connective Tissue Growth factor (CTGF) Platelet-derived Growth factor-BB (PDGF-BB)

Transforming Growth Factor ß1 In the context of fibrosis maintenance, the key aspect of TGF-ß function is related to its self- induction ability. This autoinduction contributes to progression of RIF by persistent ECM production, as well as fibrogenic differentiation of mesenchymal cells.

TGFβbindingRI recruitmentRI phosphorylation and activation ll l P P PP P PP P P PP P P-P Activin TGFβ S2/3 SARA S7 Smurf1/2 R-S S4S6 Smurf1/2 S4 R-S TF S1/5/8 BMPs Flanders KC. Int J Exp Path 2004, 85: 47.

Gervaz P et al., Cur Mol Med 2009, 9: 273.

Haydont V. BrJ Radiol 2007, 80:S32.

Connective Tissue Growth Factor (CTGF) CTGF/ CCN2 (CYR61, CTGF, NOV) –the main downstream mediator of TGF-ß1-induced activation of fibroblasts an essential mediator of fibrosis maintenance N-terminal domain---mediates myofibroblast differentiation and collagen synthesis C-terminal domain mediates fibroblast proliferation

Platelet-Derived Growth Factor-BB (PDGF-BB) a potent mitogen agent that shares biological properties with TGF-ß, or may act in conjunction with it crosstalk between the two growth factors has not been fully investigated and some functional redundancies can be expected

Gervaz P et al., Cur Mol Med 2009, 9: 273.