Abstract
Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-β1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Rα2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Rα2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics.
Highlights
(0 Gy). (a) Hematoxylin and Eosin (H&E) staining and Masson Trichrome staining of lung demonstrates fibrotic foci
We evaluated the progression of radiation-induced pulmonary fibrosis in wild-type and IL-13-deficient mice, and characterized the inflammatory milieu in irradiated lung tissue, demonstrating that this cytokine is essential to the development of pulmonary fibrosis
Assessment of the cellular composition of Bronchoalveolar lavage (BAL) fluid at 16 weeks after irradiation revealed that accumulation of macrophages is largely responsible for the increase in BAL cellularity (Fig. 1c,d)
Summary
(0 Gy). (a) Hematoxylin and Eosin (H&E) staining (top panels) and Masson Trichrome staining (bottom panels, collagen: light blue, epithelia: red, nuclei: dark blue) of lung demonstrates fibrotic foci. (d) Representative image of stained macrophages isolated from BAL fluid (upper panel). We examined the role of type 2 cytokines, IL-13, as mediators of fibrotic progression following radiation-induced lung injury. We evaluated the progression of radiation-induced pulmonary fibrosis in wild-type and IL-13-deficient mice, and characterized the inflammatory milieu in irradiated lung tissue, demonstrating that this cytokine is essential to the development of pulmonary fibrosis. We discovered that the circulating level of IL-13 exceeded the inhibitory capacity of the soluble endogenous decoy receptor, IL-13Rα2 in irradiated mice, immediately prior to fibrotic progression. Using this information, we demonstrated that administration of an IL-13 neutralizing antibody can interrupt fibrotic progression following radiation injury. Our findings provide evidence that IL-13 is a critical mediator of radiation lung injury, and may be a candidate biomarker and target for therapeutic intervention
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