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Transforming growth factor alpha is a critical mediator of radiation lung injury.

ABSTRACT: Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-?, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-?(-/-)) and control C57Bl/6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ? 5 per group) and tissue collection (n = 3 per strain and time point). Collagen accumulation in irradiated lungs was assessed by Masson's trichrome staining and analysis of hydroxyproline content. Cytokine levels in lung tissue were assessed with ELISA. The effects of TGF-? on pneumocyte and fibroblast proliferation and collagen production were analyzed in vitro. Lysyl oxidase (LOX) expression and activity were measured in vitro and in vivo. Irradiated C57-WT mice had a median survival of 24.4 weeks compared to 48.2 weeks for irradiated TGF-?(-/-) mice (P = 0.001). At 20 weeks after irradiation, hydroxyproline content was markedly increased in C57-WT mice exposed to radiation compared to TGF-?(-/-) mice exposed to radiation or unirradiated C57-WT mice (63.0, 30.5 and 37.6 ?g/lung, respectively, P = 0.01). C57-WT mice exposed to radiation had dense foci of subpleural fibrosis at 20 weeks after exposure, whereas the lungs of irradiated TGF-? (-/-) mice were largely devoid of fibrotic foci. Lung tissue concentrations of IL-1?, IL-4, TNF-?, TGF-? and EGF at multiple time points after irradiation were similar in C57-WT and TGF-?(-/-) mice. TGF-? in lung tissue of C57-WT mice rose rapidly after irradiation and remained elevated through 20 weeks. TGF-?(-/-) mice had lower basal LOX expression than C57-WT mice. Both LOX expression and LOX activity were increased after irradiation in all mice but to a lesser degree in TGF-?(-/-) mice. Treatment of NIH-3T3 fibroblasts with TGF-? resulted in increases in proliferation, collagen production and LOX activity. These studies identify TGF-? as a critical mediator of radiation-induced lung injury and a novel therapeutic target in this setting. Further, these data implicate TGF-? as a mediator of collagen maturation through a TGF-? independent activation of lysyl oxidase.

SUBMITTER: Chung EJ

PROVIDER: S-EPMC4169125 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Transforming growth factor alpha is a critical mediator of radiation lung injury.

Chung Eun Joo EJ Hudak Kathryn K Horton Jason A JA White Ayla A Scroggins Bradley T BT Vaswani Shiva S Citrin Deborah D

Radiation research 20140812 3

Radiation fibrosis of the lung is a late toxicity of thoracic irradiation. Epidermal growth factor (EGF) signaling has previously been implicated in radiation lung injury. We hypothesized that TGF-α, an EGF receptor ligand, plays a key role in radiation-induced fibrosis in lung. Mice deficient in transforming growth factor (TGF-α(-/-)) and control C57Bl/6J (C57-WT) mice were exposed to thoracic irradiation in 5 daily fractions of 6 Gy. Cohorts of mice were followed for survival (n ≥ 5 per group) ...[more]

PMID: 25117621

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Project description:IntroductionThe objective of this study was to model the effects of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF), both present in rheumatoid arthritis (RA) synovia, on the behavior of fibroblast-like synoviocytes (FLS) in response to pro-inflammatory cytokine (interleukin (IL)1beta, tumor necrosis factor-alpha (TNFalpha)) challenge.MethodsGene and protein expression by fibroblast-like synoviocytes in vitro was studied by quantitative Polymerase Chain Reaction (qPCR), ELISA and multiplex bead cytokine assays. Intracellular signaling pathway activation was determined by Western blot for phospho-kinases and the use of specific inhibitors.ResultsIn combination, TGF-beta and PDGF (2GF) synergistically augmented TNFalpha- or IL1beta-induced matrix metalloproteinase 3 (MMP3), IL6, IL8, and macrophage inflammatory protein 1 alpha (MIP1alpha) secretion by FLS. Other FLS-derived mediators remained unaffected. Individually, neither growth factor significantly potentiated TNFalpha or IL1beta-induced MMP3 secretion, and only slightly enhanced IL6. The effect of 2GF on TNFalpha-induced gene expression was transcriptionally mediated; blocked by imatinib mesylate; and occurred even if 2GF was added as much as four hours prior to TNFalpha. In addition, a 15-minute pulse of 2GF four hours prior to TNFalpha stimulation yielded a synergistic response. The extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling pathways were induced for at least four hours by 2GF, as demonstrated by persistently upregulated levels of phospho-Akt and phospho-ERK. However, pharmacologic inhibitor studies demonstrated that the potentiating action of 2GF was dependent on PI3 kinase only, and not on ERK.ConclusionsThe combination of PDGF and TGF-beta dramatically potentiates FLS response to cytokines in a receptor-mediated and PI3 kinase-dependent fashion. These data suggest that 2GF contribute to synovitis by directing synovial fibroblasts toward a more aggressive phenotype in response to TNFalpha. Therefore, inhibition of growth factor signaling may constitute a complementary therapeutic approach to cytokine-targeted treatments for RA.

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Transforming growth factor alpha is a critical mediator of radiation lung injury.

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Transforming growth factor alpha is a critical mediator of radiation lung injury.

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