Abstract:These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases.
“…The data clearly indicate the presence of EMTs occurring 250 days after irradiation, with greater frequency in the Nrf2 null mouse. These data are consistent with the knowledge that radiation-induced epithelial injury results in chronic overexpression of TGF-β [54] and connective tissue growth factor (CTFG) [55], two cytokines that have major roles in myofibroblast formation. Furthermore it is known that the expression of these cytokines is enhanced in the Nrf2 null mouse following injury [16, 56] and thus may account for the increase in EMT events and the concomitant loss of type 2 cells observed in this genotype.…”
The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Δ/Δ; SPC-Cre) were administered a thoracic dose of 12 Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson’s trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung’s capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis.
“…The data clearly indicate the presence of EMTs occurring 250 days after irradiation, with greater frequency in the Nrf2 null mouse. These data are consistent with the knowledge that radiation-induced epithelial injury results in chronic overexpression of TGF-β [54] and connective tissue growth factor (CTFG) [55], two cytokines that have major roles in myofibroblast formation. Furthermore it is known that the expression of these cytokines is enhanced in the Nrf2 null mouse following injury [16, 56] and thus may account for the increase in EMT events and the concomitant loss of type 2 cells observed in this genotype.…”
The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Δ/Δ; SPC-Cre) were administered a thoracic dose of 12 Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson’s trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced ΔNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung’s capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits ΔNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis.
“…Chemotherapy and radiation induced lung fibrosis models are frequently utilized for preclinical evaluation of novel biomarker and candidate modulators of the fibrosis process . However, the settings are often artificial, e.g., fibrosis develops after a very short latency period of days post intratracheal installation, or mice are often irradiated with a single high lethal dose thoracic irradiation.…”
Pulmonary fibrosis represents a leading cause of morbidity and mortality worldwide. Therapy induced lung fibrosis constitutes a pivotal dose‐limiting side effect of radiotherapy and other anticancer agents. We aimed to develop objective criteria for assessment of fibrosis and discover pathophysiological and molecular correlates of lung fibrosis as a function of fractionated whole thoracic irradiation. Dose–response series of fractionated irradiation was utilized to develop a non‐invasive and quantitative measure for the degree of fibrosis – the fibrosis index (FI). The correlation of FI with histopathology, blood‐gas, transcriptome and proteome responses of the lung tissue was analyzed. Macrophages infiltration and polarization was assessed by immunohistochemistry. Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24‐week post radiation insult. FI favorably correlated with radiation dose and surrogates of lung fibrosis i.e., enhanced pro‐inflammatory response, tissue remodeling and extracellular matrix deposition. The loss of lung architecture correlated with decreased epithelial marker, loss of microvascular integrity with decreased endothelial and elevated mesenchymal markers. Lung fibrosis was further attributed to a switch of the inflammatory state toward a macrophage/T‐helper cell type 2‐like (M2/Th2) polarized phenotype. Together, the multiscale characterization of FI in radiation‐induced lung fibrosis (RILF) model identified pathophysiological, transcriptional and proteomic correlates of fibrosis. Pathological immune response and endothelial/epithelial to mesenchymal transition were discovered as critical events governing lung tissue remodeling. FI will be instrumental for deciphering the molecular mechanisms governing lung fibrosis and discovery of novel targets for treatment of this devastating disease with an unmet medical need.
“…We (and other colleagues) have recently shown a key role for macrophages in radiation-induced lung fibrosis. 7,8 One of the important questions that was asked and that persists is whether the acute inflammation is at the origin of the late chronic inflammation/tissue injury. Interestingly, the late inflammation/injury arises after a latent period during which nothing occurs at the clinical level suggesting that this period is more infraclinical rather than an inert phase.10.1080/2162402X.2018.1494488-F0001Figure 1.Dynamic changes in myeloid cells in the lung after IR.…”
Section: Immune Response To Radiotherapy and Lung Radiation Injurymentioning
confidence: 99%
“…4 Accordingly, recent studies have confirmed earlier data reporting macrophage infiltration within the site of the radiation-induced toxicity in the heart 26 and in the lung. 7,8 Scientists have long wondered whether the recruitment of macrophages is the cause or the consequence of the development of the RIF. The Huber group showed that CTGF inhibitor protects against radiation-induced fibrogenesis via normalization of the expression of genes that is associated with anti-inflammatory macrophage influx.…”
Section: Macrophages Involvement In Radiation-induced Injurymentioning
confidence: 99%
“…The Huber group showed that CTGF inhibitor protects against radiation-induced fibrogenesis via normalization of the expression of genes that is associated with anti-inflammatory macrophage influx. 7 We recently showed that radiation-induced fibrosis is associated with a large increase in Arg1 mRNA (an anti-inflammatory marker) in IMs with an increase in membrane expression of CD206 suggesting that IMs adopt an anti-inflammatory profile during radiation-induced lung toxicity. 8 It seems that anti-inflammatory macrophages are more radio-resistant than proinflammatory macrophages.…”
Section: Macrophages Involvement In Radiation-induced Injurymentioning
Radiotherapy can induce toxicity in healthy tissues such as radiation-induced fibrosis (RIF), and macrophages are proposed as new profibrogenic cells. In this Point-of-View, we summarize the role of the immune response in ionizing radiation injury, and we focus on macrophages as a new therapeutic target in RIF.
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