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Radiation induced lung fibrosis (RILF) is a common late complication after radiotherapy without effective treatment. Thyroid hormone (TH) is known to reverse bleomycin-induced pulmonary fibrosis in recent study. We therefore sought to examine TH effect in RILF. Aerosolized TH delivery prevented pulmonary fibrosis according to either micro-computed tomography scans or histological evaluations, without significant changes in serum THs in a murine model of RILF by attenuating TGF-β1 and phosphorylated Smad2/3 expressions and reducing the accumulation of M2-like macrophages. Furthermore, hypothyroidism was significantly correlated with RILF in a retrospectively analyzed data from nasopharyngeal carcinoma patients treated by intensity-modulated radiation therapy with a median follow-up time of 25.5 months. Together, aerosolized TH may prevent RILF by inhibiting the TGF-β1/SMADs signaling pathway.

Background: Brain metastasis incidence in non-small cell lung cancer (NSCLC) patients is high; however, identifying patients that are most likely to develop brain metastases is difficult. The interleukin 6 (IL6)/interleukin 6 receptor (IL6R)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway contributes to lung cancer pathogenesis. Methods: We investigated whether the genetic variants of this pathway are useful for predicting brain metastases in non-small cell lung cancer (NSCLC). Thirty-eight single nucleotide polymorphisms (SNPs) in six core genes (IL6, IL6R, JAK1, JAK2, STAT1, and STAT3) were tested for potential associations with brain metastasis. Multivariate Cox regression analysis was used to analyse correlations between genotype variants and brain metastasis. Kaplan–Meier analysis was performed to evaluate cumulative hazard of brain metastasis. Bioinformatics tools were applied to assess the functional relevance of genetic variants. Findings: The GT/TT genotype of IL6R rs4845618 and the GA/AA genotype of JAK2 rs10815144 were associated with a higher risk of brain metastasis, after correcting for clinicopathologic variables (hazard ratio [HR], 7.888, 95% confidence interval [CI], 1.973–31.536, P = 0.003; HR, 4.378; 95% CI, 1.144–16.747; P = 0.031, respectively). These two SNPs had a cumulative effect on brain metastasis risk, and patients carrying both genotypes had a higher risk of brain metastasis. These two SNPs also affected the mRNA expression of genes. Interpretation: IL6R rs4845618 and JAK2 rs10815144 were associated with the risk of brain metastasis in NSCLC patients and may potentially be used as biomarkers of brain metastasis. Funding: This work was supported by the National Natural Science Foundation of China (Grant no. 81773360). Conflict of Interest: The authors declare no competing interests. Ethical Approval: The study was approved by the Ethics Committee of Tongji Medical College (IRBID: TJ-C20121219). All patients signed an informed consent form before the interview.

Radiation pneumonitis is a common complication of thoracic irradiation for lung cancer patients. The healthy gut microbiota plays an important role in the local mucosal defense process as well as pulmonary immunomodulation of the host. However, the effect of the intestinal microbiota on radiation pneumonitis is not well understood. Here we studied how the intestinal microbiota affected the host response to radiation pneumonitis. C57BL/6 mice were administered antibiotics to induce disequilibrium in the gut microbiota, and subsequently irradiated. We found that the intestinal microbiota served as a protective mediator against radiation pneumonitis, as indicated by decreased body weight and increased mortality in antibiotic-treated mice. In mice with gut microbiota disequilibrium, more serious pathological lung damage was observed at two and four weeks postirradiation. Fecal microbiota transplantation into irradiated mice led to improvement from radiation-induced inflammation two weeks postirradiation. High-throughput sequencing of murine feces displayed conversion of flora diversity, bacterial composition and community structure in the absence of normal intestinal flora. We filtered the potentially important species among the gut microbiota and considered that the tissue-type plasminogen activator might be involved in the inflammatory process. This study reveals that the gut microbiota functions as a protective regulator against radiation pneumonitis. Additionally, fecal microbiota transplantation was shown to alleviate lung injury in the irradiated model. The protective role of the healthy gut microbiota and the utilization of the gut-lung axis show potential for innovative therapeutic strategies in radiation-induced lung injury.

Radiation-induced complications of the respiratory system are a common side effect of thoracic radiotherapy with no viable treatment option. Here, we investigated the potential therapeutic effect of the orphan drug pirfenidone for treating radiation-induced pulmonary fibrosis. C57BL/6 mice received a single fraction of 16 Gy to the thorax and were subsequently treated with 300 mg/kg/day pirfenidone for four weeks. Survival and body weight of the mice were quantified. Micro-CT in vivo lung imaging was performed to dynamically observe the developmental process of pulmonary fibrosis. The lungs were excised at the end of the experiment and evaluated for histological changes. Compared to the irradiated mice that received no pirfenidone, mice treated with pirfenidone after irradiation had an extended median survival time (>140 days vs. 73 days, P < 0.01). The accumulation of collagen and fibrosis in lung tissues after irradiation was decreased with pirfenidone treatment. Pirfenidone also reduced the expression of TGF-β1 and phosphorylation of Smad3 in lung tissues. The dose level of Pirfenidone used in this study attenuated pulmonary fibrosis and prolonged the life span of irradiated mice. It may offer a promising approach to treat or minimize radiation-induced pulmonary fibrosis.