Promising Biomarkers of Radiation-Induced Lung Injury: A Review.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC8470495 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Radiation pneumonitis (RP) and radiation fibrosis (RF) are two dose-limiting toxicities of radiotherapy (RT), especially for lung, and esophageal cancer. It occurs in 5-20% of patients and limits the maximum dose that can be delivered, reducing tumor control probability (TCP) and may lead to dyspnea, lung fibrosis, and impaired quality of life. Both physical and biological factors determine the normal tissue complication probability (NTCP) by Radiotherapy. A better understanding of the pathophysiological sequence of radiation-induced lung injury (RILI) and the intrinsic, environmental and treatment-related factors may aid in the prevention, and better management of radiation-induced lung damage. In this review, we summarize our current understanding of the pathological and molecular consequences of lung exposure to ionizing radiation, and pharmaceutical interventions that may be beneficial in the prevention or curtailment of RILI, and therefore enable a more durable therapeutic tumor response.
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Project description:In 2018, lung cancer was the most common cancer and the most common cause of cancer death, accounting for a 1.76 million deaths. Radiotherapy (RT) is a widely used and effective non-surgical cancer treatment that induces remission in, and even cures, patients with lung cancer. However, RT faces some restrictions linked to the radioresistance and treatment toxicity, manifesting in radiation-induced lung injury (RILI). About 30-40% of lung cancer patients will develop RILI, which next to the local recurrence and distant metastasis is a substantial challenge to the successful management of lung cancer treatment. These data indicate an urgent need of looking for novel, precise biomarkers of individual response and risk of side effects in the course of RT. The aim of this review was to summarize both preclinical and clinical approaches in RILI monitoring that could be brought into clinical practice. Next to transforming growth factor-?1 (TGF?1) that was reported as one of the most important growth factors expressed in the tissues after ionizing radiation (IR), there is a group of novel, potential biomarkers-microRNAs-that may be used as predictive biomarkers in therapy response and disease prognosis.
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Project description:PURPOSE:Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. METHODS:High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. RESULTS:A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. CONCLUSIONS:These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.
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Project description:Chemo-radiotherapy and systemic therapies have proven satisfactory outcomes as standard treatments for various thoracic malignancies; however, adverse pulmonary effects, like pneumonitis, can be life-threatening. Pneumonitis is caused by direct cytotoxic effect, oxidative stress, and immune-mediated injury. Radiotherapy Induced Lung Injury (RILI) encompasses two phases: an early phase known as Radiation Pneumonitis (RP), characterized by acute lung tissue inflammation as a result of exposure to radiation; and a late phase called Radiation Fibrosis (RF), a clinical syndrome that results from chronic pulmonary tissue damage. Currently, diagnoses are made by exclusion using clinical assessment and radiological findings. Pulmonary function tests have constituted a significant step in evaluating lung function status during radiotherapy and useful predictive tools to avoid complications or limit toxicity. Systemic corticosteroids are widely used to treat pneumonitis complications, but its use must be standardized, and consider in the prophylaxis setting given the fatal outcome of this adverse event. This review aims to discuss the clinicopathological features of pneumonitis and provide practical clinical recommendations for prevention, diagnosis, and management.
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Project description:BackgroundVentilator-induced lung injury (VILI) can occur as a result of mechanical ventilation to two lungs. Thoracic surgery often requires one-lung ventilation (OLV). The potential for VILI is likely higher in OLV. The impact of OLV on development of post-operative pulmonary complications is not well understood. We aimed to perform a scoping review to determine reliable biomarkers of VILI after OLV.MethodsA scoping review was performed using Cochrane Collaboration methodology. We searched Medline, EMBASE and SCOPUS. Gray literature was searched. Studies of adult human or animal models without pre-existing lung damage exposed to OLV, with biomarker responses analyzed were included.ResultsAfter screening 5,613 eligible papers, 89 papers were chosen for full text review, with 29 meeting inclusion. Approximately half (52%, n=15) of studies were conducted in humans in an intra-operative setting. Bronchoalveolar lavage (BAL) & serum analyses with enzyme-linked immunosorbent assay (ELISA)-based assays were most commonly used. The majority of analytes were investigated by a single study. Of the analytes that were investigated by two or more studies (n=31), only 16 were concordant in their findings. Across all sample types and studies 84% (n=66) of the 79 inflammatory markers and 75% (n=6) of the 8 anti-inflammatory markers tested were found to increase. Half (48%) of all studies showed an increase in TNF-α or IL-6.ConclusionsA scoping review of the state of the evidence demonstrated that candidate biomarkers with the most evidence and greatest reliability are general markers of inflammation, such as IL-6 and TNF-α assessed using ELISA assays. Studies were limited in the number of biomarkers measured concurrently, sample size, and studies using human participants. In conclusion these identified markers can potentially serve as outcome measures for studies on OLV.
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Project description:Currently, there are no biomarkers to predict lethal lung injury by radiation. Since it is not ethical to irradiate humans, animal models must be used to identify biomarkers. Injury to the female WAG/RijCmcr rat has been well-characterized after exposure to eight doses of whole thorax irradiation: 0-, 5-, 10-, 11-, 12-, 13-, 14- and 15-Gy. End points such as SPECT imaging of the lung using molecular probes, measurement of circulating blood cells and specific miRNA have been shown to change after radiation. Our goal was to use these changes to predict lethal lung injury in the rat model, 2 weeks post-irradiation, before any symptoms manifest and after which a countermeasure can be given to enhance survival. SPECT imaging with 99mTc-MAA identified a decrease in perfusion in the lung after irradiation. A decrease in circulating white blood cells and an increase in five specific miRNAs in whole blood were also tested. Univariate analyses were then conducted on the combined dataset. The results indicated that a combination of percent change in lymphocytes and monocytes, as well as pulmonary perfusion volume could predict survival from radiation to the lungs with 88.5% accuracy (95% confidence intervals of 77.8, 95.3) with a p-value of < 0.0001 versus no information rate. This study is one of the first to report a set of minimally invasive endpoints to predict lethal radiation injury in female rats. Lung-specific injury can be visualized by 99mTc-MAA as early as 2 weeks after radiation.
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Project description:For drug-induced interstitial lung disease (DIILD) translational imaging biomarkers are needed to improve detection and management of lung injury and drug-toxicity. Literature was reviewed on animal models in which in vivo imaging was used to detect and assess lung lesions that resembled pathological changes found in DIILD, such as inflammation and fibrosis. A systematic search was carried out using three databases with key words "Animal models", "Imaging", "Lung disease", and "Drugs". A total of 5749 articles were found, and, based on inclusion criteria, 284 papers were selected for final data extraction, resulting in 182 out of the 284 papers, based on eligibility. Twelve different animal species occurred and nine various imaging modalities were used, with two-thirds of the studies being longitudinal. The inducing agents and exposure (dose and duration) differed from non-physiological to clinically relevant doses. The majority of studies reported other biomarkers and/or histological confirmation of the imaging results. Summary of radiotracers and examples of imaging biomarkers were summarized, and the types of animal models and the most used imaging modalities and applications are discussed in this review. Pathologies resembling DIILD, such as inflammation and fibrosis, were described in many papers, but only a few explicitly addressed drug-induced toxicity experiments.
| S-EPMC7795017 | biostudies-literature
Project description:Cryptotanshinone (CTS) was reported to repress a variety of systemic inflammation and alleviate cardiac fibrosis, but it is still unclear whether CTS could prevent radiation-induced lung injury (RILI). Here, we investigated the effects and underlying mechanisms of CTS on a RILI rat model. Our data revealed that CTS could efficiently preserve pulmonary function in RILI rats and reduce early pulmonary inflammation infiltration elicited, along with marked decreased levels of IL-6 and IL-10. Moreover, we found that CTS is superior to prednisone in attenuating collagen deposition and pulmonary fibrosis, in parallel with a marked drop of HYP (a collagen indicator) and ?-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-?1 and NOX-4 expressions, while enhancing the levels of antifibrotic enzyme MMP-1 in lung tissues. It is noteworthy that CTS treatment, in consistent with trichrome staining analysis, exhibited a clear advantage over PND in enhancing MMP-1 levels. However, CTS exhibited little effect on CTGF activation and on COX-2 suppression. Finally, CTS treatment significantly mitigated the radiation-induced activation of CCL3 and its receptor CCR1. In summary, CTS treatment could attenuate RILI, especially pulmonary fibrosis, in rats. The regulation on production and release of inflammatory or fibrotic factors IL-6, IL-10, TGF-?1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.
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Project description:Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-?, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-?1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.
| S-EPMC4482753 | biostudies-literature
Project description:Background. Radiation induced lung injury (RILI) is one of the most common and severe side effects of thoracic radiotherapy. In this meta-analysis, the effects of Chinese herbal extractions (CHE) for preventing and treating RILI are evaluated. Methods. Randomized Controlled Trials (RCTs) from five databases were identified. Studies were evaluated and the relevant data were extracted by two authors independently. Differences were resolved by a third party. Meta-analysis was conducted using RevMan 5.0. Results. In total, 2734 participants receiving thoracic radiotherapy were included in 28 RCTs, and 16 CHE were evaluated. Meta-analysis showed that CHE intervention significantly reduced the incidence of acute radiation pneumonitis (RP) and radiation induced pulmonary fibrosis (RIPF). In CHE group, total effective rate and remission rate of RILI patients were significantly higher. Patient's quality of life (Qol) and clinical symptoms and signs were improved significantly. Inflammatory cytokines decreased, and thymus dependent lymphocytes subgroups were improved. Conclusion. CHE intervention may have clinical effectiveness for relieving RILI and related symptoms and signs and lead to improvement of Qol. However, more double-blind, multicenter, large-scale RCTs are needed to support this theory. Trial Registration. PROSPERO International prospective register of systematic reviews has registration number CRD42016043538.
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