scholarly journals Cryptotanshinone Ameliorates Radiation-Induced Lung Injury in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yifang Jiang ◽  
Fengming You ◽  
Jie Zhu ◽  
Chuan Zheng ◽  
Ran Yan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Pulmonary Function ◽  
Cardiac Fibrosis ◽  
Pulmonary Inflammation ◽  
Collagen Deposition ◽  
Radiation Induced ◽  
Cox 2 ◽  
Underlying Mechanisms ◽  
Marked Drop

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 α-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-β1 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-β1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.

scholarly journals The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis

2020 ◽  
Author(s):  
Dan JK Yombo ◽  
Nishanth Gupta ◽  
Anil G. Jegga ◽  
Satish K Madala
Keyword(s):  
T Cells ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Gene Networks ◽  
Pulmonary Inflammation ◽  
Collagen Deposition ◽  
Lung Function Decline ◽  
Elevated Expression ◽  
Fibrotic Lung Disease

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Multiple Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 TH2 T cells, but its signaling receptor called IL-31RA has been shown predominately expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including ECM- and epithelial cell-associated gene networks. Furthermore, the lungs of IPF showed an elevated expression of IL-31 when compared to control subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. In summary, therapeutic targeting of the IL-31-IL-31RA axis could be beneficial in pulmonary fibrosis and has translational benefits specifically by preventing collagen deposition and improving lung function.

scholarly journals Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Duncan C. Humphries ◽  
Ross Mills ◽  
Ross Dobie ◽  
Neil C. Henderson ◽  
Tariq Sethi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Respir Crit ◽  
Pulmonary Inflammation ◽  
Myeloid Cell ◽  
Clinical Development ◽  
Galectin 3 ◽  
Direct Targeting

Rationale: Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury.Methods:LgalS3fl/fl mice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yield LysM-cre+/-/LgalS3fl/fl and Pdgfrb-cre+/-/LgalS3fl/fl mice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficient Gal-3−/− mice.Results: Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed in Pdgfrb-cre+/-/LgalS3fl/flmice.Conclusions: Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation.

scholarly journals The relationship between pulmonary function metrics and radiation-induced lung injury

2012 ◽  
Vol 3 (1) ◽  
Author(s):  
Justin M. Linam ◽  
David Madtes ◽  
Laura Chow ◽  
Karen Liu ◽  
Rodney Schmidt ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Function ◽  
Radiation Induced ◽  
The Relationship

scholarly journals Atractylodin Suppresses TGF-β-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

2021 ◽  
Vol 22 (20) ◽  
pp. 11152
Author(s):  
Kai-Wei Chang ◽  
Xiang Zhang ◽  
Shih-Chao Lin ◽  
Yu-Chao Lin ◽  
Chia-Hsiang Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Collagen Deposition ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic change in alveolar epithelial cells and leads to the irreversible deterioration of pulmonary function. Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells contributes to excessive collagen deposition and plays an important role in IPF. Atractylodin (ATL) is a kind of herbal medicine that has been proven to protect intestinal inflammation and attenuate acute lung injury. Our study aimed to determine whether EMT played a crucial role in the pathogenesis of pulmonary fibrosis and whether EMT can be utilized as a therapeutic target by ATL treatment to mitigate IPF. To address this topic, we took two steps to investigate: 1. Utilization of anin vitro EMT model by treating alveolar epithelial cells (A549 cells) with TGF-β1 followed by ATL treatment for elucidating the underlying pathways, including Smad2/3 hyperphosphorylation, mitogen-activated protein kinase (MAPK) pathway overexpression, Snail and Slug upregulation, and loss of E-cadherin. Utilization of an in vivo lung injury model by treating bleomycin on mice followed by ATL treatment to demonstrate the therapeutic effectiveness, such as, less collagen deposition and lower E-cadherin expression. In conclusion, ATL attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in mice.

Relating radiation-induced regional lung injury to changes in pulmonary function tests

2001 ◽  
Vol 51 (2) ◽  
pp. 311-317 ◽  
Author(s):  
Ming Fan ◽  
Lawrence B Marks ◽  
Pehr Lind ◽  
Donna Hollis ◽  
Roxanne T Woel ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Function ◽  
Pulmonary Function Tests ◽  
Function Tests ◽  
Regional Lung ◽  
Radiation Induced

scholarly journals PO-0679: Radiation-induced lung injury (RILI): correlation with dosimetric parameters and pulmonary function

2013 ◽  
Vol 106 ◽  
pp. S261
Author(s):  
G.R. D'Agostino ◽  
F. De Rose ◽  
M. Balducci ◽  
F. Micciché ◽  
A.R. Larici ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Function ◽  
Radiation Induced

scholarly journals The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan J. K. Yombo ◽  
Varshini Odayar ◽  
Nishant Gupta ◽  
Anil G. Jegga ◽  
Satish K. Madala
Keyword(s):  
T Cells ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Gene Networks ◽  
Therapeutic Potential ◽  
Pulmonary Inflammation ◽  
Protective Effects ◽  
Collagen Deposition ◽  
Lung Function Decline

Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.

scholarly journals Murine Radiation-Induced Stomach Pathology from Whole Thoracic Irradiation

2020 ◽  
Author(s):  
Daniel R. McIlrath ◽  
Carlos J. Perez-Torres
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Ex Vivo ◽  
Ct Images ◽  
Common Side Effect ◽  
Lung Pathology ◽  
Breast Cancers ◽  
Radiation Induced ◽  
Stomach Pathology ◽  
Stomach Distention

AbstractPurposeRadiation-induced lung injury is a common side effect in the treatment of lung and breast cancers. There is a large focus in the field on leveraging mouse models of radiation-induced lung injury to find novel treatments for the condition. While attempting to irradiate mouse lungs for purposes of creating a radiation-induced pulmonary fibrosis model, noticeable declines in health were observed at much earlier time points than recorded for lung pathology. This was later attributed to stomach pathology observed in CT images and ex vivo dissection.MethodsFor this study, we used longitudinal microCT to characterize male C57Bl/6 mice irradiated with a single dose of 20 Gy to the whole thoracic area delivered by an X-Rad cabinet irradiator. CT was performed with respiratory gating at 2 to 4 week timepoints to construct a timeline of pathology leading up to fibrosis and quantify severity of fibrosis afterwards. However, a mouse imaged at the 10 week timepoint showed evidence of stomach distention. These mice were sacrificed and their stomachs removed. Histology was performed on the stomachs using H&E staining.ResultsOn the CT images, we observed a large, spherical volume of hypointense signal, caudal to the lungs (Figure 1). This correlated with a distended stomach caused by constipation and gas build-up within the stomach. Statistical analysis showed 81% of mice (n=105) died prematurely after irradiation and before significant development of pulmonary fibrosis. Mice sacrificed and dissected showed unpassed bolus as contents of the stomach, and histology showed cell necrosis of the stomach walls.ConclusionThe histology indicated an inability for food to be digested and moved into the small intestine. This lead to a blockage and ensuing stomach distention. Given the severity of the pathology’s consequences, it lead to the mouse’s imminent mortality inhibiting the efficacy of the study. Future studies need to consider careful placement of shields or any beam contouring devices to ensure protection of the stomach given its higher radiosensitivity in contrast to the lungs.

scholarly journals Expression of Interleukin-17A in Lung Tissues of Irradiated Mice and the Influence of Dexamethasone

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Li-Ping Wang ◽  
Yan-Wen Wang ◽  
Bao-Zhong Wang ◽  
Gui-Ming Sun ◽  
Xiu-Yu Wang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Treated Group ◽  
Protective Role ◽  
Collagen Deposition ◽  
Interleukin 17A ◽  
Radiation Induced

Purpose.To investigate the expressions of IL-17A in different phases of radiation-induced lung injury and the effect of dexamethasone.Methods.The thorax of C57BL/6 mice was irradiated with 15 Gy rays. Mice from dexamethasone-treated group were injected intraperitoneally with dexamethasone (0.42 mg/kg/day) every day for the first month after irradiation. IL-17A in lung tissues was detected by immunohistochemistry. IL-17A, TGF-β1, and IL-6 in bronchoalveolar lavage fluid were detected by ELISA. Lung inflammation and collagen deposition were observed by H&E and Masson methods. The degree of alveolitis and fibrosis was judged according to scoring.Results.IL-17A expression was appreciable at 1 week, peaked at 4 weeks, and subsequently declined at 8 weeks after irradiation. IL-17A was reduced after dexamethasone application at all the observation periods. Dexamethasone also inhibited expressions of TGF-β, IL-6, and TNF-αin bronchoalveolar lavage fluid. Moreover, dexamethasone attenuated the severity of lung injury by reducing the infiltration of inflammatory cells and collagen deposition. Terms of survival and the time of death in mice of treatment group were postponed and survival rate was improved.Conclusions.IL-17A plays an important role in the process of radiation-induced lung injury. And dexamethasone may provide a protective role in lung injury induced by radiation.

scholarly journals Crossed Pathways for Radiation-Induced and Immunotherapy-Related Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Zengfu Zhang ◽  
Jialin Zhou ◽  
Vivek Verma ◽  
Xu Liu ◽  
Meng Wu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathways ◽  
Radiation Pneumonitis ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Normal Lung ◽  
Injury Treatment ◽  
Radiation Induced ◽  
The Common ◽  
Underlying Mechanisms

Radiation-induced lung injury (RILI) is a form of radiation damage to normal lung tissue caused by radiotherapy (RT) for thoracic cancers, which is most commonly comprised of radiation pneumonitis (RP) and radiation pulmonary fibrosis (RPF). Moreover, with the widespread utilization of immunotherapies such as immune checkpoint inhibitors as first- and second-line treatments for various cancers, the incidence of immunotherapy-related lung injury (IRLI), a severe immune-related adverse event (irAE), has rapidly increased. To date, we know relatively little about the underlying mechanisms and signaling pathways of these complications. A better understanding of the signaling pathways may facilitate the prevention of lung injury and exploration of potential therapeutic targets. Therefore, this review provides an overview of the signaling pathways of RILI and IRLI and focuses on their crosstalk in diverse signaling pathways as well as on possible mechanisms of adverse events resulting from combined radiotherapy and immunotherapy. Furthermore, this review proposes potential therapeutic targets and avenues of further research based on signaling pathways. Many new studies on pyroptosis have renewed appreciation for the value and importance of pyroptosis in lung injury. Therefore, the authors posit that pyroptosis may be the common downstream pathway of RILI and IRLI; discussion is also conducted regarding further perspectives on pyroptosis as a crucial signaling pathway in lung injury treatment.

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