Abstract
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.
Highlights
Radiation-induced lung injury (RILI) is a common and fetal complication of thoracic radiotherapy
We observed the impacts of CTS on the body weight, which serve as an important indicator of the general health condition, in RILI rats
Model RILI rats had marked lower tidal volumes and maximum voluntary ventilation, as well as higher respiratory rates after 3-month radiation, which suggest a decline of pulmonary function seen in RILI rats
Summary
Radiation-induced lung injury (RILI) is a common and fetal complication of thoracic radiotherapy. RILI develops in almost ∼5% to 20% lung cancer patients receiving radiotherapy [1] and generally leads to discontinuation of treatment. RILI is a complex pathological process mainly comprising early pneumonitis and late pulmonary fibrosis. Radiation leads to early damage of epithelial cells and inflammatory response. Impaired cells provoke the production and release of various inflammatory cytokines, accompanying with macrophages or neutrophils infiltration in lung tissue. To protect against cellular injury and death, impaired cells induce the production and release of proliferative molecules or profibrotic cytokines such as transforming growth factor-β (TGF-β) [2], connective tissue growth factor (CTGF) [3], and alpha-smooth muscle actin (αSMA) [4], leading to fibroblast replication and differentiation of fibroblast into myofibroblast. The progressive replacement of the normal lung interstitium by fibrous tissues results in restriction of lung and gradual loss of function [5]
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