Triptolide mitigates radiation-induced pulmonary fibrosis via inhibition of axis of alveolar macrophages-NOXes-ROS-myofibroblasts.

Abstract

PURPOSE:

IR-induced pulmonary fibrosis is one of the most severe late complications of radiotherapy for lung cancer. It is urgently needed to discover a new drug for anti-IR lung fibrosis. Our previous studies have indicated that TPL exhibits both anti-IR lung fibrosis and anti-tumor activities. To reveal the mechanism of TPL on anti-IR lung fibrosis, alveolar macrophages (AMs) were examined for TPL effect on their axis of Nicotinamide adenine dinucleotide phosphate oxidase-reactive oxygen species (NOXes-ROS) and myofibroblast activation.

METHODS AND MATERIALS:

The fibrosis-prone C57BL/6 mice were irradiated with 15 Gy on whole chest, then one day later, mice were treated without or with TPL (i.v. 0.25 mg/kg, qod for 1 month). The AMs were collected from bronchoalveolar lavage fluids and studied for the production of ROS and the levels of NOXes. The effect of AMs on myofibroblast activation as labeled with F4/80 or α-SMA (α-smooth muscle actin) were examined using flow cytometry, Western blotting, or immunohistochemical staining.

RESULTS:

TPL effectively reduced the IR-induced lung fibrosis as evidenced by the less myofibroblasts, less collagen deposit and less ROS in the IR-lung tissues. We found that ROS which responsible for myofibroblasts activation was mainly from AMs and was NOX2 and NOX4 dependent. TPL significantly reduced the infiltrated AMs in IR-lung tissues, and in addition, down regulated the level of NOX2 and NOX4 in AMs both in vitro and in vivo. Furthermore, by inhibiting NOXes dependent ROS in AMs, TPL deprived AMs' paracrine activation of myofibroblasts.

CONCLUSIONS:

Our work demonstrated that the anti-fibrotic effect of TPL on IR-induced pulmonary fibrosis was related to its inhibition on the axis of alveolar macrophages-NOXes-ROS-myofibroblasts.

• Authors: Chun Chen, Shanmin Yang, Mei Zhang, Zhenhuan Zhang, Jingshen Hong, Deping Han, Jun Ma, Steven B Zhang, Paul Okunieff, Lurong Zhang
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 17 Issue 4 Pg. 381-9 (04 02 2016) ISSN: 1555-8576 [Electronic] United States
• PMID: 27003327 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Alkylating
• Diterpenes
• Epoxy Compounds
• Phenanthrenes
• Reactive Oxygen Species
• triptolide

Topics

• Animals
• Antineoplastic Agents, Alkylating (administration & dosage, pharmacology, therapeutic use)
• Diterpenes (administration & dosage, pharmacology, therapeutic use)
• Epoxy Compounds (administration & dosage, pharmacology, therapeutic use)
• Female
• Humans
• Macrophages, Alveolar (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Myofibroblasts (metabolism, pathology)
• Phenanthrenes (administration & dosage, pharmacology, therapeutic use)
• Pulmonary Fibrosis
• Reactive Oxygen Species