The Triterpenoid CDDO-Me Inhibits Bleomycin-Induced Lung Inflammation and Fibrosis

Ajit A Kulkarni,Terry W Wright,Hsi-Min Hsiao,Keith C Olsen,Robert Matthew Kottmann,Thomas H Thatcher,Patricia J Sime,Jason Morrissette,Richard P Phipps,Bernhard Ryffel

doi:10.1371/journal.pone.0063798

Abstract

Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA) on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01), inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001), and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05). On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation) and by systemic autoimmune diseases.

Highlights

Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function are compromised by scarring
We have reported that CDDO has potent in vitro antifibrotic activities in primary human lung fibroblasts (HLFs) from both normal [9,10,11] and Idiopathic pulmonary fibrosis (IPF) donors [10]
Several reports have indicated that the derivative CDDO-Me is 5-10-fold more potent than the parent compound and has increased bioavailability [17,18,19,20]

Summary

Introduction

Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function are compromised by scarring. One hallmark of the fibrotic lung is excess deposition of extracellular matrix (ECM) proteins in areas that are enriched in proliferating fibroblasts and myofibroblasts. Deposition of ECM proteins leads to impairment of normal lung function and structure, which compromises gaseous exchange and can lead to respiratory failure [1,2]. PF can be caused by systemic diseases (such as rheumatoid arthritis and sarcoidosis), exposure to environmental agents (asbestos, silica), chemicals (chemotherapy drugs including bleomycin, busulfan, carmustine and chlorambucil), or radiation therapy [1,3]. Idiopathic pulmonary fibrosis (IPF), in which the cause is unknown, is the worst form of lung scarring, with a median survival time of 2.9 years and no effective treatments [1]

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Results

Conclusion