A New Treatment Strategy for Pulmonary Fibrosis Targeting the Bone Morphogenetic Protein Pathway, and the Importance of Radiological Pattern for Selecting Candidates for Receiving a New Treatment for Pulmonary Fibrosis

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. As the efficacy of currently available medicines is limited, development of new therapy is warranted. Transforming growth factor (TGF)-β plays a central role in the pathogenesis of IPF through such mechanisms as promoting extracellular matrix production by fibroblasts. Conversely, bone morphogenetic protein (BMP)4 and 7 bind to BMP receptor type 2 (BMPR2) and counterbalance TGF-β signalling. However, the impact of BMPR2 overexpression for modulating the imbalance of the TGF-β/BMP axis has never been studied in pulmonary fibrosis. How to select patients for new treatments is another concern, as IPF can be difficult to distinguished from other idiopathic interstitial pneumonias (IIPs). Although a “usual interstitial pneumonia (UIP) pattern” on chest computed tomography (CT) is necessary for diagnosing IPF in IIP patients without undergoing lung biopsy in the current guideline, recent studies have suggested that a “probable UIP pattern” is also sufficient for diagnosing IPF without histopathology. However, this “broader IPF diagnosis” has never been validated outside clinical trials by long-term outcomes such as survival. Methods For investigating the effect of BMPR2 overexpression, I have transduced BMPR2 into lung fibroblasts or the lungs of rats with bleomycin-induced pulmonary fibrosis, using adenovirus, BMPR2-overexpressing endothelial progenitor cells (EPCs) or exosomes from them. Suppression of Smad2/3 phosphorylation and fibronectin production were used as surrogates for treatment effect. For validating the “broader IPF diagnosis”, I have conducted a retrospective cohort study to compare probability of non-IPF diagnosis between patients with a UIP pattern and those with a probable UIP pattern on chest CT. As IPF has poorer prognosis than other interstitial pneumonias, survival time and time to first acute exacerbation (AE) were also compared. Results BMPR2 was downregulated in rat lungs with fibrosis and in human/rat lung fibroblasts stimulated with TGF-β. Although BMP7 did not reduce TGF-β-induced p-Smad2/3 and fibronectin in lung fibroblasts, adenoviral BMPR2 transduction has reduced p-Smad2/3 by itself and, when given with BMP7, reduced fibronectin. The studies for treatment of rats with pulmonary fibrosis using BMPR2-transduced EPCs and fibroblasts using BMPR2-carrying exosomes could not be completed due to some technical problems. In another study, 402 IIP patients’ data were reviewed. Among patients with a “probable” UIP pattern, the probability of IPF was only 66%, while it was 81% in those with a UIP pattern. Probable UIP pattern was independently associated with longer survival and time to first AE. In IPF patients only, CT pattern was not associated with prognosis. Conclusions BMPR2 was reduced in fibrotic lungs and lung fibroblasts stimulated with TGF-β. Adenoviral BMPR2 transduction showed effects on suppressing TGF-β-induced profibrotic markers in lung fibroblasts. Further study is needed to elucidate the clinical effectiveness of BMPR2 overexpression. Patients with a probable UIP pattern had a higher probability of non-IPF diagnoses and better prognosis than those with a UIP pattern. Although the “broader IPF diagnosis” may be valid when IPF is strongly suspected, prudent clinical evaluation and care for not misdiagnosing other interstitial pneumonias with better prognosis as IPF are important.