Vascular BMPRs Strike Out the Rolling Ball of Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease in which normal lung tissue is progressively replaced with persistent scar, resulting in shortness of breath, reduced lung function, and death after a median survival of approximately 4 years from the time of diagnosis (1, 2). Unfortunately, 30–50% of patients with IPF will experience pulmonary hypertension (PH), a comorbidity that increases mortality and may increase the risk of acute exacerbations (3). Although the development of PH is a significant predictor of IPF mortality, the mechanisms of vascular remodeling and how they may contribute to the progression of IPF remain largely unknown (4, 5).

A sustained increase in pulmonary pressure is a result of severe pulmonary vascular remodeling potentiated by vascular smooth muscle cell (VSMC) proliferation and endothelial cell (EC) dysfunction (4). PH in IPF was initially thought to develop solely as a result of fibrotic lung tissue destruction leading to hypoxic vasoconstriction and reduced capillary bed density, promoting vascular remodeling (4). However, more recent data show a poor correlation between the severity of fibrosis and the presence of PH (4). In addition, on pathologic examination, vascular changes in the IPF lung are more diffuse in the IPF-PH lung (4). Specifically, in IPF, abnormalities in the pulmonary vasculature (i.e., endothelial injury, loss of capillaries, and increased vascular permeability) are generally localized to fibrotic areas of the lung (4). However, in IPF-PH, these vascular changes are observed throughout the lung, with evidence of vascular thickening spreading to normal areas of the fibrotic lung (4). Taken together, these findings suggest that fibrotic tissue destruction is not the only driver of PH-associated vascular remodeling, and perhaps signals originating in fibrotic regions can influence distal areas via paracrine factors to contribute to the development of PH secondary to IPF.

In this issue of the Journal, Yanagihara and colleagues (pp. 1498–1514) examine the cross-talk between fibroblasts and vascular cells (ECs and VSMCs) to unravel a mechanistic link between IPF and the development of PH (5). Using in vitro coculture and conditioned media systems, the authors observed that VSMCs from fibrotic rat lungs and pulmonary artery ECs from patients with IPF promoted a fibrotic profile in normal fibroblasts, a potential pathologic feed-forward mechanism contributing to the increased mortality in patients with IPF-PH. Interestingly, they also found that fibroblasts isolated from IPF tissue promoted EC apoptosis and VSMC migration, hallmark cellular changes in PH. Investigation into specific signaling pathways revealed altered expression of the bone morphogenetic protein receptor type 2 (BMPR2) axis in a rat AdTGFβ (adenovirus expressing transforming growth factor-β) model of fibrosis and in IPF lung tissue. Because BMPR2 has a major role in opposing TGF-β signaling, it is not surprising that BMPR2 expression and signaling are also dysregulated in IPF (6). To address the disconnect as to whether BMPR2 dysfunction causally links fibrotic disease to the development of PH, the authors employed a therapeutic dosing strategy using tacrolimus (TAC; i.e., FK506) in their in vivo rat model of TGF-β–induced lung fibrosis.

Based largely on the PANTHER-IPF (Prednisone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response in IPF) trial data, American Thoracic Society guidelines conclude that immunosuppression may be harmful to patients with IPF (7, 8). TAC has not been studied specifically in IPF, but it is sometimes given to patients with acute IPF exacerbations in Japan (9, 10), and there are data to support its use in non-IPF progressive fibrotic diseases (11). In support of this, it has been shown in vitro that subimmunosuppressive doses of TAC can enhance BMPR2 signaling and reduce dysfunction in ECs isolated from patients with PH (12). To validate the targeting of BMPR2 with TAC in vivo, the authors excitingly show that intervention with daily TAC starting 10 days post instillation (dpi) of AdTGFβ was sufficient to attenuate pulmonary fibrosis and PH, with increased BMPR2 signaling at 28 dpi (5). However, it must be noted that, while this model has a more persistent phenotype than traditional single-dose bleomycin–induced fibrosis, it relies on a single mediator to drive fibrosis and does not recapitulate the progressive nature of IPF. As such, other fibrogenic signals may be lacking in this model, which could preclude clinical translatability. Unfortunately, a single animal model that wholly recapitulates the pathology and progression of IPF has yet to be developed (13), and validation of promising targets, such as enhanced BMPR2 via TAC treatment, should be extended across multiple available models in future studies.

In terms of translatability, pharmacologic strategies that begin after disease onset are the gold standard. However, identifying the optimal therapeutic window is often challenging and limits conclusions drawn from animal models. In this study, treatment was begun at 10 dpi with AdTGFβ, when the authors propose fibrotic changes were just becoming evident. Thus, it is challenging to surmise whether the benefit observed at 28 dpi is due simply to inhibition of these pathologic changes or whether targeting BMPR2 in established disease would promote regression of fibrosis and PH. Moreover, with a single late time point, it is difficult to ascertain if reducing fibrosis was sufficient to prevent PH or whether the shared benefit of enhanced BMPR2 signaling improved the outcomes in parallel. Of course, TAC is not a specific BMPR2 agonist, and the authors do address this to some degree by evaluating T cell numbers in animals after treatment, but additional mechanisms contributing to the effect of TAC cannot be completely excluded. Despite these limitations, this study suggests low-dose TAC as an intervenable therapeutic option that warrants further study to determine its potential to improve outcomes and patient care.

BMPR2 mutations have long been of interest in the study of PH pathogenesis, with BMPR2 mutations associated with >80% of familial and approximately 20% of sporadic cases of PH (5). Although the authors were able to identify only two BMPR2 mutations with low prevalence in an IPF cohort, it is notable that they observed BMPR2 expression to be decreased in lung tissue across fibrotic diseases, even in those patients in whom PH had not developed. Interestingly, these changes were observed in fibrotic and nonfibrotic areas of IPF lungs, and BMPR2 expression did not correlate with clinical features of IPF. These findings, together with their data of paracrine fibroblast cross-talk to vascular cells, raise the notion that loss of BMPR2 may represent an early change in the development of IPF-PH. Accordingly, the concept that early modulation of vascular factors prevents fibrotic progression is intriguing, and it is exciting to see research advance in this area. Although concern remains high for the risk of immunosuppression in IPF, the improvement seen with low-dose TAC suggests that augmenting BMPR2 may be a viable therapeutic strategy in early disease, which is desperately needed.