Defining a pathological role for the vasculature in the development of fibrosis and pulmonary hypertension in interstitial lung disease
2019; American Physical Society; Volume: 317; Issue: 4 Linguagem: Inglês
10.1152/ajplung.00330.2019
ISSN1522-1504
AutoresPeter M. George, Jane A. Mitchell,
Tópico(s)Chronic Obstructive Pulmonary Disease (COPD) Research
ResumoEditorial FocusDefining a pathological role for the vasculature in the development of fibrosis and pulmonary hypertension in interstitial lung diseasePeter M. George and Jane A. MitchellPeter M. GeorgeInterstitial Lung Disease Unit, Royal Brompton and Harefield NHS Foundation Trust, London, United KingdomDepartment of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, London, United Kingdom and Jane A. MitchellDepartment of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, London, United KingdomPublished Online:17 Sep 2019https://doi.org/10.1152/ajplung.00330.2019This is the final version - click for previous versionMoreSectionsPDF (56 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Interstitial lung disease is an umbrella term that encompasses approximately 200 conditions. A large proportion manifest with the development of irreversible pulmonary fibrosis; it is these which have the worst outcomes and yet a fully developed understanding of disease pathogenesis remains elusive. Idiopathic pulmonary fibrosis (IPF) is one such example and has the gravest prognosis. Life expectancy for this condition has historically been estimated at 3–5 years from diagnosis (21) although the advent of antifibrotic therapy (15, 24) has improved survival (14). Other progressive fibrotic lung diseases such as chronic hypersensitivity pneumonitis and rheumatoid arthritis-associated interstitial lung disease can have a similarly poor prognosis and although preclinical studies suggest the potential benefit of antifibrotic therapy (22), data from randomized controlled trials remain eagerly awaited. The development of pulmonary hypertension portends a poor prognosis for patients with pulmonary fibrosis impacting quality of life and significantly reducing life expectancy (17); indeed in the context of IPF, its presence should trigger consideration of lung transplantation (9).The mechanisms by which pulmonary hypertension develops in patients with interstitial lung disease include a varied combination of hypoxic vasoconstriction, endothelial dysfunction, genetic predisposition, and altered immune pathways. The relative contribution of these factors and others differs between individuals and it is this heterogeneity that has made interstitial lung disease-associated pulmonary hypertension (ILD-PH) particularly challenging to treat. For example, it is clinically apparent that a group of patients with established diagnoses of IPF, each displaying hallmark histopathological features of usual interstitial pneumonia and similar extent of disease, will experience clear variability in the degree of pulmonary vasculopathy. Indeed, whereas epithelial injury has been traditionally considered the central protagonist in the development of pulmonary fibrosis, with vascular dysfunction a secondary phenomenon, there is an emerging hypothesis that the vasculature can itself play a pathogenic role in the incitement and development of IPF and other progressive fibrotic lung diseases.To date, trials of pulmonary vasodilators in this patient group have been disappointing—at best negative (5, 29) and in some cases associated with increased risk of harm (18, 20). The approach taken thus far has been to repurpose existing therapies licensed for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. There remain no approved treatments for ILD-PH (11) and so it is clear that a fresh approach is now required whereby it is considered a disease entity in its own right. By doing so, pathogenic mechanisms specific to this condition can be identified and novel therapeutic avenues explored.Oliveira and colleagues (19) have utilized this approach in their article published in this issue of the Journal. Building on the hypothesis that ILD-PH shares common pathobiology with cancer, they explore the role of CXC chemokine receptor 2 (CXCR2), which is a central regulator of tumor cell proliferation and is also highly expressed on many cell types including myeloid-derived suppressor cells (MDSC) and endothelial cells. The group had previously established that in the bleomycin murine model of pulmonary fibrosis, the polymorphonuclear subpopulation of MDSC (PMN-MDSC) was key to the development of pulmonary hypertension and that CXCR2 was a key regulator (4). The authors build on these observations by demonstrating that in patients with ILD-PH (compared with ILD without PH and controls) there is increased peripheral blood PMN-MDSC expression of CXCR2. Alongside this they demonstrate a reduction in vascular endothelial CXCR2 expression in lung tissue from patients with ILD-PH and in pulmonary microvascular endothelial cells isolated from lungs of patients undergoing transplantation.Using the bleomycin mouse model of pulmonary fibrosis and the hypoxic mouse model of pulmonary hypertension, the authors validate the role of MDSC in the pathogenesis of pulmonary vascular remodeling and then through the use of myeloid cell and separately endothelial cell CXCR2 knockout mice, conclude that CXCR2 expressed by myeloid cells plays a causative role in the development of ILD-PH whereas endothelial cell CXCR2 has a protective role—both in regard to progression of fibrosis and pulmonary vasculopathy. Deficiency of endothelial cell CXCR2 resulted in an increase in lung PMN-MDSC accumulation with consequent pulmonary vascular remodeling potentially regulated by CXCL1. Furthermore, endothelial cell CXCR2 knockout mice exposed to bleomycin had increased lung levels of matrix metalloproteinase 9 (MMP9), a protein which has previously been implicated in the pathogenesis of IPF with raised levels in the bronchoalveolar lavage fluid and lung tissue of patients with IPF (10, 25).The authors summarize that while CXCR2 expression of myeloid cells promotes the progression of pulmonary hypertension, its presence on endothelial cells has a protective role with hypothesized cross talk between the two compartments. The authors are to be congratulated for their approach in dissecting proposed mechanisms for this complex disease area. Their finding that CXCR2 is differentially expressed on cells from myeloid lineage and the vascular endothelium is intriguing and once again highlights the pleiotropic nature of these systems (27) and the need for future therapies to undergo rigorous preclinical testing. Oliveira and colleagues elegantly demonstrate the importance of high-quality basic science studies to explore tissue specificity when considering novel therapies with potential relevance to future treatments for ILD-PH.Three important questions remain from their study. First, it is unclear why there was an observed disconnect in readouts seen between the pulmonary vascular and right heart compartments. For example, while mCXCR2 mice were protected in both bleomycin and hypoxic models at the level of right ventricular systolic pressure and vessel remodeling, right heart hypertrophy was unchanged. Considering that heart failure accounts for the leading cause of death in pulmonary hypertension, these interesting results require further investigation. Perhaps they suggest a distinct relationship between CXCR2 signaling in myeloid and resident cells within the heart and lung. Second, the study reports similar trends for each type of mouse in the bleomycin and hypoxic models, which mimic pulmonary fibrosis with pulmonary hypertension and pulmonary hypertension, respectively. This together with the fact that a PAH without ILD patient group was not included in the human tissue CXCL2/IL-8 release studies leaves the value of their observations in other forms of pulmonary hypertension open to further investigation. Third, it should be acknowledged that the bleomycin mouse model is, at least in the early phase, an inflammatory model (13). As an inflammatory milieu will disrupt endothelial cell function, there are inherent limitations when extrapolating findings to patients with IPF.The authors stop short of suggesting that the vasculature may play a role in the development of pulmonary fibrosis and this is an area which does merit further study. The demonstrated interaction between myeloid stem cells and the vascular endothelium to result in increased levels of MMP9, a protein implicated in IPF pathogenesis, is intriguing and adds weight to a study that has demonstrated that pulmonary vessel volume is a key determinant of mortality in IPF (12). More recently in a randomized controlled trial of sildenafil versus placebo in IPF patients treated with nintedanib, although the primary end point (change in health-related quality of life as measured by the St. George's Respiratory Questionnaire) was not met, there appeared to be a beneficial effect of sildenafil on the rate of lung function decline which was a pre-specified secondary end point. At 24 weeks, patients receiving nintedanib + placebo declined by a forced vital capacity (FVC) of 66.7 mL whereas those receiving nintedanib + sildenafil declined by an FVC of 20.4 mL (difference, 46.3 mL; 95% CI, −8.3 to 100.9) (16). Furthermore, it has also been demonstrated that riociguat, a soluble guanylate cyclase (sGC) stimulator approved for use in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, slows the rate of FVC decline in patients with systemic sclerosis associated ILD; FVC decline at 52 weeks was −2.7% (SD 4.0) in the treatment group and −8.9% (SD 13.1) in the placebo arm (6). The fact that the RISE-IIP study of riociguat in the treatment of pulmonary hypertension associated with idiopathic interstitial pneumonia was terminated early due to a mortality signal (18) underscores the need for more studies akin to that of Oliveira and colleagues coupled with validation of advanced biomanufacturing techniques using precision biomaterials (2) to ensure that off target and/or unappreciated disease-specific effects of therapies can be identified before clinical trials are embarked upon.Therefore, a concerted focus on vascular cells and their interactions with MDSCs in PAH and IPF is warranted. For example, along with fibroblasts, vascular smooth muscle cells (VSMCs) are directly relevant to PAH. Importantly, VSMCs release mediators of PAH (8) including CXCL8 (7) under inflammatory conditions and CXCL8 derived from mesenchymal progenitor cells has been shown to drive fibrosis in IPF (28). It would therefore be of importance to address the role of CXCR2 and associated ligands in these cells using the workflow defined by Oliveira and colleagues.Finally, if we are to consider that the vasculature is a crucial player in the pathogenesis of both pulmonary fibrosis and associated pulmonary hypertension, a complementary approach which may yield benefit is the use of blood outgrowth endothelial cells (BOECs) to study effects of novel therapies. Our group (8) and others (26) have demonstrated that BOECs from patients with pulmonary hypertension retain a disease phenotype with other groups showing a pathological phenotype of BOECs in IPF (3). Furthermore, we have recently demonstrated that autologous pairs of BOECs and blood outgrowth smooth muscle cells can be obtained from healthy donors (1). It is therefore feasible to utilize blood outgrowth "vascular cells" as biomarkers and a test bed for novel therapies (23) in fibrotic lung diseases.In summary, it is clear that the treatment of ILD-PH is an area of real unmet clinical need and that the simple use of therapies approved in PAH does not work. As illustrated by Oliveira and colleagues, it is critical that we establish a clear understanding of how myeloid cells interact with vascular cells, particularly the endothelium, to design effective targeted cell-specific therapies. Exploring the role of the vasculature in driving pulmonary fibrosis has the potential to unlock a thus far underappreciated mechanism of disease with huge promise of new therapeutic opportunities.DISCLOSURESP. M. George acknowledges speakers fees, honoraria, and support for conference attendance from Boehringer Ingelheim and Roche Laboratory. J. A. Mitchell acknowledges speakers fees, honoraria, and support for conference attendance and awards from Actelion, United Therapeutics and Merck Sharp & Dohme Corp.AUTHOR CONTRIBUTIONSP.M.G. and J.A.M. drafted manuscript; P.M.G. and J.A.M. edited and revised manuscript; P.M.G. and J.A.M. approved final version of manuscript.REFERENCES1. Ahmetaj‐Shala B, Kawai R, Marei I, Bhatti F, Gashaw H, Kirkby NS, Mitchell JA. A bioassay system of autologous human endothelial and smooth muscle cells for use in cardiovascular drug discovery and patient phenotyping (Abstract). Br J Pharmacol 176: 3040–3041, 2019. doi:10.1111/bph.14681. https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.14681.Crossref | ISI | Google Scholar2. Bailey KE, Floren ML, D'Ovidio TJ, Lammers SR, Stenmark KR, Magin CM. Tissue-informed engineering strategies for modeling human pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 316: L303–L320, 2019. doi:10.1152/ajplung.00353.2018. Link | ISI | Google Scholar3. 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George, Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK (e-mail: p.[email protected]nhs.uk). 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